J. Pathol. [JOURNAL]
Sun
200 papers
SMARCB1-deficient malignant melanocytic uveal tumours: a new neural crest-derived tumour entity with SMARCB1-related germline predisposition.
Cyrta J, Masliah-Planchon J, Hoare O … +20 more , Brillet R, Andrianteranagna M, Sohier P, Cardoen L, Bouchoucha Y, Filser M, Goncalves A, Caly M, Fréneaux P, Stefanaki K, Pefkianaki M, Moschovi M, Matet A, Cassoux N, Lumbroso-Le Rouic L, Gauthier-Villars M, Stern MH, Vincent-Salomon A, Rodrigues M, Bourdeaut F
J Pathol · 2025 Mar · PMID 39853675 · Full text
Rhabdoid tumours (RT) are an aggressive malignancy affecting <2-year-old infants, characterised by biallelic loss-of-function alterations in SWI/SNF-related BAF chromatin remodelling complex subunit B1 (SMARCB1) in nearl...
Rhabdoid tumours (RT) are an aggressive malignancy affecting <2-year-old infants, characterised by biallelic loss-of-function alterations in SWI/SNF-related BAF chromatin remodelling complex subunit B1 (SMARCB1) in nearly all cases. Germline SMARCB1 alterations are found in ~30% of patients and define the RT Predisposition Syndrome type 1 (RTPS1). Uveal melanoma (UVM), the most common primary intraocular cancer in adults, does not harbour SMARCB1 alterations. We report two cases of a previously undescribed intraocular malignancy that shared some features with UVM and RT, but was also distinct from these entities. Both female patients, aged 23 and 14 years, underwent enucleation, and the tumours were subjected to comprehensive genomic, DNA methylation, and transcriptomic profiling. Pathological examination showed large, amelanotic intraocular tumours with epithelioid features, expressing melanocytic markers [S100P, SOX10, Melan-A, PMEL (HMB45), TYR] as seen using immunohistochemistry (IHC), but with little or no melanin production. Both tumours harboured biallelic loss-of-function SMARCB1 alterations, associated with loss of SMARCB1 (BAF47/INI1) expression on IHC. Their genomic profiles were atypical both for UVM and for RT, and no pathogenic variants were found in other genes tested, including those recurrently altered in UVM. In both patients, a germline SMARCB1 variant was found. However, there was no relevant family history of cancer. Transcriptome and methylome profiling suggested that these tumours were distinct from RT, UVM, and skin melanomas. RNAseq confirmed expression of early and late genes related to melanocytic differentiation. The first patient died of metastatic disease 16 months after diagnosis, the second was disease-free 10 months after completion of treatment. In summary, we report two cases of a previously undescribed, aggressive SMARCB1-deficient intraocular malignancy with melanocytic differentiation, which occurs in young patients, is distinct from UVM and RT, and expands the RTPS1 spectrum. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Alternative driver pathways in peripheral nerve sheath tumors - including DICER1 and/or KRAS alterations.
Chang HY, Saoud C, Torrence D … +3 more , Tap W, Chi P, Antonescu CR
J Pathol · 2025 Mar · PMID 39846292 · Full text
DICER1-associated sarcoma is an emerging entity, defined by either somatic or germline dicer 1, ribonuclease III (DICER1) mutations and sharing characteristic morphologic features irrespective of the site of origin. In a...
DICER1-associated sarcoma is an emerging entity, defined by either somatic or germline dicer 1, ribonuclease III (DICER1) mutations and sharing characteristic morphologic features irrespective of the site of origin. In addition to the DICER1 driver mutation, concurrent genomic alterations, including tumor protein 53 (TP53) inactivation and RAS pathway activation, are frequently detected. Tumors that morphologically resemble malignant peripheral nerve sheath tumor (MPNST) have rarely been reported among DICER1 sarcomas and often pose diagnostic challenges. This study was prompted by a case involving morphologic features of MPNST, which harbored co-existing DICER1 and hotspot KRAS mutations. Hence, we investigated the incidence of these alterations in PNST from our molecular database compared to the genomic and morphologic spectrum of DICER1-mutant sarcomas. In total, we identified three cases diagnosed as MPNST with co-existing DICER1, ATRX chromatin remodeler (ATRX), and KRAS G12V/A alterations occurring in brain, cerebellopontine angle, and intra-abdominal sites. Two additional cases each of MPNSTs and neurofibromas were identified with hotspot KRAS mutations. All five MPNSTs lacked canonical neurofibromin 1 (NF1)/neurofibromin 2 (NF2) alterations, displaying a classic morphologic appearance with fascicular monomorphic spindle cells and followed a diverse clinical behavior. Among the 38 DICER1-associated sarcomas in our database, eight (21%) had secondary KRAS hotspot mutations, all composed of monomorphic spindle and/or round cells, including three with an MPNST-like histology. In contrast, all 10 (26%) DICER1-mutant sarcomas with TP53 mutations showed a pleomorphic phenotype. The DNA-based methylation profile of our index case clustered within the group of sarcomas with DICER1 alterations. Our results highlight a small subset of MPNST associated with DICER1 and/or KRAS mutations. However, their relationship with conventional MPNST remains to be determined in larger studies. © 2025 The Pathological Society of Great Britain and Ireland.
Extracellular matrix cancer-associated fibroblasts promote stromal fibrosis and immune exclusion in triple-negative breast cancer.
Lu X, Gou Z, Chen H … +5 more , Li L, Chen F, Bao C, Bu H, Zhang Z
J Pathol · 2025 Mar · PMID 39846260 · Publisher ↗
The impact of high heterogeneity of cancer-associated fibroblasts (CAFs) on triple-negative breast cancer (TNBC) immunotherapy response has not been fully elucidated, restricting progress in precision immuno-oncology. We...
The impact of high heterogeneity of cancer-associated fibroblasts (CAFs) on triple-negative breast cancer (TNBC) immunotherapy response has not been fully elucidated, restricting progress in precision immuno-oncology. We integrated single-cell transcriptomic data from 18 TNBC patients and analyzed fibroblast subpopulations. Extracellular matrix CAFs (ecmCAFs) were identified as a fibroblast subpopulation with distinct ECM-associated characteristics. The ecmCAFs were significantly enriched in TNBC patients with residual disease after neoadjuvant immunotherapy and contributed to a fibrotic tumor microenvironment and T-cell exclusion. Secreted phosphoprotein 1 (SPP1) positive macrophages (SPP1 Mφs) were closely localized to ecmCAFs and produced more transforming growth factor beta (TGFB1), interleukin 1 beta (IL1B), and SPP1 under hypoxic conditions. SPP1 Mφs were found to facilitate the differentiation of normal breast fibroblasts to ecmCAFs, thus promoting ECM remodeling and stromal fibrosis. Our work revealed the critical role of ecmCAFs in generating a desmoplastic architecture and driving immunosuppression in TNBC. © 2025 The Pathological Society of Great Britain and Ireland.
Assessing spatial sequencing and imaging approaches to capture the molecular and pathological heterogeneity of archived cancer tissues.
Vo T, Prakrithi P, Jones K … +14 more , Yoon S, Lam PY, Kao YC, Ma N, Tan SX, Jin X, Zhou C, Crawford J, Walters S, Gupta I, Soyer PH, Khosrotehrani K, Stark MS, Nguyen Q
J Pathol · 2025 Mar · PMID 39846232 · Full text
Spatial transcriptomics (ST) offers enormous potential to decipher the biological and pathological heterogeneity in precious archival cancer tissues. Traditionally, these tissues have rarely been used and only examined a...
Spatial transcriptomics (ST) offers enormous potential to decipher the biological and pathological heterogeneity in precious archival cancer tissues. Traditionally, these tissues have rarely been used and only examined at a low throughput, most commonly by histopathological staining. ST adds thousands of times as many molecular features to histopathological images, but critical technical issues and limitations require more assessment of how ST performs on fixed archival tissues. In this work, we addressed this in a cancer-heterogeneity pipeline, starting with an exploration of the whole transcriptome by two sequencing-based ST protocols capable of measuring coding and non-coding RNAs. We optimised the two protocols to work with challenging formalin-fixed paraffin-embedded (FFPE) tissues, derived from skin. We then assessed alternative imaging methods, including multiplex RNAScope single-molecule imaging and multiplex protein imaging (CODEX). We evaluated the methods' performance for tissues stored from 4 to 14 years ago, covering a range of RNA qualities, allowing us to assess variation. In addition to technical performance metrics, we determined the ability of these methods to quantify tumour heterogeneity. We integrated gene expression profiles with pathological information, charting a new molecular landscape on the pathologically defined tissue regions. Together, this work provides important and comprehensive experimental technical perspectives to consider the applications of ST in deciphering the cancer heterogeneity in archived tissues. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
C1GALT1 expression predicts poor survival in osteosarcoma and is crucial for ABCC1 transporter-mediated doxorubicin resistance.
Liu CW, Huang JH, Chang HH … +9 more , Chen CH, Tsai YH, Chen WL, Lin JA, Chang HL, Chen CC, Lin MC, Huang MC, Lin NY
J Pathol · 2025 Mar · PMID 39844613 · Full text
Osteosarcoma is an aggressive bone malignancy with a high propensity for drug resistance and metastasis, leading to poor clinical outcomes. This study investigates the role of core 1 β1,3-galactosyltransferase 1 (C1GALT1...
Osteosarcoma is an aggressive bone malignancy with a high propensity for drug resistance and metastasis, leading to poor clinical outcomes. This study investigates the role of core 1 β1,3-galactosyltransferase 1 (C1GALT1) in osteosarcoma, focusing on its implications in chemoresistance. Our findings reveal that high expression of C1GALT1 is associated with advanced stages, adverse overall survival, and increased recurrence rates. Elevated levels of C1GALT1 were observed in doxorubicin-selected osteosarcoma cells, where its suppression significantly promoted doxorubicin-induced apoptosis and reduced drug efflux. Pharmacological inhibition of C1GALT1 using itraconazole replicated these effects, suggesting a potential therapeutic strategy to overcome chemoresistance. Additionally, we identified the involvement of the ATP-binding cassette (ABC) transporter ABCC1 in the drug-resistance phenotype mediated by C1GALT1. C1GALT1-mediated O-glycan changes were found to influence the cell-surface targeting and lysosomal degradation of ABCC1, thereby modulating its efflux capacity. In vitro and in vivo studies confirmed that C1GALT1 impacts ABCC1 expression and function, further supporting its role in osteosarcoma chemoresistance. These results highlight the clinical relevance of C1GALT1 as a biomarker for prognosis and a potential therapeutic target for osteosarcoma. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
CHIT1 regulates the neuroinflammation and phagocytosis of microglia and suppresses Aβ plaque deposition in Alzheimer's disease.
Yuan S, Zhong F, Wan T … +9 more , Qin Z, Chen L, Xing D, Zhang W, Yu W, Huang L, Song J, Yu W, Lü Y
J Pathol · 2025 Mar · PMID 39829408 · Publisher ↗
Chitinase 1 (CHIT1), as a chitin-specific hydrolase, significantly influences the progression of Alzheimer's disease (AD) through microglia-associated inflammation and amyloid beta (Aβ) plaque accumulation. However, the...
Chitinase 1 (CHIT1), as a chitin-specific hydrolase, significantly influences the progression of Alzheimer's disease (AD) through microglia-associated inflammation and amyloid beta (Aβ) plaque accumulation. However, the precise mechanism of CHIT1 action in AD remains uncertain. The effects of CHIT1 on cerebral blood flow (CBF), hippocampal volume, and cognitive function were investigated in APP/PS1 mice. Protein alterations resulting from CHIT1 overexpression were analyzed using four-dimensional (4D) label-free quantitative (LFQ) protein spectrometry. Additionally, the influence of CHIT1 on microglial electrophysiology was assessed using patch clamp measurements, and its effects on neuroinflammation, phagocytosis, microglia migration, and neuronal apoptosis under AD-like conditions were examined using the cell lines N9, BV-2, and HT-22. CHIT1 ameliorated hippocampal atrophy, hypoperfusion, and cognitive function deficits in the APP/PS1 mouse. CHIT1 regulates microglial function and neuronal protection through its interactions in AD. Increased levels of CHIT1/IDH1 contributed to an anti-inflammatory phenotype in microglia via the Ca2-activated K+ channel, enhanced microglial phagocytosis, and promoted Aβ clearance. Conversely, knocking down IDH1 reduced the secretion of anti-inflammatory agents and increased the production of inflammatory factors, as well as diminishing the expression of phagocytic factors and inhibiting Aβ endocytosis. Moreover, CHIT1 reduced neuronal apoptosis by diminishing the expression of apoptotic factors. However, IDH1 knockdown abrogated the protective effect of CHIT1 on neurons. CHIT1 exerts a protective role in AD pathogenesis through its interaction with IDH1. The CHIT1/IDH1 pathway promotes Aβ clearance via a shift in microglia toward an anti-inflammatory state and prevents neuronal apoptosis and dysfunction caused by Aβ toxicity. © 2025 The Pathological Society of Great Britain and Ireland.
Oronasal mucosal melanoma is defined by two transcriptional subtypes in humans and dogs with implications for diagnosis and therapy.
Blacklock KLB, Donnelly K, Lu Y … +21 more , Pozo JD, Glendinning L, Polton G, Selmic L, Tanis JB, Killick D, Parys M, Morris JS, Breathnach I, Zago S, Gould SM, Shaw DJ, Tivers MS, Malucelli D, Marques A, Purzycka K, Cantatore M, Mathers ME, Stares M, Meynert A, Patton EE
J Pathol · 2025 Mar · PMID 39828982 · Full text
Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and limited existing therapeutic interventions, in part due to a lack of actionable targets and translational animal models for preclinical tri...
Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and limited existing therapeutic interventions, in part due to a lack of actionable targets and translational animal models for preclinical trials. Comprehensive data on this tumour type are scarce, and existing data often overlooks the importance of the anatomical site of origin. We evaluated human and canine oronasal mucosal melanoma (OMM) to determine whether the common canine disease could inform the rare human equivalent. Using a human and canine primary OMM cohort of treatment-naive archival tissue, alongside clinicopathological data, we obtained transcriptomic, immunohistochemical, and microbiome data from both species. We defined the transcriptomic landscape in both species and linked our findings to immunohistochemical, microbiome, and clinical data. Human and dog OMM stratified into two distinctive transcriptional groups, which we defined using a species-independent 41-gene signature. These two subgroups are termed CTLA4-high and MET-high and indicate actionable targets for OMM patients. To guide clinical decision-making, we developed immunohistochemical diagnostic tools that distinguish between transcriptomic subgroups. We found that OMM had conserved transcriptomic subtypes and biological similarity between human and canine OMM, with significant implications for patient classification, treatment, and clinical trial design. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Recombinant Klotho administration after myocardial infarction reduces ischaemic injury and arrhythmias by blocking intracellular calcium mishandling and CaMKII activation.
Vázquez-Sánchez S, Blasco A, Fernández-Corredoira P … +13 more , Cantolla P, Mercado-García E, Rodríguez-Sánchez E, González-Lafuente L, Poveda J, González-Moreno D, Matutano A, Peribañez S, García-Consuegra I, Volpe M, Fernández-Velasco M, Ruilope LM, Ruiz-Hurtado G
J Pathol · 2025 Mar · PMID 39815421 · Full text
Ischaemic heart disease (IHD) remains a major cause of death and morbidity. Klotho is a well-known anti-ageing factor with relevant cardioprotective actions, at least when renal dysfunction is present, but its actions ar...
Ischaemic heart disease (IHD) remains a major cause of death and morbidity. Klotho is a well-known anti-ageing factor with relevant cardioprotective actions, at least when renal dysfunction is present, but its actions are much less known when renal function is preserved. This study investigated Klotho as a biomarker and potential novel treatment of IHD-associated complications after myocardial infarction (MI) under preserved renal function. Association between circulating Klotho levels and cardiac injury was investigated in patients after ST-elevation MI (STEMI). Biochemical, in vivo and in vitro cardiac function and histological and molecular studies were performed to determine the effect of recombinant Klotho in the failing hearts of mice after MI. We demonstrated that STEMI patients showed lower systemic Klotho levels, with the lowest Klotho tertile in those patients with higher N-terminal pro B-type natriuretic peptide (NT-proBNP) levels. Mice also showed a decrease in systemic Klotho levels after MI induction. Furthermore, recombinant Klotho administration in mice reduced infarct area and attenuated cardiac hypertrophy and fibrosis. We also demonstrated that Klotho treatment prevented reduction in ejection fraction and MI-related ECG changes, including prolonged QRS, JT, QTc, and TT intervals and premature ventricular contractions. In adult mouse cardiomyocytes, Klotho treatment restricted systolic calcium (Ca) release and cell shortening disturbances after MI. Klotho prevented increased diastolic Ca leak and pro-arrhythmogenic events in PMI mice by blocking activation of the Ca/calmodulin-dependent kinase type II (CaMKII) pathway, preventing ryanodine receptor type 2 (RyR) hyperphosphorylation. In conclusion, Klotho supplementation protected against functional and structural cardiac remodelling and ameliorated ventricular arrhythmic events by preventing intracardiomyocyte Ca mishandling in mice following MI. These data uncover a new cardioprotective role of Klotho, emerging as a biomarker of ventricular injury and potential treatment for patients after MI. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
DNA methylation patterns are influenced by Pax3::Foxo1 expression and developmental lineage in rhabdomyosarcoma tumours forming in genetically engineered mouse models.
Sun W, Hewitt SM, Wright H … +2 more , Keller C, Barr FG
J Pathol · 2025 Mar · PMID 39812007 · Full text
Rhabdomyosarcoma (RMS) is a family of phenotypically myogenic paediatric cancers consisting of two major subtypes: fusion-positive (FP) RMS, most commonly involving the PAX3::FOXO1 fusion gene, formed by the fusion of pa...
Rhabdomyosarcoma (RMS) is a family of phenotypically myogenic paediatric cancers consisting of two major subtypes: fusion-positive (FP) RMS, most commonly involving the PAX3::FOXO1 fusion gene, formed by the fusion of paired box 3 (PAX3) and forkhead box O1 (FOXO1) genes, and fusion-negative (FN) RMS, lacking these gene fusions. In humans, DNA methylation patterns distinguish these two subtypes as well as mutation-associated subsets within these subtypes. To investigate the biological factors responsible for these methylation differences, we profiled DNA methylation in RMS tumours derived from genetically engineered mouse models (GEMMs) in which various driver mutations were introduced into different myogenic lineages. Our unsupervised analyses of DNA methylation patterns in these GEMM tumours yielded two major clusters, corresponding to high and no/low expression of Pax3::Foxo1, which mirrored the results for human FP and FN RMS tumours. Two distinct methylation-defined subsets were found for GEMM RMS tumours with no/low Pax3::Foxo1 expression: one subset enriched in Pax7 lineage tumours and a second subset enriched in myogenic factor 5 (Myf5) lineage tumours. Integrative analysis of DNA methylation and transcriptomic data in mouse and human RMS revealed a common group of differentially methylated and differentially expressed genes, highlighting a conserved set of genes functioning in both human RMS models and GEMMs of RMS. In conclusion, these studies provide insight into the roles of oncogenic fusion proteins and developmental lineages in establishing DNA methylation patterns in FP and FN RMS respectively. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Dynamic change of polarity in spread through air spaces of pulmonary malignancies.
Matsuura Y, Onuma K, Coppo R … +10 more , Uematsu H, Kondo J, Miyagawa-Hayashino A, Takeda-Miyata N, Kameyama K, Furuya T, Okada S, Shimomura M, Inoue M, Inoue M
J Pathol · 2025 Mar · PMID 39804150 · Full text
Spread through air spaces (STAS) is a histological finding of lung tumours where tumour cells exist within the air space of the lung parenchyma beyond the margin of the main tumour. Although STAS is an important prognost...
Spread through air spaces (STAS) is a histological finding of lung tumours where tumour cells exist within the air space of the lung parenchyma beyond the margin of the main tumour. Although STAS is an important prognostic factor, the pathobiology of STAS remains unclear. Here, we investigated the mechanism of STAS by analysing the relationship between STAS and polarity switching in vivo and in vitro. Histopathological analysis revealed that apical membranes were observed outside the STAS lesions around colorectal cancer (CRC) lung metastases and lung adenocarcinomas. When apical-out CRC organoids were administered intratracheally to mice, the organoids had greater metastatic potential than did single cells. To investigate the pathobiology of STAS, we established an in vitro model of STAS in which CRC or lung cancer organoids were co-cultured with 2D-cultured mouse airway epithelial organoids (2D-MAOs). Adhesion of cancer organoids to 2D-MAOs was much less than to type I collagen or endothelial cells, suggesting a protective role of the airway epithelium against adhesion. Loss of the apical membrane of CRC organoids at the contact surface with 2D-MAOs after adhesion was responsible for establishing adhesion. When airway epithelium was stimulated by transforming growth factor beta 1 (TGF-β1), adhesion of CRC organoids was enhanced. Among TGF-β1-induced genes in airway epithelium, follistatin-like protein 1 (FSTL1) increased CRC organoid adhesion by promoting loss of the apical membrane. These results suggested that TGF-β1-induced FSTL1 may promote metastatic progression of STAS by altering the polarity status. Elucidating the mechanism of STAS could contribute to the improvement of survival in patients with pulmonary malignancies associated with STAS. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Silencing GRHL3 promotes multiple organ distant metastasis of lung squamous cell carcinoma cells by enhancing SOX2 stability via SIRT1.
Li Z, Yang B, Long M … +13 more , Chen J, Zhi Y, Li R, Cao L, Yang S, Sun J, Meng Z, Wu W, Mai Y, Zhang X, Huang Y, Chen Q, Liu A
J Pathol · 2025 Mar · PMID 39804049 · Publisher ↗
Aberrant expression of grainyhead-like transcription factor 3 (GRHL3) has been extensively reported in the development and progression of several squamous cell carcinomas, such as cutaneous, head and neck, and esophageal...
Aberrant expression of grainyhead-like transcription factor 3 (GRHL3) has been extensively reported in the development and progression of several squamous cell carcinomas, such as cutaneous, head and neck, and esophageal squamous cell carcinoma. However, the clinical significance and biological roles of GRHL3 in lung squamous cell (LUSC) carcinoma are largely unclear. Herein, we report that GRHL3 was significantly upregulated in lung squamous epithelium of LUSC tissues, bronchiole, and bronchus. Moreover, expression levels of GRHL3 were decreased with the advance of pathological grade, and low GRHL3 level presented poor overall survival and short progression-free and distant metastasis-free survival in LUSC patients but had no prognostic significance in LUAD patients. Functional experiments in vivo showed that downregulating GRHL3 promoted not only lung colonization and growth but also multiple organ distant metastasis of LUSC cells, including bone, brain, and liver. Moreover, silencing GRHL3 promoted anoikis resistance and cancer stem cell (CSCs) characteristics of LUSC cells in vitro. Mechanistically, silencing GRHL3 stabilized SOX2 via SIRT1-mediated decreasing acetylation and subsequent ubiquitination-dependent degradation in LUSC cells. Thus, in-depth understanding of the underlying mechanism of GRHL3 in the progression of LUSC will facilitate the development of prognostic biomarker and therapeutic avenues against LUSC, which will present favorable prospects in improving outcomes of LUSC patients. © 2025 The Pathological Society of Great Britain and Ireland.
Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome.
Trahearn N, Sakr C, Banerjee A … +15 more , Lee SH, Baker AM, Kocher HM, Angerilli V, Morano F, Bergamo F, Maddalena G, Intini R, Cremolini C, Caravagna G, Graham T, Pietrantonio F, Lonardi S, Fassan M, Sottoriva A
J Pathol · 2025 Feb · PMID 39788558 · Full text
Colorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To...
Colorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To improve our understanding, it is critical that the TME is studied systematically within clinically annotated patient cohorts with long-term follow-up. Here we studied the TME in three clinical cohorts of metastatic CRC with diverse molecular subtype and treatment history. The MISSONI cohort included cases with microsatellite instability that received immunotherapy (n = 59, 24 months median follow-up). The BRAF cohort included BRAF V600E mutant microsatellite stable (MSS) cancers (n = 141, 24 months median follow-up). The VALENTINO cohort included RAS/RAF WT MSS cases who received chemotherapy and anti-EGFR therapy (n = 175, 32 months median follow-up). Using a Deep learning cell classifier, trained upon >38,000 pathologist annotations, to detect eight cell types within H&E-stained sections of CRC, we quantified the spatial tissue organisation and colocalisation of cell types across these cohorts. We found that the ratio of infiltrating endothelial cells to cancer cells, a possible marker of vascular invasion, was an independent predictor of progression-free survival (PFS) in the BRAF+MISSONI cohort (p = 0.033, HR = 1.44, CI = 1.029-2.01). In the VALENTINO cohort, this pattern was also an independent PFS predictor in TP53 mutant patients (p = 0.009, HR = 0.59, CI = 0.40-0.88). Tumour-infiltrating lymphocytes were an independent predictor of PFS in BRAF+MISSONI (p = 0.016, HR = 0.36, CI = 0.153-0.83). Elevated tumour-infiltrating macrophages were predictive of improved PFS in the MISSONI cohort (p = 0.031). We validated our cell classification using highly multiplexed immunofluorescence for 17 markers applied to the same sections that were analysed by the classifier (n = 26 cases). These findings uncovered important microenvironmental factors that underpin treatment response across and within CRC molecular subtypes, while providing an atlas of the distribution of 180 million cells in 375 clinically annotated CRC patients. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Loss of Mist1 alters the characteristics of Paneth cells and impacts the function of intestinal stem cells in physiological conditions and after radiation injury.
Huang Y, Tu S, Xu Z … +9 more , Xu L, Wang X, Tian H, He Q, Huang L, Lei X, Wang S, Qu M, Liu D
J Pathol · 2025 Feb · PMID 39748654 · Publisher ↗
Intestinal stem cells (ISCs) and Paneth cells (PCs) reside at the bottom of the crypts of Lieberkühn in the small intestine. Recent studies have shown that the transcription factor Mist1, also named BHLHA15, plays an imp...
Intestinal stem cells (ISCs) and Paneth cells (PCs) reside at the bottom of the crypts of Lieberkühn in the small intestine. Recent studies have shown that the transcription factor Mist1, also named BHLHA15, plays an important role in the maturation of PCs. Since there is an intimate interaction between PCs and ISCs, we speculated that the loss of Mist1 could impact these two neighboring cell types. Here, we report that mice lacking Mist1 had fewer but larger PCs with shrunken secretory granules, accompanied by an increase in goblet cells and tuft cells. Mist1 loss significantly decreased the number of proliferative crypt cells, especially columnar basal cells (CBCs). In addition, Mist1-deficient enteroids needed supplemental Wnt3a to support their growth. Results from RNA sequencing (RNA-seq) demonstrated an apparent deficiency of innate immunity in Mist1-knockout mice. Intriguingly, Mist1 loss increased the survival rate of mice subjected to whole abdominal irradiation (WAI). Moreover, radiation injury was ameliorated in Mist1-knockout mice compared with their wild-type littermates based on histological analysis and enteroid culture, which might be a consequence of increased contents of the endoplasmic reticulum (ER) and the increased activity of mTORC1 in Paneth cells. In summary, our data uncover that Mist1 plays an important functional role in PCs and regulates the maintenance of ISCs and their response to radiation injury. © 2025 The Pathological Society of Great Britain and Ireland.
Primary thyroid B-cell lymphoma: molecular insights into its clonal evolution and relapse.
Tzioni MM, Watanabe N, Chen Z … +9 more , Wu F, Madej E, Makker J, Guo S, Attygalle AD, Wotherspoon A, Sugino K, Ito K, Du MQ
J Pathol · 2025 Feb · PMID 39722652 · Full text
Primary thyroid lymphomas comprise largely extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL) and diffuse large B-cell lymphoma (DLBCL), followed by follicular lymphoma (FL). They commonly deve...
Primary thyroid lymphomas comprise largely extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL) and diffuse large B-cell lymphoma (DLBCL), followed by follicular lymphoma (FL). They commonly develop from a background of Hashimoto's thyroiditis (HT), where dysregulated immune responses trigger autoreactive infiltrates and drive clonal B-cell evolution. To understand how these lymphomas and their relapse evolve, we investigated 10 cases by mutation profiling, including five with metachronous lymphomas [primary lymphoma (EMZL = 4, DLBCL = 1) with local relapse (EMZL = 3, DLBCL = 2)], one composite EMZL and Epstein-Barr virus (EBV)-positive DLBCL, and four lymphomas (EMZL = 3, FL = 1) with prior or subsequent biopsy showing HT. In four cases with metachronous lymphomas, both common and distinct variants were seen in the paired lesions, indicating their divergent evolution from clonally related lymphoma precursor (CLP) cells. In the remaining case with metachronous lymphomas, the relapsed lesion was progressed from the initial lymphoma. In the case with composite lymphoma, the EBV-positive DLBCL was transformed from EMZL. Finally, in the four cases with paired lymphoma and HT biopsies, two showed shared mutations between the paired lesions, indicating involvement and divergent evolution from CLP cells. Thyroid lymphoma relapse may frequently develop via divergent evolution from a CLP cell, which is likely premalignant. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Tumour purity assessment with deep learning in colorectal cancer and impact on molecular analysis.
Schoenpflug LA, Chatzipli A, Sirinukunwattana K … +23 more , Richman S, Blake A, Robineau J, Mertz KD, Verrill C, Leedham SJ, Hardy C, Whalley C, Redmond K, Dunne P, Walker S, Beggs AD, McDermott U, Murray GI, Samuel LM, Seymour M, Tomlinson I, Quirke P, S:CORT consortium, Rittscher J, Maughan T, Domingo E, Koelzer VH
J Pathol · 2025 Feb · PMID 39710952 · Full text
Tumour content plays a pivotal role in directing the bioinformatic analysis of molecular profiles such as copy number variation (CNV). In clinical application, tumour purity estimation (TPE) is achieved either through vi...
Tumour content plays a pivotal role in directing the bioinformatic analysis of molecular profiles such as copy number variation (CNV). In clinical application, tumour purity estimation (TPE) is achieved either through visual pathological review [conventional pathology (CP)] or the deconvolution of molecular data. While CP provides a direct measurement, it demonstrates modest reproducibility and lacks standardisation. Conversely, deconvolution methods offer an indirect assessment with uncertain accuracy, underscoring the necessity for innovative approaches. SoftCTM is an open-source, multiorgan deep-learning (DL) model for the detection of tumour and non-tumour cells in H&E-stained slides, developed within the Overlapped Cell on Tissue Dataset for Histopathology (OCELOT) Challenge 2023. Here, using three large multicentre colorectal cancer (CRC) cohorts (N = 1,097 patients) with digital pathology and multi-omic data, we compare the utility and accuracy of TPE with SoftCTM versus CP and bioinformatic deconvolution methods (RNA expression, DNA methylation) for downstream molecular analysis, including CNV profiling. SoftCTM showed technical repeatability when applied twice on the same slide (r = 1.0) and excellent correlations in paired H&E slides (r > 0.9). TPEs profiled by SoftCTM correlated highly with RNA expression (r = 0.59) and DNA methylation (r = 0.40), while TPEs by CP showed a lower correlation with RNA expression (r = 0.41) and DNA methylation (r = 0.29). We show that CP and deconvolution methods respectively underestimate and overestimate tumour content compared to SoftCTM, resulting in 6-13% differing CNV calls. In summary, TPE with SoftCTM enables reproducibility, automation, and standardisation at single-cell resolution. SoftCTM estimates (M = 58.9%, SD ±16.3%) reconcile the overestimation by molecular data extrapolation (RNA expression: M = 79.2%, SD ±10.5, DNA methylation: M = 62.7%, SD ±11.8%) and underestimation by CP (M = 35.9%, SD ±13.1%), providing a more reliable middle ground. A fully integrated computational pathology solution could therefore be used to improve downstream molecular analyses for research and clinics. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Characterisation of GPR17-expressing oligodendrocyte precursors in human ischaemic lesions and correlation with reactive glial responses.
Raffaele S, Clausen BH, Mannella FC … +9 more , Wirenfeldt M, Marangon D, Tidgen SB, Corradini S, Madsen K, Lecca D, Abbracchio MP, Lambertsen KL, Fumagalli M
J Pathol · 2025 Feb · PMID 39703181 · Full text
White matter damage and subsequent demyelination significantly contribute to long-term functional impairment after ischaemic stroke. Identifying novel pharmacological targets to restore myelin integrity by promoting the...
White matter damage and subsequent demyelination significantly contribute to long-term functional impairment after ischaemic stroke. Identifying novel pharmacological targets to restore myelin integrity by promoting the maturation of oligodendrocyte precursor cells (OPCs) into new myelinating oligodendrocytes may open new perspectives for ischaemic stroke treatment. In this respect, previous studies highlighted the role of the G protein-coupled membrane receptor 17 (GPR17) as a key regulator of OPC differentiation in experimental models of brain injury, including ischaemic stroke. To determine the translational value of GPR17 as a possible target in the context of human disease, we exploited immunohistochemistry to characterise the distribution of GPR17-expressing cells in brain tissue samples from ischaemic stroke cases and correlated it with the reactive state of neighbouring glial cells. The results showed that GPR17 specifically decorates a subpopulation of differentiation-committed OPCs, labelled by the peculiar marker breast carcinoma-amplified sequence 1 (BCAS1), that accumulates in the peri-infarct region in the later stages after the ischaemic event. Interestingly, the response of GPR17-expressing cells appears to be paralleled by the switch of reactive microglia/macrophages from a phagocytic to a dystrophic phenotype and by astrocytic scar formation. A negative correlation was found between GPR17-expressing OPCs and reactive microglia/macrophages and astrocytes surrounding chronic ischaemic lesions in female subjects, while the same relationship was less pronounced in males. These results were reinforced by bioinformatic analysis of a publicly available transcriptomic dataset, which implicated a possible role of inflammation and defective neuron-to-OPC communication in remyelination failure after ischaemic damage. Hence, these data strengthen the relevance of GPR17-based remyelinating therapies for the treatment of ischaemic stroke. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Genomic characterization and histologic analysis of uterine leiomyosarcoma arising from leiomyoma with bizarre nuclei.
Felicelli C, Lu X, Coty-Fattal Z … +7 more , Feng Y, Yin P, Schipma MJ, Kim JJ, Jennings LJ, Bulun SE, Wei JJ
J Pathol · 2025 Feb · PMID 39691991 · Full text
Leiomyoma with bizarre nuclei (LM-BN) is a rare variant of leiomyoma with a benign clinical course. In contrast, leiomyosarcoma (LMS) is a high-grade, malignant neoplasm characterized by high recurrence rates and poor su...
Leiomyoma with bizarre nuclei (LM-BN) is a rare variant of leiomyoma with a benign clinical course. In contrast, leiomyosarcoma (LMS) is a high-grade, malignant neoplasm characterized by high recurrence rates and poor survival. While LM-BN and LMS show distinct morphologies, they share similar immunoprofiles and molecular alterations, with both considered 'genomically unstable'. Rare cases of LM-BN associated with LMS have been reported; however, the histogenesis and molecular relationship between these two tumors remains unclear. In this study, we assessed 11 cases of LMS arising in conjunction with LM-BN confirmed by histology and immunohistochemistry (IHC), further analyzed by clinical, histologic, and molecular characteristics of these distinct components. LM-BN and LMS had similar p16 and p53 IHC patterns, but LMS had a higher Ki-67 index and lower estrogen and progesterone eceptor expression. Digital image analysis based on cytologic features revealed spatial relationships between LMS and LM-BN. Genomic copy number alterations (CNAs) demonstrated the same clonal origin of LMS arising from existing LM-BN through conserved CNAs. LMS harbored highly complex CNAs and more frequent losses of the TP53, RB1, and PTEN genomic regions than LM-BN (p = 0.0031), with CDKN2A/B deletion identified in LMS only. Mutational profiling revealed many shared oncogenic alterations in both LM-BN and LMS; however, additional mutations were present within LMS, indicative of tumor progression through progressive genomic instability. Analysis of spatial transcriptomes defined uniquely expressed gene signatures that matched the geographic distribution of LM-BN, LMS, and other cell types. Our findings indicate for the first time that a subset of LMS arises from an existing LM-BN, and highly complex genomic alterations could be potential high risks associated with disease progression in LM-BN. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Podocyte YAP ablation decreases podocyte adhesion and exacerbates FSGS progression through α3β1 integrin.
Shao G, Xu J, Hu C … +13 more , Jia W, Xu X, Gu Y, Zhang L, Zheng Z, Zhong J, Zhu S, Meng S, Zhao Z, Zhang Z, Liu J, Xu Y, Wu H
J Pathol · 2025 Jan · PMID 39668547 · Publisher ↗
Severe proteinuria in focal segmental glomerulosclerosis (FSGS) is closely associated with decreased adhesion, and subsequent loss, of podocytes. Yes-associated protein (YAP) is a key transcriptional coactivator that pla...
Severe proteinuria in focal segmental glomerulosclerosis (FSGS) is closely associated with decreased adhesion, and subsequent loss, of podocytes. Yes-associated protein (YAP) is a key transcriptional coactivator that plays a significant role in maintaining cellular homeostasis. However, its role in podocyte adhesion and its specific mechanism in FSGS progression remain unclear. In this study, an adriamycin (ADR)-induced FSGS model was established using podocyte-specific Yap knockout (KO) mice and control mice. These mice were further treated with Pyrintegrin, an agonist of α3β1 integrin, or a vehicle. Additionally, an ADR-induced FSGS model was constructed using podocyte-specific Itga3 KO mice, which were subsequently treated with 1-oleoyl lysophosphatidic acid (LPA), a YAP activator, or a vehicle. Our findings demonstrated that YAP was positively correlated with podocyte adhesion. Podocyte-specific Yap KO mice exhibited reduced levels of α3β1 integrin and podocyte adhesion. Yap KO aggravated the ADR-induced reduction in α3β1 integrin and podocyte adhesion, resulting in significantly increased segmental or global glomerulosclerosis and proteinuria. Notably, treatment with a β1 integrin agonist partially ameliorated the decrease of podocyte adhesion and the worsening FSGS progression caused by Yap KO. Mechanistically, YAP was found to transcriptionally regulate α3- and β1 integrin via transcriptional enhanced associate domain 3 (TEAD3), with TEAD3 binding to the promoter region of Itga3. Furthermore, Itga3 KO or knockdown abolished the beneficial effects of YAP activation on podocyte adhesion and FSGS progression. In conclusion, our results demonstrate that YAP regulates podocyte adhesion and FSGS progression through its transcriptional regulation of α3β1 integrin via TEAD3. This suggests that the YAP-TEAD3-α3β1 integrin axis may serve as a promising therapeutic target for FSGS. © 2024 The Pathological Society of Great Britain and Ireland.
Stress testing deep learning models for prostate cancer detection on biopsies and surgical specimens.
Flannery BT, Sandler HM, Lal P … +16 more , Feldman MD, Santa-Rosario JC, Pathak T, Mirtti T, Farre X, Correa R, Chafe S, Shah A, Efstathiou JA, Hoffman K, Hallman MA, Straza M, Jordan R, Pugh SL, Feng F, Madabhushi A
J Pathol · 2025 Feb · PMID 39660731 · Full text
The presence, location, and extent of prostate cancer is assessed by pathologists using H&E-stained tissue slides. Machine learning approaches can accomplish these tasks for both biopsies and radical prostatectomies. Dee...
The presence, location, and extent of prostate cancer is assessed by pathologists using H&E-stained tissue slides. Machine learning approaches can accomplish these tasks for both biopsies and radical prostatectomies. Deep learning approaches using convolutional neural networks (CNNs) have been shown to identify cancer in pathologic slides, some securing regulatory approval for clinical use. However, differences in sample processing can subtly alter the morphology between sample types, making it unclear whether deep learning algorithms will consistently work on both types of slide images. Our goal was to investigate whether morphological differences between sample types affected the performance of biopsy-trained cancer detection CNN models when applied to radical prostatectomies and vice versa using multiple cohorts (N = 1,000). Radical prostatectomies (N = 100) and biopsies (N = 50) were acquired from The University of Pennsylvania to train (80%) and validate (20%) a DenseNet CNN for biopsies (M), radical prostatectomies (M), and a combined dataset (M). On a tile level, M and M achieved F1 scores greater than 0.88 when applied to their own sample type but less than 0.65 when applied across sample types. On a whole-slide level, models achieved significantly better performance on their own sample type compared to the alternative model (p < 0.05) for all metrics. This was confirmed by external validation using digitized biopsy slide images from a clinical trial [NRG Radiation Therapy Oncology Group (RTOG)] (NRG/RTOG 0521, N = 750) via both qualitative and quantitative analyses (p < 0.05). A comprehensive review of model outputs revealed morphologically driven decision making that adversely affected model performance. M appeared to be challenged with the analysis of open gland structures, whereas M appeared to be challenged with closed gland structures, indicating potential morphological variation between the training sets. These findings suggest that differences in morphology and heterogeneity necessitate the need for more tailored, sample-specific (i.e. biopsy and surgical) machine learning models. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
CRISPR-Cas9 screening identifies the role of FER as a tumor suppressor.
Wang J, Yang R, Wang F … +18 more , Zhang J, Dong Y, Wang J, Yu M, Xu Y, Liu L, Cheng Y, Zhang C, Yang Y, Yang W, Wang J, Chen G, Huang Y, Tian Y, Jian R, Ni B, Wu W, Ruan Y
J Pathol · 2025 Feb · PMID 39648412 · Publisher ↗
It is important to systematically identify tumor suppressor genes (TSGs) to improve our understanding of tumorigenesis and develop strategies for early diagnosis and mitigating disease progression. In the present study,...
It is important to systematically identify tumor suppressor genes (TSGs) to improve our understanding of tumorigenesis and develop strategies for early diagnosis and mitigating disease progression. In the present study, we used an in vivo genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) screen and identified FPS/FES-related (FER) as a TSG. Single-cell RNA sequencing (scRNA-seq) revealed that normal cells with low FER expression exhibited elevated malignant transformation potential and stemness properties. FER knockout promoted the tumorigenic transformation, characterized by high colony-forming efficiency and suspension growth ability, acquired tumorigenicity in vivo, increased metabolic activity, dedifferentiation properties, and immune evasion. Moreover, analysis revealed that low FER expression tumors share molecular phenotypes with FER knockout cells, suggesting the consistent role of FER in tumor initiation and progression. Taken together, our findings not only provide insights into the essential role of FER as a tumor suppressor in tumor initiation and progression but also highlight its potential as a target for future clinical diagnosis. © 2024 The Pathological Society of Great Britain and Ireland.
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