The Journal Of Pathology[JOURNAL]
Sun
200 papers
New insights into the genetic progression of cancer through longitudinal analysis of oral lesions.
Wils LJ, Poell JB, Brink A … +7 more , Peferoen LA, Evren I, Brouns ER, de Visscher JG, van der Meij EH, Bloemena E, Brakenhoff RH
J Pathol · 2025 Oct · PMID 40728388 · Full text
Genetic progression models of cancer continue to determine the roadmap of carcinogenesis, although the sequence of genetic events is inferred rather than empirically determined through longitudinal analyses. Here, we pre...
Genetic progression models of cancer continue to determine the roadmap of carcinogenesis, although the sequence of genetic events is inferred rather than empirically determined through longitudinal analyses. Here, we present a unique longitudinal study of oral leukoplakia lesions that transformed into carcinoma. Lesions were followed from initial diagnosis through to malignant transformation. For each lesion, biopsies at baseline, the carcinoma, and all available intermediate biopsies were studied for the presence of dysplasia, genomic copy number aberrations, and mutations in selected head and neck cancer genes. Using this information, the phylogenetic history of all carcinomas was reconstructed within the context of applied interventions. In total, 71 biopsies of 21 lesions were studied. The median time to malignant transformation was 60 months. Oral carcinogenesis emerged as a multi-(sub)clonal process. Treatment interventions appeared to impact clonal selection, although lesions always remained after excision. Notably, the lesions demonstrated different routes of progression. A canonical pattern of progression was observed, characterized by longitudinal accumulation of abnormal morphology and genetic changes. However, some lesions followed an alternative, stable pattern of oncogenic progression, with no apparent increase in morphological changes or accumulation of genetic aberrations. This latter pattern appeared to be associated with the development of previously identified 'copy number quiet' head and neck tumors. This study provides a novel perspective on the temporal evolution of oral leukoplakia and the different routes to cancer progression and highlights the key role of multiclonal field cancerization in lesion recurrence and cancer development. © 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.
Maternal-foetal immune rejection: parallels between placental CHI and allograft rejection.
Shangaris P, Martín Monreal MT
J Pathol · 2025 Oct · PMID 40728254 · Full text
Chronic histiocytic intervillositis (CHI) is a rare placental inflammatory lesion increasingly viewed through maternal-foetal immune rejection. In this invited commentary, we discuss how a recent study bolsters the parad...
Chronic histiocytic intervillositis (CHI) is a rare placental inflammatory lesion increasingly viewed through maternal-foetal immune rejection. In this invited commentary, we discuss how a recent study bolsters the paradigm that CHI represents maternal immune rejection of the semi-allogeneic foetus, analogous to antibody-mediated rejection in organ transplantation. We highlight the shared histological and molecular features between CHI and kidney allograft rejection, including macrophage-dominated inflammation, complement activation, and interferon-gamma-driven gene expression signatures and explore the implications of this common pathogenesis for clinical practice. Recognising CHI as an alloimmune process opens new avenues for early prediction, diagnosis, and intervention. We particularly emphasise the need for early identification of CHI, even in a first pregnancy, where no prior obstetric history exists to raise suspicion. Finally, we outline how transplant immunotherapy principles (e.g. immunosuppression and immune modulation) could transform the management of CHI, and we call for forward-looking research that bridges immune pathology, maternal-foetal medicine, and translational therapeutics to improve pregnancy outcomes. © 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.
LncRNA GAS5 ameliorates intestinal barrier injury by targeting the miR-223-3p/FBXW7 axis and inactivating NF-κB signaling in vitro and in vivo.
Wang Z, Yuan J, Qin X … +4 more , Yin H, Zhong C, Qu R, Wang G
J Pathol · 2025 Sep · PMID 40719162 · Publisher ↗
Sepsis is a potentially lethal syndrome that leads to multiple organ dysfunction. LncRNA GAS5 is closely related to sepsis; however, its detailed functions and mechanism in sepsis-triggered intestinal barrier dysfunction...
Sepsis is a potentially lethal syndrome that leads to multiple organ dysfunction. LncRNA GAS5 is closely related to sepsis; however, its detailed functions and mechanism in sepsis-triggered intestinal barrier dysfunction are unclear. In this study, NCM460 cells were stimulated with lipopolysaccharide (LPS) to mimic septic intestinal injury in vitro, and a sepsis mouse model was established via the cecum ligation and perforation method. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was performed for cell apoptosis evaluation. RNA and protein levels were examined by RT-qPCR and western blotting, respectively. Additionally, cell permeability and intestinal mucosa permeability were measured. ELISA was utilized to detect inflammatory cytokine production. H&E staining was conducted for histologic examination of the intestine. Luciferase reporter and RNA pull-down assays were employed to verify the interaction between GAS5, miR-223-3p, and FBXW7. The results showed that GAS5 was downregulated in LPS-exposed NCM460 cells as well as the intestine of septic mice. GAS5 overexpression mitigated LPS-triggered intestinal epithelial cell damage and apoptosis in vitro and reduced pathological damage, inflammation, and intestinal hyperpermeability in septic mice. GAS5 upregulated FBXW7 by interacting with miR-223-3p. Depletion of FBXW7 reversed the protective effects of GAS5 overexpression in vitro. Additionally, GAS5 overexpression inactivated NF-κB signaling in LPS-stimulated NCM460 cells. NF-κB inactivation exerted effects in septic mice similar to those observed with GAS5 overexpression. In conclusion, GAS5 ameliorates sepsis-triggered intestinal barrier disruption by mediating the miR-223-3p/FBXW7 axis and inactivating NF-κB signaling. © 2025 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Spatial transcriptomics identifies SPARC as a prognostic marker in interstitial lung diseases.
Niitsu T, Kataoka T, Fukushima K … +11 more , Motooka D, Shichino S, Natsume-Kitatani Y, Kitamura H, Niwa T, Baba T, Okuzaki D, Kumanogoh A, Akira S, Okudela K, Ogura T
J Pathol · 2025 Sep · PMID 40719154 · Full text
Interstitial lung diseases (ILDs) encompass a diverse group of pulmonary disorders, with progressive fibrosis leading to poor prognosis. Here we aimed to identify key molecules involved in progressive fibrosis across var...
Interstitial lung diseases (ILDs) encompass a diverse group of pulmonary disorders, with progressive fibrosis leading to poor prognosis. Here we aimed to identify key molecules involved in progressive fibrosis across various ILDs, using spatial transcriptomics (ST). ST analysis (Visium) was performed on lung cryobiopsy specimens from five patients with various ILDs. Two cases, rich in young fibrotic lesions, as defined by fibroblastic foci and destructive alveolar organization, were selected for spatial high-dimensional weighted gene coexpression network analysis (hdWGCNA) to identify key gene networks with biological significance in active fibrosis. We utilized public single-cell RNA sequencing datasets of various ILDs, performed enrichment analysis and trajectory-based differential expression analysis, and quantified cell-cell communication to evaluate the involvement of the spatially extracted module in fibrosis. Immunohistochemical staining of the extracted molecules was performed. Using hdWGCNA, we identified a distinct gene module (the SM2 module) enriched in young fibrotic lesions. The SM2 module was characterized by distinct features of fibroblast activation that were represented across various lesions. Key hub genes within this module, including COL1A2, COL3A1, COL1A1, and SPARC, formed a robust coexpression network. Immunohistochemical staining showed that SPARC, a component of the SM2 module, was highly expressed in young fibrotic lesions, but not in old scarring lesions, across various ILDs. To assess the prognostic significance of SPARC immunohistochemical expression, we extended our analysis to a cohort of 71 patients with unclassifiable ILDs (uILDs), a particularly heterogeneous subtype with unclear pathogenesis and limited treatment options. Higher SPARC levels in the upper, lower, or both lung lobes in uILD were significantly associated with poor overall survival. In summary, an integrated cross-disease approach using ST revealed key gene expression patterns central to active fibrosis and successfully identified SPARC as a potentially beneficial prognostic marker. © 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.
Elevated NPM1 and FBL expression correlates with prostate cancer aggressiveness and progression.
Saffarian S, Cai Z, Lam J … +2 more , Oo HZ, Somasekharan S
J Pathol · 2025 Sep · PMID 40705480 · Full text
The nucleolus is a membrane-less body present in the nucleus of the cell. The nucleolus is mainly involved in ribosomal RNA (rRNA) transcription and ribosome biogenesis for protein translation. During cancer formation, n...
The nucleolus is a membrane-less body present in the nucleus of the cell. The nucleolus is mainly involved in ribosomal RNA (rRNA) transcription and ribosome biogenesis for protein translation. During cancer formation, nucleolar morphology is altered, and many nucleolar proteins are expressed at a higher level, leading to enhanced ribosome biogenesis and protein translation, which supports cancer aggressiveness, proliferation, migration, and invasion. In this study, we investigated the association of two nucleolar proteins, nucleophosmin (NPM1), and fibrillarin (FBL), with prostate cancer (PCa) aggressiveness and progression. We investigated their cellular localization and expression in different PCa patient tissue specimens and their role in regulating proliferation, migration, invasion, and nucleolar morphology. Our results indicate that NPM1 and FBL are present in the nucleolus of both PCa and noncancerous prostatic cells. The expression of NPM1 and FBL was enhanced in aggressive castration-resistant PCa (CRPC) and neuro-endocrine PCa (NEPC) patient specimens compared to hormone-naïve PCa (HNPC) patient specimens. The expression of NPM1 was enhanced in high-Gleason score PCa compared to low-Gleason score PCa. Silencing of NPM1 and FBL significantly reduced the proliferation, migration, and invasion of PCa cells without affecting noncancerous prostatic cells. Silencing of NPM1 and FBL also changed the morphology of nucleoli in both PCa and noncancerous prostatic cells, where NPM1 silencing fragmented the nucleoli and FBL silencing condensed the nucleoli. Our results suggest that NPM1 and FBL expression correlates with PCa aggressiveness and PCa cells may exhibit a unique dependence on NPM1 or FBL for PCa progression. © 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.
Tumor-associated macrophages: potential role in skeletal involvement in classic Hodgkin lymphoma.
Andersen MD, Wolter K, Enemark MH … +8 more , Pedersen MA, Gormsen LC, Lauridsen KL, Starklint J, Hamilton-Dutoit SJ, d'Amore F, Ludvigsen M, Kamper P
J Pathol Clin Res · 2025 Jul · PMID 40704910 · Full text
The biology of tumor spread to bone is poorly understood, not least in classic Hodgkin lymphoma (cHL). We used gene expression profiling and immunohistochemistry to characterize the nodal tumor microenvironment of cHL ca...
The biology of tumor spread to bone is poorly understood, not least in classic Hodgkin lymphoma (cHL). We used gene expression profiling and immunohistochemistry to characterize the nodal tumor microenvironment of cHL cases with and without skeletal involvement at diagnosis. Gene expression profiling of 66 pretreatment lymphoma samples revealed that lymph nodes from patients with skeletal cHL (s-cHL) exhibited a higher abundance of cells expressing macrophage markers, particularly M2-like markers, than nodal-only cHL (n-cHL). These markers included CD163, MRC1 (CD206), MARCO, and SIGLEC1. Additionally, there was a notable downregulation of genes encoding B-cell-associated markers such as MS4A1 (CD20), CD19, PAX5, and CD79A/B. We further evaluated the protein expression of macrophage markers (CD68, CD163, and CD206) and the B-cell marker CD20 in 193 pretreatment lymphoma samples using immunohistochemistry. Our analysis revealed significantly higher expression levels of all three macrophage markers in s-cHL samples compared to n-cHL samples (p < 0.001). Conversely, the expression level of CD20 was significantly lower in s-cHL compared with n-cHL (p < 0.001). All three macrophage markers correlated positively with Ann Arbor stage, indicating their potential involvement in the dissemination of cHL in general. Our findings suggest a potential role for tumor-associated macrophages in the dissemination of cHL to bone.
Enhanced diagnostic potential of CSPG4 in melanoma and nevi: a comparative study with PRAME, CDC7 and Ki67.
Koch EAT, Seidel C, Erber R … +6 more , Erdmann M, Heppt MV, Schliep S, Berking C, Dörrie J, Schaft N
J Pathol · 2025 Sep · PMID 40700516 · Full text
Chondroitin sulfate proteoglycan 4 (CSPG4) is a promising target for melanoma immunotherapy, but its expression in benign melanocytic lesions and its diagnostic value remain unexplored. This study assessed CSPG4 expressi...
Chondroitin sulfate proteoglycan 4 (CSPG4) is a promising target for melanoma immunotherapy, but its expression in benign melanocytic lesions and its diagnostic value remain unexplored. This study assessed CSPG4 expression in benign nevi (BN), dysplastic nevi (DN), and superficial spreading melanomas (SSM), comparing it with PRAME (PReferentially expressed Antigen in MElanoma) and evaluating the cell division cycle 7-related protein kinase (CDC7) and the proliferation marker Ki67. Histological sections were stained using automated instruments, digitized, and analyzed using QuPath. Cohorts of BN, DN, and SSM were created, and positive cells/mm and H-scores were determined. A total of 336 IHC stainings from 84 specimens were analyzed. CSPG4 expression was readily detected in SSM and was significantly stronger in DN (p = 0.005), with the highest intensity observed in BN (p < 0.001). PRAME showed the highest density of positive cells/mm in SSM, was significantly reduced in DN (p < 0.001), and was lowest in BN (p < 0.001). Ki67 expression was strong in SSM, moderate in DN (p = 0.62), and low in BN (p = 0.008). CDC7 expression was most intense in DN, less in SSM (p = 0.39), and weakest in BN (p = 0.002). ROC AUC values for SSM versus DN and SSM versus BN were 0.764 and 0.921 for CSPG4, 0.85 and 0.889 for PRAME, 0.735 and 0.742 for Ki67, and 0.425 and 0.767 for CDC7. While PRAME was the most reliable marker for differentiating DN and SSM, CSPG4 was superior for distinguishing BN from SSM due to its high expression in BN. However, CSPG4-targeting therapies may trigger on-target/off-tumor effects due to its high expression in melanocytic nevi. © 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.
BIRC3 deficiency blocks the ubiquitination and degradation of GOT2 to impede antitumor immune responses in lung squamous cell carcinoma.
Zhang Q, Sheng H, Ping D … +1 more , Gao J
J Pathol · 2025 Oct · PMID 40690196 · Publisher ↗
In lung squamous cell carcinoma (LUSC), the proportion of exhausted CD8 T cells is considerably higher than in lung adenocarcinoma (LUAD). The exhaustion of CD8 T cells is responsible for the failure of immunotherapies,...
In lung squamous cell carcinoma (LUSC), the proportion of exhausted CD8 T cells is considerably higher than in lung adenocarcinoma (LUAD). The exhaustion of CD8 T cells is responsible for the failure of immunotherapies, as terminally exhausted CD8 T cells do not respond to immune checkpoint blockade. Therefore, investigating the regulatory mechanisms underlying CD8 T-cell exhaustion in LUSC is essential for potentiating the efficacy of immunotherapy in this context. In our study, cellular assays revealed that elevated expression of GOT2 in LUSC reinforced the exhaustion of cocultured CD8 T cells, as evidenced by elevated levels of TIGIT and TIM-3, while simultaneously impairing tumor-killing capabilities, as indicated by reduced LDH activity and diminished apoptosis. Animal experiments confirmed that knockdown of GOT2 effectively curbed tumor growth and boosted the CD8 T cell infiltration and tumor-killing function. Mechanistic studies demonstrated that BIRC3, acting as an E3 ubiquitin ligase, can recognize the 366-372 sequence of GOT2, mediating its ubiquitination and degradation. The deficiency of BIRC3 in LUSC interrupted ubiquitination and subsequent degradation of GOT2, leading to elevated GOT2 protein levels, which in turn facilitated CD8 T-cell exhaustion and ultimately compromised their antitumor immune responses. Collectively, our findings elucidated the regulatory role of protein ubiquitination in CD8 T cell functionality, highlighting a novel approach to enhance the sensitivity of LUSC to immunotherapy through the intervention of the BIRC3/GOT2 ubiquitination axis. © 2025 The Pathological Society of Great Britain and Ireland.
Which descriptor should spread through air spaces (STAS) be incorporated into? T descriptor versus residual tumor classification.
Mi Y, Chen D, Chen Z … +9 more , Li Y, Dai X, Shen S, Shu J, Li Y, Tan L, Mao Y, Ding Q, Chen Y
J Pathol Clin Res · 2025 Jul · PMID 40689870 · Full text
It has not been determined which descriptor spread through air spaces (STAS) should be incorporated into the context of the ninth Tumor, Node and Metastasis (TNM) staging system: the T or the uncertain resection [R(un)]...
It has not been determined which descriptor spread through air spaces (STAS) should be incorporated into the context of the ninth Tumor, Node and Metastasis (TNM) staging system: the T or the uncertain resection [R(un)] category. A multicenter retrospective cohort of 807 patients with pathological stage I lung adenocarcinoma was included in this study to assess the feasibility of incorporating STAS into the T descriptor or the R(un) category by analyzing recurrence-free survival (RFS) and overall survival (OS). Decision curve analysis (DCA) was performed to evaluate the standardized net benefit of the proposed T (nT) and that of the proposed residual tumor classification (nR) versus the current staging systems. Log-rank tests indicated that patients with pT1/STAS-positive lung adenocarcinoma had similar RFS and OS to patients with pT2a disease irrespective of R status. Regarding STAS as an indicator for upgrading R0 to R(un), comparable survival was observed between pT1-2a/STAS-positive patients undergoing R0 segmentectomy and pT1-2a patients undergoing R(un) segmentectomy. We further assessed the effects of the combination of STAS with either T or R category on survival in a validation cohort. Subgroup analyses stratified by surgical procedures further identified the consistency of the nT category in discriminating RFS and OS. However, the separation of nR0 and nR(un) disease in pT2a tumors treated by lobectomy or segmentectomy was not sufficiently distinguished. DCA further corroborated a greater predictive capability of nT versus the current T category. In conclusion, STAS might be preferentially considered as an indicator for upgrading pT1 disease into pT2a in the future TNM staging system.
Pathogenesis of peritoneal high-grade serous carcinoma after risk-reducing surgery: a systematic review.
Gootzen TA, Bouwmeester AB, de Hullu JA … +4 more , Piek JM, van der Laak JA, Simons M, Steenbeek MP
J Pathol Clin Res · 2025 Jul · PMID 40682790 · Full text
Germline BRCA1/2 pathogenic variant carriers have an increased risk for high-grade serous carcinoma (HGSC) and are therefore advised to have risk-reducing salpingo-oophorectomy around the age of 40. However, a risk of 0....
Germline BRCA1/2 pathogenic variant carriers have an increased risk for high-grade serous carcinoma (HGSC) and are therefore advised to have risk-reducing salpingo-oophorectomy around the age of 40. However, a risk of 0.9% to develop peritoneal HGSC remains in these women, which increases to 27.5% when serous tubal intraepithelial carcinoma (STIC) is detected. The pathophysiological mechanism that leads to the development of peritoneal HGSC after salpingectomy or salpingo-oophorectomy is still largely unknown. In this systematic review, we aim to provide insights into the pathogenic pathways of peritoneal HGSC after salpingectomy or salpingo-oophorectomy. Therefore, we performed a systematic search for studies investigating pathophysiological mechanisms related to peritoneal HGSC in PubMed and EMBASE. A total of 49 articles were included in this study. Most evidence was found on mechanisms following a tubal origin, such as clonality between STIC and peritoneal HGSC as well as molecular similarities between fallopian tube (FT) epithelium and peritoneal HGSC. Additionally, FT epithelium was shown to adhere to the ovary and could therefore stay present after isolated salpingectomy. There might be a role for the endometrium, as it was observed that serous endometrial intraepithelial carcinoma (SEIC) has a clonal relationship with extra-uterine HGSC. The role of the ovary seems limited, although some mouse models show a role for follicular fluid in the dissemination of malignant cells on the peritoneum. In conclusion, different mechanisms might be responsible for peritoneal HGSC development after bilateral salpingectomy or salpingo-oophorectomy. Most available evidence supports the dissemination of precursor cells originating in the FT. Also, a possible role for the endometrium was found. An ovarian origin seems less likely; however, execution of oophorectomy does not seem obsolete in clinical practice as follicular fluid might promote dissemination and residual tubal tissue can be present on the ovary after salpingectomy.
Automated tumor-stroma ratio estimation for improved prognostic stratification of squamous cell carcinoma of the oral tongue.
Wang L, Sörensen K, Coates PJ … +4 more , Gu X, Sgaramella N, Barre MM, Nylander K
J Pathol Clin Res · 2025 Jul · PMID 40673653 · Full text
Squamous cell carcinoma of the oral tongue (SCCOT) represents an aggressive malignancy characterized by high metastatic potential and significant heterogeneity in its tumor microenvironment. The tumor-stroma ratio (TSR)...
Squamous cell carcinoma of the oral tongue (SCCOT) represents an aggressive malignancy characterized by high metastatic potential and significant heterogeneity in its tumor microenvironment. The tumor-stroma ratio (TSR) has emerged as a prognostic biomarker, with higher stromal content frequently correlating with worse survival outcomes. Traditional approaches using the standard 50% TSR cutoff may not be optimal for SCCOT, and visual TSR estimation introduces variability during TSR region annotation. This study aimed to develop and validate a dedicated TSR estimation model for SCCOT by incorporating representative TSR regions from the invasive tumor front of whole slide images and to determine the optimal TSR threshold for prognostic stratification. Using hematoxylin and eosin-stained images from The Cancer Genome Atlas as a discovery cohort and whole slide images from Norrland's University Hospital Umea, Sweden (NUS) as a validation cohort, we developed a computational model to estimate TSR. The model demonstrated a high correlation with pathologist-based TSR estimation in both discovery (R = 0.848, p < 0.01) and validation (R = 0.783, p < 0.01) cohorts. The optimal 55% cutoff identified by the model improved prognostic accuracy over the traditional 50% threshold, with patients having high stroma within the tumor invasive front showing worse overall (log-rank p = 0.006) and disease-specific (log-rank p = 0.016) survival. Our computational TSR model for SCCOT demonstrates that automated TSR estimation enhances prognostic accuracy at an optimal cutoff of 55%, contributing to more precise risk stratification and potentially enabling personalized treatment strategies in SCCOT management.
The case for homebrew AI in diagnostic pathology.
Calderaro J, Morement H, Penault-Llorca F … +2 more , Gilbert S, Kather JN
J Pathol · 2025 Aug · PMID 40613320 · Full text
Artificial intelligence (AI) methods for digital pathology have tremendous potential to improve cancer diagnostics, biomarkers, and ultimately patient care. These AI methods, if marketed and sold, require authorisation o...
Artificial intelligence (AI) methods for digital pathology have tremendous potential to improve cancer diagnostics, biomarkers, and ultimately patient care. These AI methods, if marketed and sold, require authorisation or clearance as in vitro diagnostic (IVD) devices by regulatory bodies like the Food and Drug Administration (FDA) in the USA or Notified Bodies in the European Union (EU). Many AI tools for digital pathology are unlikely to be commercially viable and taken up by commercial entities ready to navigate these complex and costly processes. However, a longstanding quality framework already exists that allows for lab-developed tests, colloquially known as 'homebrew' tests, that are locally validated and performed under the responsibility and oversight of the pathologist. Here we argue for advancing homebrew AI systems within this existing framework to enhance patients' access to supportive digital diagnostic tools. We outline how homebrew AI models are currently permitted under regulatory provisions in the USA and the European Union, how a new US FDA rule may effectively regulate them out of existence, and propose steps to facilitate the safe and effective integration of homebrew AI models in pathology practice. © 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.
Involvement of KEAP1/NRF2 pathway in non-BRAF mutated squamous cell carcinoma of the thyroid.
Schoultz E, Dahlberg J, Nilsson LM … +11 more , Dzanan JJ, Carlsson T, Dahr N, Andersson E, Muhammad G, Muth A, Elias E, Fagman H, Sayin VI, Nilsson JA, Nilsson M
J Pathol · 2025 Aug · PMID 40600748 · Full text
Squamous cell carcinoma (SCC) of the thyroid is a rare tumor that is classified as an anaplastic thyroid cancer (ATC) due to its similar unresponsiveness to chemoradiotherapy and an outstandingly poor prognosis. Due to i...
Squamous cell carcinoma (SCC) of the thyroid is a rare tumor that is classified as an anaplastic thyroid cancer (ATC) due to its similar unresponsiveness to chemoradiotherapy and an outstandingly poor prognosis. Due to its rarity, current knowledge about this tumor is mostly based on single-case reports. The tumor-cell-origin and molecular pathogenesis remain unclear, although the presence of BRAF mutations in some cases suggest it may evolve from papillary thyroid carcinoma (PTC). Here we provide direct evidence of derivation of SCC of the thyroid from PTC, based on a unique combination of likely pathogenic mutations in KEAP1, STK11 (LKB1), and RB1 found in both tumor components, along with loss of one copy of chromosome 11 and additional somatic mutations in the SCC tumor. Transdifferentiation from PTC to SCC was also evident by immunohistochemistry. Out of eight attempted patient-derived xenografts (PDX) from advanced thyroid cancers, only one derived from thyroid SCC successfully engrafted in immunodeficient NOG mice. Untreated PDXs showed high Ki67 indices but did not reproduce the conspicuous stromal invasion of CDH1/SNAI2/CDH2 cells that characterized the primary tumor. Based on the mutation profile (NFE2L2, PIK3CA, CDKN2A, and TP53), experiments were designed to evaluate targeted drug therapy using third-passage PDX transplants. The combination of TRK and PI3K inhibitors, cabozantinib and GDC-0326, additively reduced PDX growth by nearly 90%. Remarkably, CB-839 (telaglenastat), a glutaminase inhibitor targeting metabolic rewiring downstream of NRF2 activation, was equally effective. Both combined treatment with cabozantinib + GDC-0326 and CB-839 monotherapy diminished the expression of NQO1, an NRF2 transcriptional target, in tumor cells. Glutaminase inhibition further promoted squamous differentiation in engrafted tumors. Both investigated SCC tumors were negative for BRAFV600E or any other common driver mutation of thyroid cancer. Collectively, these findings indicate that aberrant activation of the KEAP1/NRF2 pathway due to somatic mutations is a previously unrecognized feature of thyroid SCC and suggest that glutaminase inhibition may serve as a potential therapeutic option for this subgroup of ATC 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.
Correction to 'CC chemokine receptor-like 1 functions as a tumour suppressor by impairing CCR7-related chemotaxis in hepatocellular carcinoma'.
J Pathol · 2025 Sep · PMID 40590422 · Publisher ↗
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Mucinous cystic neoplasms of the pancreas and liver share a similar DNA methylation profile with mucinous ovarian tumors.
Leoni Z, Calina TG, Janik T … +18 more , Grafenhorst E, Taube ET, Neumann CC, Chen B, Braicu EI, Sehouli J, Malinka T, Schöning W, Pratschke J, Calin GA, Klimstra DS, Benhamida JK, Esposito I, Möbs M, Horst D, Schallenberg S, Capper D, Dragomir MP
J Pathol · 2025 Sep · PMID 40557758 · Full text
The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10%...
The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian-like stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN-P) and six hepatic MCNs (MCN-L). Using immunohistochemistry and targeted DNA sequencing, we unequivocally established the diagnosis of MCN. Unsupervised DNA methylation profile analysis of reference classes of pancreatic neoplasms (11 entities and normal pancreatic tissue from 224 unique samples) revealed that MCN-P predominantly forms a distinct group. In the DNA methylation landscape of liver tumors, encompassing five tumor types and normal bile duct tissue from 136 unique samples, MCN-L demonstrated a specific methylation profile when compared with all other entities. Furthermore, within the DNA methylation landscape of ovarian tumors - featuring five tumor types, normal Fallopian tube, and normal ovarian tissue from 90 unique samples - we found that both MCN-P and MCN-L grouped with mucinous ovarian carcinoma and mucinous borderline ovarian tumors (mBOTs). Notably, low-grade MCNs exhibited greater DNA methylation similarities to mBOTs, while high-grade or invasive MCNs were primarily associated with mucinous ovarian carcinomas. When analyzing all samples together (19 tumor types and four normal tissue types, n = 430), MCNs similarly grouped with mucinous ovarian tumors and normal ovarian tissue. Additionally, in a network analysis of differentially methylated probes, MCN-P and MCN-L share significant methylation traits, closely resembling mucinous ovarian tumors. In conclusion, our findings highlight that MCN-P and MCN-L are distinct entities in the landscape of pancreatic and hepatic tumors and show DNA methylation profile similarities with mucinous ovarian tumors, suggesting a potential common origin. © 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.
Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer.
Ward JC, Morgan M, Wood J … +20 more , Woolley C, de Menezes AAN, Finch A, Sherwood K, Huang Q, Henry CS, Fernández-Tajes J, Soriano I, Thorn S, Legge I, McCullagh J, Kerr D, Kerr R, Hejmadi RK, Arends MJ, S:CORT Consortium, Domingo E, Maughan T, Bardella C, Tomlinson I
J Pathol · 2025 Sep · PMID 40545636 · Full text
The CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), b...
The CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), but its origins have been obscure. A few CRCs carry oncogenic (gain-of-function) mutations in isocitrate dehydrogenase IDH1. Whilst IDH1 is an established CRC driver gene, the low frequency of IDH1-mutant CRCs (about 0.5%) has meant that the effects and molecular covariates of those mutations have not been established. We first showed computationally that IDH2 is also a CRC driver. Using multiple public and in-house CRC datasets, we then identified IDH mutations at the hotspots (IDH1 codons 132 and IDH2 codons 140 and 172) frequently mutated in other tumour types. Somatic IDH mutations were associated with BRAF mutations and expression of mucinous/goblet cell markers, but not with KRAS mutations or MSI. All IDH-mutant CRCs were CIMP-positive, mostly at a high level. Cell and mouse models showed that IDH mutation was plausibly causal for DNA hypermethylation. Whilst the aetiology of hypermethylation generally remains unexplained, IDH-mutant tumours did not form a discrete methylation subcluster, suggesting that different underlying mechanisms can converge on similar final methylation phenotypes. Although further analysis is required, IDH mutations may be the first cause of hypermethylation to be identified in a common cancer type, providing evidence that CIMP and DNA methylation represent more than aging-related epiphenomena. Cautious exploration of mutant IDH inhibitors and DNA demethylating agents is suggested in managing IDH-mutant CRCs. © 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.
Circulating metabolomics reveals guanosine monophosphate synthetase (GMPS) as a novel therapeutic target in lung adenocarcinoma.
Yu M, Yang D, Zhu D … +6 more , Wang Y, Cao M, Zhu J, Zhu W, Wang G, Aa J
J Pathol · 2025 Aug · PMID 40539844 · Publisher ↗
Metabolic reprogramming is pivotal in the initiation and progression of lung adenocarcinoma (LUAD). However, a substantial gap remains in the understanding of the primary drivers of metabolic reprogramming and alteration...
Metabolic reprogramming is pivotal in the initiation and progression of lung adenocarcinoma (LUAD). However, a substantial gap remains in the understanding of the primary drivers of metabolic reprogramming and alterations in early-stage LUAD. Using an unbiased, large-scale metabolomics analysis of 2,531 plasma and serum samples from three independent clinical centers, we identified significant perturbations in purine metabolism that characterized reprogrammed metabolism in early-stage LUAD. Additionally, hypoxanthine (p < 0.001) and xanthine (p < 0.05) were identified as two typical early risk indicators, with odd ratios (ORs) more than 2.8 and 1.45, respectively. Guanosine monophosphate synthetase (GMPS) was identified as a pivotal factor in the early development and malignant progression of LUAD. Progression of LUAD was significantly attenuated by GMPS knockdown and markedly exacerbated by its overexpression. Further data indicated that GMPS primarily contributed to the reprogrammed metabolic phenotypes of LUAD through its enzymatic activity and subsequent production of purine nucleotides, based on the relative abundance of the labeled isotope metabolites. Collectively, dysregulated purine metabolism emerged as a key characteristic of early-stage LUAD, and targeting GMPS activity may offer a promising therapeutic potential for LUAD treatment. © 2025 The Pathological Society of Great Britain and Ireland.
Genetic deletion of histone deacetylase 6 prevents peritoneal fibrosis via suppression of heat shock protein 90 deacetylation.
Shi Y, Li J, Zhong Q … +9 more , Chen H, Ma X, Hu Y, Wang Y, Jiang D, Zhou X, Li X, Zhuang S, Liu N
J Pathol · 2025 Aug · PMID 40539829 · Publisher ↗
Peritoneal fibrosis (PF) is a serious complication contributing to ultrafiltration failure in patients undergoing peritoneal dialysis that currently lacks effective treatment strategies. Our recent studies highlighted th...
Peritoneal fibrosis (PF) is a serious complication contributing to ultrafiltration failure in patients undergoing peritoneal dialysis that currently lacks effective treatment strategies. Our recent studies highlighted the key role of histone deacetylase 6 (HDAC6) in the development of PF. To better understand the mechanisms underlying the involvement of HDAC6 in PF, we conducted in vivo experiments using Hdac6 KO mice and in vitro studies using human peritoneal mesothelial cells (HPMCs). Our results demonstrated that HDAC6 gene silencing improved PF and angiogenesis in vivo and altered pathological phenotypes in vitro. In Hdac6 KO mice, the key pathways regulating extracellular matrix accumulation, angiogenesis, and secretion of inflammatory cytokines (including TGFB1/SMAD3, HIF-1α/VEGFR-2/MAPK3/MAPK1, and TLR4/NF-κB pathways) were inhibited. We also identified heat shock protein 90 (HSP90) as the substrate of HDAC6 in both PF mice and HPMCs and demonstrated that HDAC6 exerted its regulatory function in PF through the deacetylation of HSP90. Overall, our study provides novel insights into the critical role of the HDAC6-HSP90 interplay in PF using Hdac6 KO mice. We identify HSP90 as an essential substrate through which HDAC6 exerts its function in PF, providing an experimental basis for the development of novel therapeutic strategies. © 2025 The Pathological Society of Great Britain and Ireland.
Development and characterisation of improved unifocal primary mouse lung cancer models with metastatic potential.
Pedrosa AR, Castillo-Kauil A, Kravchuk Y … +18 more , Reynolds L, Williams B, Moore D, Lang C, Allanki S, Maniati E, Hardas A, Haj J, Drake R, Cleaver J, Foster J, Kim J, Stern E, Sosabowski J, Fruhwirth GO, Sahai E, Wald O, Hodivala-Dilke K
J Pathol · 2025 Aug · PMID 40530801 · Full text
Lung cancer is the leading cause of cancer-related death globally. To better understand the biology of lung cancer, mouse models have been developed using either tail vein-injected tumour cell lines or genetically modifi...
Lung cancer is the leading cause of cancer-related death globally. To better understand the biology of lung cancer, mouse models have been developed using either tail vein-injected tumour cell lines or genetically modified mice. The current gold-standard models typically present with multiple lung foci. However, although these models are widely used, their correlation with human disease are limited, as early-stage human lung cancer usually presents as a single lesion rather than multiple foci. Additionally, a major challenge of using multifocal lung tumour models is the difficulty in distinguishing primary lung tumours from intrathoracic metastasis and lethal levels of lung congestion before distant metastases develop. Here, we present a refined and detailed surgical method in which murine tumour cells [Lewis lung carcinoma (LLC), alveogenic lung carcinoma (CMT), or Kras/Trp53-KP mutant cells] were injected directly into the left lung lobe of C57BL/6 mice, or, alternatively, adenoviral-Cre or adenoviral-FlpO was administered directly into the left lung lobe of Kras;Trp53 or Kras;Trp53 (KP) mice, respectively. This method generated unifocal primary left lung lobe tumours with traceable spread to local and distant sites. A cross-comparison of the unifocal models described commonalties and differences between LLC, CMT, KP cells, and adenoviral-Cre or -FlpO methods in terms of timings for primary lung tumour growth and traceable spread to local and distant sites, histological analysis of CD3 and CD11b immune cell infiltration, and Picrosirius Red analysis of extracellular matrix complexity. Lastly, the frequency of clinical histopathological features typical of human lung cancer were assessed across the unifocal mouse models to provide a direct comparison with human lung cancer. Overall, this study details a refined and reproducible protocol for intralobular lung injection to generate unifocal lung cancer models that resemble key features of human lung cancer. This approach can be applied to other lung cancer initiation strategies. The cross-comparative histological analysis across the models tested here offers a valuable resource to aid researchers in selecting the most appropriate next-generation unifocal lung cancer models for their specific research needs. © 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.
Hyaluronan accumulation is associated with reduced hyaluronidase expression in renal cell carcinoma, with CD44, HAS1, and HYAL2 emerging as prognostic markers.
Jokelainen O, Rintala T, Remes S … +3 more , Pasonen-Seppänen S, Nykopp TK, Sironen R
J Pathol Clin Res · 2025 Jul · PMID 40528762 · Full text
Hyaluronan (HA), a large extracellular matrix glycosaminoglycan, is associated with malignant features in several human cancers. The accumulation of HA in renal cell carcinomas (RCC) correlates with unfavorable outcomes,...
Hyaluronan (HA), a large extracellular matrix glycosaminoglycan, is associated with malignant features in several human cancers. The accumulation of HA in renal cell carcinomas (RCC) correlates with unfavorable outcomes, higher tumor grade, and more advanced disease stages. However, the mechanisms responsible for HA buildup in these neoplasms remain unclear, and studies on the expression of hyaluronan-metabolizing and -degrading enzymes are either lacking or conflicting. This study aims to address this knowledge gap. Formalin-fixed paraffin-embedded (FFPE) RCC samples of various histological subtypes from 315 patients were immunohistochemically stained for CD44 (the main receptor of HA), hyaluronan-synthesizing enzymes HAS1-3, and degrading enzymes HYAL1-2. Protein expression levels were correlated with clinicopathological variables and their prognostic significance was evaluated. Additionally, the mRNA expression levels of these proteins were examined using RNA extracted from the same samples and publicly available data from the cancer genome atlas (TCGA). CD44 protein expression was associated with increased tumoral HA content, poor prognosis, higher tumor grade, advanced stage, and sarcomatoid/rhabdoid changes. HYAL1 and HYAL2 protein levels were reduced in HA-positive tumors, and low HYAL2 expression predicted worse prognosis. Elevated HAS2 protein expression was associated with poor differentiation, while low HAS1 protein levels were associated with reduced survival. mRNA levels of CD44 and HYAL2 correlated with their respective protein expression levels, and CD44 mRNA expression was also associated with HA content. In RCC, HA accumulation appears to be primarily driven by decreased degradation. HAS1 and HYAL2 were identified as novel prognostic biomarkers. These findings provide new insights into HA metabolism in RCC and open potential avenues for better understanding and management of these tumors.
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