J. Pathol. [JOURNAL]
Sun
200 papers
Cystathionine gamma-lyase-mediated hypoxia inducible factor 1-alpha expression drives clear cell ovarian cancer progression.
El-Naggar AM, Li Y, Turgu B … +25 more , Ding Y, Wei L, Chen SY, Trigo-Gonzalez G, Kalantari F, Vallejos R, Lynch B, Senz J, Lum A, Douglas JM, Salamanca C, Thornton S, Qin Y, Parmar K, Spencer SE, Leung S, Woo MMM, Yong PJ, Zhang HF, Hughes CS, Negri GL, Wang Y, Morin GB, Sorensen PH, Huntsman DG
J Pathol · 2025 Jul · PMID 40371821 · Full text
Clear cell ovarian cancer (CCOC) is the second most common ovarian cancer subtype, accounting for 5%-11% of ovarian cancers in North America. Late-stage CCOC is associated with a worse prognosis compared to other ovarian...
Clear cell ovarian cancer (CCOC) is the second most common ovarian cancer subtype, accounting for 5%-11% of ovarian cancers in North America. Late-stage CCOC is associated with a worse prognosis compared to other ovarian cancer histotypes, a challenge that has seen limited progress in recent decades. CCOC typically originates within the toxic microenvironment of endometriotic ovarian cysts and is characterized by its intrinsic chemoresistance, a strong hypoxic signature, and abundant expression of cystathionine gamma-lyase (CTH). CTH is a key enzyme in the transsulfuration pathway and serves as a marker of ciliated cells derived from the Müllerian tract. CTH plays a pivotal role in de novo cysteine synthesis, which is essential for glutathione (GSH) production and redox homeostasis. Using an array of molecular tools and cancer models, including in vivo studies, we demonstrated that CTH expression was induced under various stress conditions, such as exposure to endometriotic cyst content and hypoxia. This induction enables cell survival and creates a differentiation state manifested by CCOC that potentiates tumor progression and metastasis. In addition to regulating redox homeostasis, CTH enhances hypoxia inducible factor 1-alpha (HIF1α) expression, independently of hydrogen sulfide (HS) production. Re-expression of HIF1α in CTH KO cells fully restored metastatic capacity in in vivo models. Co-expression of CTH and HIF1α proteins was also observed in human CCOC samples. Importantly, targeting CTH in CCOC significantly reduced its metastatic potential in in vivo models and enhanced sensitivity to chemotherapy. These findings underscore that CTH is both a defining feature of CCOC and a promising therapeutic target, not only for CCOC patients but also for those with other CTH-expressing cancers. © 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.
Resistance mechanisms and clonal dynamics in mantle cell lymphoma treated with sequential BTKi and venetoclax therapy.
László T, Pinczés LI, Bátai B … +17 more , Varga L, Timár B, Gulyás A, Tárkányi I, Plander M, Nagy Z, Rajnics P, Egyed M, Molnár Z, Rottek J, Masszi A, Tamáska P, Szász R, Illés Á, Alpár D, Magyari F, Bödör C
J Pathol · 2025 Aug · PMID 40371810 · Full text
In recent years, targeted therapies have become the standard of care for refractory/relapsed mantle cell lymphoma (MCL). Although the mutational profile of MCL has been extensively studied, there is a lack of understandi...
In recent years, targeted therapies have become the standard of care for refractory/relapsed mantle cell lymphoma (MCL). Although the mutational profile of MCL has been extensively studied, there is a lack of understanding of resistance mechanisms and genetic factors that impact the response to novel treatments. Since patients relapsing on targeted treatment experience poor clinical outcomes, understanding the genetic foundation of resistance mechanisms in MCL is essential. In this study, we aimed to scrutinize the copy number profile and clonal dynamics of double-resistant MCL patients treated sequentially with Bruton's tyrosine kinase inhibitor (BTKi) and venetoclax using low-coverage whole genome sequencing (lcWGS). Samples obtained after systemic therapy showed more copy number alterations (CNAs) (p = 0.039; Wilcoxon) compared to samples collected before treatment initiation. Patients showing early progression on BTKi demonstrated CNAs affecting cytobands encompassing the coding regions of NOTCH1, TRAF2, BIRC2, BIRC3, and ATM. A deletion in chromosome 9p21.3 was identified in two out of three venetoclax-resistant patients. For patient MCL2, progressing on ibrutinib but showing venetoclax resistance, a 9p21.3 deletion was found throughout the disease course, with acquired SMARCA4-del(19)(p13.3-q13.11) and DLC1-del(8)(p23.2-q11.1) observed at relapse, highlighting their role in disease progression and therapy resistance. Using lcWGS, an innovative genome-wide approach, this study revealed novel putative primary and acquired resistance mechanisms in BTKi and venetoclax double-resistant MCL 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.
The TBXT rs2305089 SNP links the benign notochordal cell tumour and chordoma.
Usher I, O'Donnell P, Ligammari L … +6 more , Harder D, Brown W, Choi D, Cool P, Cottone L, Flanagan AM
J Pathol · 2025 Jul · PMID 40323130 · Full text
The aim of this research was to investigate the pathogenesis of the bone cancer chordoma and the role of the germline rs2305089 SNP in TBXT. Using medical imaging and genotyping studies, we observed that benign notochord...
The aim of this research was to investigate the pathogenesis of the bone cancer chordoma and the role of the germline rs2305089 SNP in TBXT. Using medical imaging and genotyping studies, we observed that benign notochordal cell tumours (BNCTs) were associated with chordomas and with the variant rs2305089 A-allele with enrichment of the AA genotype compared to controls. We engineered in vitro mesoderm models, representing notochord, which showed higher expression of TBXT and activation of its regulatory network in the presence of the variant A allele. Heterozygotes (GA) displayed enrichment of Wnt/β-catenin and epithelial mesenchymal transition pathways, faster cell migratory capacity, and altered expression of endoplasmic reticulum and intracellular transport mediators. WT lines (GG) were enriched for metabolic pathways and MTORC1 signalling, suggesting that rs2305089 genotype regulates notochord vacuoles during notochord regression. By leveraging patient-derived data and functional studies, we show that the variant rs2305089 A-allele predisposes to BNCTs and ultimately to chordomas. © 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.
Clinicopathological and molecular characterization of KRAS wild-type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in RAS pathway genes.
Toriyama K, Masago K, Shibata N … +12 more , Haneda M, Kuwahara T, Natsume S, Kobayashi S, Fujita Y, Sasaki E, Yamao K, Kawashima H, Shimizu Y, Hara K, Yatabe Y, Hosoda W
J Pathol · 2025 Jul · PMID 40317966 · Full text
Pancreatic ductal adenocarcinomas (PDACs) with wild-type KRAS constitute a small fraction of PDACs, and these tumors were recently shown to harbor frequent actionable oncogenic mutations and fusions. However, the clinico...
Pancreatic ductal adenocarcinomas (PDACs) with wild-type KRAS constitute a small fraction of PDACs, and these tumors were recently shown to harbor frequent actionable oncogenic mutations and fusions. However, the clinicopathological features of KRAS wild-type PDAC have not been well studied. Additionally, precancerous lesions occurring in patients with KRAS wild-type PDACs have rarely been characterized. Here, we investigated the clinicopathological characteristics and outcomes of 75 patients with KRAS wild-type PDAC. Molecular analyses were performed in 40 patients using targeted DNA and whole-exome sequencing and targeted RNA sequencing. We demonstrated that patients with metastatic PDAC with wild-type KRAS were younger (median 59.5 years) than those with mutated KRAS (median 67 years, p < 0.000055). The wild-type KRAS status was not a significant prognostic factor for metastatic disease. Molecularly, genes in the RAS pathway are frequently mutated or rearranged (46%, 16/35), including mutations in BRAF, NRAS, HRAS, EGFR, MAP2K1, FGFR1, FGFR3 and ERBB4 and fusions of FGFR2 (FGFR2::CCDC147, FGFR2::CAT, FGFR2::TXLNA), ALK (STRN::ALK, EML4::ALK), and BRAF (TRIP11::BRAF). Mismatch repair deficiency was identified in 10% (4/39) of patients. Potentially actionable alterations were identified frequently in KRAS wild-type PDACs (30%, 12/40), in which nontubular-type carcinomas were significantly enriched with actionable alterations compared with tubular adenocarcinomas [67% (6/9) versus 16% (5/31); p = 0.007]. Finally, we investigated the precursors of PDACs in 13 pancreatectomy specimens from patients with KRAS wild-type PDAC. We identified three pancreatic intraepithelial neoplasias (PanINs) and two intraductal papillary mucinous neoplasms (IPMNs) harboring oncogenic fusions of ALK and BRAF and driver mutations in BRAF and AKT1. This study suggests that in the context of unmutated KRAS, PDAC is driven by alternative oncogenic mutations or fusions of RAS pathway genes, which may be introduced during the early phase of tumorigenesis. © 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 'Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice'.
J Pathol · 2025 Jul · PMID 40317776 · Publisher ↗
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Comprehensive functional splicing analysis of non-canonical CNGB3 variants using in vitro minigene splice assays.
Rawnsley K, Weisschuh N, Kohl S … +1 more , Reuter P
J Pathol · 2025 Jul · PMID 40304364 · Full text
Variants in the CNGB3 gene, encoding the B3-subunit of the cone photoreceptor cyclic nucleotide gated channel, are a major cause of autosomal recessive achromatopsia, a rare inherited retinal disease. The mutation spectr...
Variants in the CNGB3 gene, encoding the B3-subunit of the cone photoreceptor cyclic nucleotide gated channel, are a major cause of autosomal recessive achromatopsia, a rare inherited retinal disease. The mutation spectrum of achromatopsia-associated CNGB3 variants comprises all types of mutations, including those that are straightforward to evaluate in molecular genetic diagnostics, such as frame-shifting, nonsense, and canonical splice site variants. Additionally, variants have been identified within splice regions outside the conserved ±1,2 splice site dinucleotides, making their potential impact on disease association challenging to interpret. This poses a major hurdle for clinical interpretation of causality between the patient's genotype and the proposed clinical diagnosis, but also for the inclusion of such patients into clinical trials for gene augmentation therapy, for which only patients with confirmed (likely) pathogenic CNGB3 variants are eligible. We here performed comprehensive genetic functional analysis of 21 candidate spliceogenic CNGB3 variants-15 reported and 6 novel variants-by means of in vitro minigene splice assays and cDNA analysis, and characterization of spliceogenic events by subcloning, Sanger-sequencing, and capillary fragment analysis. For 16 variants, an impact on splicing was confirmed, supporting the reclassification of 86% of variants of uncertain significance as likely pathogenic or pathogenic according to the ACMG/AMP guidelines. This reclassification enables the confirmation of patients' genotypes, both retrospectively and prospectively. © 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.
In-frame insertions of SOX10 are highly enriched and characterize a distinct transcriptomic profile in gastrointestinal schwannomas.
Lee PH, Huang SC, Lee JC … +15 more , Li SC, Tsai JW, Chang YM, Kao YC, Fan WL, Chang CD, Chen HC, Li CH, Hu CF, Liu TT, Wu PS, Nam MH, Yu SC, Wang JC, Huang HY
J Pathol · 2025 Jul · PMID 40272443 · Publisher ↗
Gastrointestinal schwannomas are molecularly and histologically distinct from their non-gastrointestinal counterparts, lacking NF2 alterations, although the primary drivers of these tumors are barely understood. A recent...
Gastrointestinal schwannomas are molecularly and histologically distinct from their non-gastrointestinal counterparts, lacking NF2 alterations, although the primary drivers of these tumors are barely understood. A recent study has identified SOX10 in-frame insertions in schwannomas, particularly in intracranial non-vestibular lesions, whereas their role in gastrointestinal schwannomas remains unexplored. Whole exome sequencing of 15 gastrointestinal and two non-gastrointestinal schwannomas revealed recurrent SOX10 in-frame insertions in 14 gastrointestinal cases (93%) without other nerve sheath tumor-related alterations, such as NF2 mutations or SH3PXD2A::HTRA1 fusions (~14% in non-gastrointestinal cases). The prevalence, mutation spectrum, and specificity of SOX10 insertions were validated using Sanger sequencing in a large cohort comprising 61 gastrointestinal and 98 non-gastrointestinal schwannomas, as well as 110 non-schwannomatous mesenchymal and melanocytic neoplasms. SOX10 insertions, occurring within or near the high mobility group box domain, were significantly enriched in gastrointestinal schwannomas (91.8%) compared with non-gastrointestinal cases (5.1%). The most common insertion, p.Y173_Q174insKY, was present in 86.9% of gastrointestinal schwannomas but absent in non-gastrointestinal cases. Another recurrent insertion, p.P175_R176insKYQP, was rare and exclusively found in non-gastrointestinal schwannomas (3/98), while all non-schwannomatous controls were SOX10-normal. SOX10-inserted schwannomas exhibited histologic features characteristic of gastrointestinal schwannomas, including a microtrabecular arrangement of Schwann cells, peripheral lymphoid cuffs, and a lack of encapsulation. Both SOX10-inserted and SOX10-normal schwannomas demonstrated diffuse SOX10 immunoreactivity. The SOX10-inserted group was significantly associated with gastrointestinal locations (p < 0.001), older patients (p < 0.001), fusion negativity (p < 0.001), and larger tumor size (p = 0.013). Gene expression profiling of 44 cases revealed distinct transcriptomic profiles between primarily SOX10-inserted and SOX10-normal groups, with the latter group being classifiable into fusion-poor and fusion-enriched sub-clusters. This study highlights the genetic heterogeneity of schwannomas and suggests that SOX10 insertions play a pivotal role in the tumorigenesis of gastrointestinal schwannomas, distinctly separating them from non-gastrointestinal counterparts and contributing to their unique molecular profile. © 2025 The Pathological Society of Great Britain and Ireland.
Comparative transcriptomics of salivary basal cell adenoma and adenocarcinoma sustain linear neoplastic evolution and intertumor heterogeneity: classification and biological implications.
Mitani Y, Al-Maghrabi H, Karpinets TV … +8 more , Relator RT, Hilder L, Chen IY, Goepfert RP, Bell D, Zhang J, Ferrarotto R, El-Naggar AK
J Pathol · 2025 Jul · PMID 40272378 · Full text
It remains uncertain whether basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland represent two distinct neoplasms or temporal stages of a single entity. The issue is central to reconciling...
It remains uncertain whether basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland represent two distinct neoplasms or temporal stages of a single entity. The issue is central to reconciling their shared phenotypic resemblance and protracted behavior with current pathologic classification. We conducted a transcriptomic analysis on a cohort of both pathologic forms and correlated the findings with the clinicopathologic features using RNA extracted from fresh frozen samples of 25 salivary basal tumors (five BCAs and 20 BCACs) and eight instances of metastatic basal cell carcinomas (BCCs) to parotid glands. Unsupervised analysis revealed shared and intertumoral transcriptome differences within and between BCA and BCAC and distinct segregation from metastatic dermal BCC. Transcriptomic profiling delineated two intermixed subgroups of salivary basal cell neoplasms (SBNs); SBN-I group enriched with adverse pathologic features and SBN-II that lacked any of these features except for a single case. The category with the most instances of adverse pathologic features (SBN-I) manifested upregulations of transcriptional factors linked to cell proliferation pathways (HOXB13, SOX21, MYB, and EN1 genes), while those lacking adverse pathologic features (SBN-II) demonstrated a high expression of the TFAP2B transcription- and differentiation-related pathways. Our transcriptomic findings support common neoplastic evolution and intertumoral heterogeneity of both pathologic forms of basal cell neoplasms and identify molecular pathways of potential biological and clinical significance. We therefore propose a nondeterministic designation of 'basal cell salivary neoplasms, noninvasive (adenoma)/invasive (adenocarcinoma)' as a platform that integrates conventional phenotypic classification and transcriptomic characteristics pending a classification consensus. © 2025 The Pathological Society of Great Britain and Ireland.
Nicotine-driven enhancement of tumor malignancy in triple-negative breast cancer via additive regulation of CHRNA9 and IGF1R.
Kuo YC, Chen CL, Lee KL … +5 more , Wang HF, Drew VJ, Lan PC, Ho YS, Huang YH
J Pathol · 2025 Jun · PMID 40244072 · Publisher ↗
Cigarette smoking is a significant risk factor for cancer development with complex mechanisms. This study aims to investigate the impact of nicotine exposure on the regulation of stemness- and metastasis-related properti...
Cigarette smoking is a significant risk factor for cancer development with complex mechanisms. This study aims to investigate the impact of nicotine exposure on the regulation of stemness- and metastasis-related properties via cholinergic receptor nicotinic alpha 9 subunit (CHRNA9) and insulin-like growth factor-1 receptor (IGF1R) and to evaluate their therapeutic potential in triple-negative breast cancer (TNBC). We performed Kaplan-Meier survival analysis of public databases and revealed that high expression of CHRNA9, IGF1R signaling molecules, and stemness genes was significantly associated with poor recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in TNBC samples. Additionally, we examined two patient cohorts to determine the clinical associations between the expression levels of different genes (n = 67) and proteins (n = 42) and showed a strong positive correlation between the expression levels of CHRNA9, IGF1R signaling molecules, and stemness markers POU5F1/NANOG in tumor tissues. We carried out nicotine treatment and knockdown of CHRNA9 and IGF1R in TNBC cells to identify the effects on stemness-related properties in vitro. Furthermore, primary and secondary metastatic in vivo animal models were examined using micro-computed tomography (μCT) screening and in situ hybridization with a human Alu probe to detect tumor cells. Nicotine was found to upregulate the expression of CHRNA9, POU5F1, and IGF1R, influencing stemness- and metastasis-related properties. Knockdown of CHRNA9 expression attenuated nicotine-induced stemness-related properties in a TNBC cell model. Furthermore, knockdown of IGF1R expression significantly alleviated nicotine/CHRNA9-induced stemness features and cancer cell metastasis in cell cultures and lung metastatic mouse models. These results demonstrate that nicotine triggers IGF1R signaling, thereby enhancing stemness-related properties, cell migration, invasion, and tumor metastasis, resulting in a poorer prognosis for patients with TNBC. These findings highlight IGF1R as a promising therapeutic target for reducing stemness and metastasis in TNBC patients exposed to environmental nicotine. © 2025 The Pathological Society of Great Britain and Ireland.
Activated immune infiltrates expand opportunities for targeted therapy in p53-abnormal endometrial carcinoma.
Martin SD, Thornton S, Chow C … +12 more , Milne K, de Barros JS, Morris KA, Leung S, Jamieson A, Nelson BH, Cochrane DR, Huntsman DG, Gilks CB, Hoang L, McAlpine JN, Zhang AW
J Pathol · 2025 Jul · PMID 40223796 · Full text
Tumor protein p53 mutated/abnormal (p53abn) endometrial carcinomas account for over 50% of deaths but comprise only 15% of all endometrial carcinomas. Most patients show limited response to standard-of-care chemotherapy...
Tumor protein p53 mutated/abnormal (p53abn) endometrial carcinomas account for over 50% of deaths but comprise only 15% of all endometrial carcinomas. Most patients show limited response to standard-of-care chemotherapy with or without radiotherapy, and only a minority of cases are amenable to targeted therapies like poly-ADP ribose polymerase (PARP) inhibitors and HER2-directed therapies. Recent immunotherapy clinical trials have demonstrated remarkable efficacy, not only in mismatch repair deficient (MMRd) tumors but also in a subset of mismatch repair-proficient (MMRp) tumors. However, the immune microenvironment and its relationship to other therapeutic targets in MMRp endometrial carcinoma remains poorly understood. Here, we characterize the immune microenvironment of p53abn endometrial carcinoma, the most clinically aggressive subtype of MMRp endometrial carcinoma, and correlate antitumor immune signatures with other targetable alterations. We accrued 256 treatment-naïve p53abn endometrial carcinomas and systemically profiled T-cell, B-cell, myeloid, and tumor-cell populations with multiplex immunofluorescence to assess the tissue localization and functional status of immune cells. Shallow whole-genome sequencing was performed on a subset of 126 cases. Patterns of immune infiltration were compared to survival outcomes and mutational signatures. Mixture modeling divided p53abn endometrial carcinoma into tumor-infiltrating lymphocyte (TIL)-rich and TIL-poor subsets. Over 50% of tumors were TIL-rich. TIL-rich cases overexpressed targetable immune evasion molecules and were associated with longer overall and disease-specific survival in multivariate analysis. This effect was particularly pronounced in advanced stage disease and in patients who did not receive adjuvant chemotherapy. TIL did not associate with homologous recombination deficient mutational signatures or HER2 amplification. Our findings demonstrate a biological rationale for immunotherapy in a substantial subset of patients with p53abn endometrial cancer and may help inform combination therapies with immune checkpoint inhibition, PARP inhibitors, and anti-HER2 agents. © 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.
Aberrant TERT expression: linking chronic inflammation to hepatocellular carcinoma.
Dong R, Najjar G, Günes C … +1 more , Lechel A
J Pathol · 2025 Jun · PMID 40213897 · Full text
Telomerase reverse transcriptase (TERT), the catalytic enzyme component of telomerase, plays multiple roles in cellular biology. Its canonical function is primarily associated with telomere maintenance and genomic stabil...
Telomerase reverse transcriptase (TERT), the catalytic enzyme component of telomerase, plays multiple roles in cellular biology. Its canonical function is primarily associated with telomere maintenance and genomic stability. In addition, several studies revealed critical non-canonical extra-telomeric functions of TERT in various cellular processes, including cell proliferation and survival, DNA damage response, transcription, signal transduction, and metabolic regulation, both in normal and in cancer cells. Notably, TERT is aberrantly upregulated in more than 80% of hepatocellular carcinoma (HCC) cases, making it an important target in liver cancer research. However, due to the diversity and complexity of TERT's functions in vivo, the precise mechanisms by which TERT contributes to the initiation and progression of HCC remain unclear. A recent study published in The Journal of Pathology using the Alb-Cre;TertTg mouse model and clinical HCC samples addresses the role of TERT in hepatocarcinogenesis. The study demonstrates that TERT promotes cell cycle progression and hepatocarcinogenesis by enhancing NF-κB promoter activity and facilitating the ubiquitination of p21. Notably, absence of functional p53 accelerates liver tumor development in TERT transgenic mice. These findings further underscore the critical role of TERT in inflammation-driven hepatocarcinogenesis and provide new insights into its underlying mechanisms. © 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.
BMP signalling in colorectal cancer: losing the yin to WNTs yang.
Clarkson E, Lewis A
J Pathol · 2025 Jul · PMID 40212011 · Full text
Colorectal cancer (CRC) is the third most common form of cancer globally, and arises from the hyperproliferation of epithelial cells in the intestine. The architecture and maintenance of these cells is governed by two ma...
Colorectal cancer (CRC) is the third most common form of cancer globally, and arises from the hyperproliferation of epithelial cells in the intestine. The architecture and maintenance of these cells is governed by two major signalling pathways working in a counter-gradient: the stem cell WNT signalling pathway, and the prodifferentiation bone morphogenetic protein (BMP) pathway. It has long been known that this WNT-BMP balance is disrupted in CRC, with hyperactive WNT signalling leading to increased proliferation of epithelial cells and tumour progression. BMP signalling, and its prodifferentiation effects, have increasingly become a focus for CRC research. Loss of BMP signalling, and that of its receptors, has been shown to increase WNT signalling and cancer stem cells in CRC. BMP signalling is further modulated through secreted BMP antagonists localised to the intestinal crypts, which create a niche ensuring that sustained WNT signalling can maintain stem-cell self-renewal capacity. A number of studies combine to demonstrate the effects of overexpression of these BMP antagonists, showing that hyperactivity of the stem-cell-supporting WNT signalling pathway ensues, leading to deregulation of the intestinal epithelium. Cellular hyperproliferation, the emergence of ectopic crypts, and an increase in stem cell numbers and characteristics are common themes, contributing to disrupted epithelial homeostasis, an increase in CRC risk and progression, and resistance to therapy. This review aims to compile the current knowledge on BMP antagonists, their role in CRC development, and how we can utilise this information for biomarker research and novel therapeutics. © 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.
Histone deacetylase 6 inhibition attenuates pathological cardiac hypertrophy by promoting autophagy through MAP1LC3B ubiquitination.
Yao J, Sun X, Chen Y … +5 more , Xu X, Feng J, Zhang M, Liu X, Shi X
J Pathol · 2025 Jun · PMID 40212005 · Publisher ↗
Cardiac hypertrophy is an adaptive response of the heart to pathological stimuli that may lead to cardiac dysfunction and heart failure. Histone deacetylase 6 (HDAC6) participates in the progression of multiple cardiovas...
Cardiac hypertrophy is an adaptive response of the heart to pathological stimuli that may lead to cardiac dysfunction and heart failure. Histone deacetylase 6 (HDAC6) participates in the progression of multiple cardiovascular diseases, including chronic hypertension, ischemic stroke, and acute cardiac injury. A delicate balance of autophagy regulates heart homeostasis, whereas dysregulated autophagy is involved in myocardial hypertrophy. However, whether HDAC6 participates in pathological cardiac hypertrophy by regulating autophagy remains unclear. In this paper, we report for the first time that HDAC6 is involved in isoproterenol (ISO)-induced pathological cardiac hypertrophy by interacting with and ubiquitinating MAP1LC3B. First, the expression level of HDAC6 was found to be increased in cardiac hypertrophy models induced by ISO. HDAC6 overexpression promoted the expression of hypertrophic genes and enhanced cell surface area. Conversely, HDAC6 inhibition attenuated ISO-induced hypertrophic responses. Mechanistically, HDAC6 promoted hypertrophic responses by negatively regulating autophagy. Furthermore, HDAC6 interacted with MAP1LC3B and mediated its monoubiquitination, thereby contributing to reduced MAP1LC3B levels and impaired autophagy. Inhibition of HDAC6 activity in mice abrogated the hypertrophic effects of ISO by restoring MAP1LC3B expression. In summary, our data demonstrate that HDAC6 participates in ISO-induced cardiac hypertrophy by limiting the availability of MAP1LC3B and suppressing autophagy. © 2025 The Pathological Society of Great Britain and Ireland.
Utilizing aptamers in targeted protein degradation strategies for disease therapy.
Li L, Xie S, Zhou J … +1 more , Ran J
J Pathol · 2025 Jun · PMID 40207978 · Publisher ↗
Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy, offering the potential to reduce disease-causing proteins that have traditionally been challenging to target using conventional small mo...
Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy, offering the potential to reduce disease-causing proteins that have traditionally been challenging to target using conventional small molecules. Despite significant advances made with TPD technologies, challenges such as high molecular weight, difficulties in identifying suitable ligands, suboptimal absorption, and metabolic instability remain unresolved. Recently, aptamers - single-stranded DNA or RNA oligonucleotides known for their high specificity and affinity for protein targets - have introduced novel opportunities to expand the scope of TPD, a strategy now referred to as aptamer-based TPD. This approach has demonstrated considerable promise in treating various diseases, such as cancer and ocular disorders. For example, an aptamer-proteolysis-targeting chimera (PROTAC) conjugate (APC) improved tumor targeting and reduced toxicity in a breast cancer model, and a vascular endothelial growth factor-degrading (VED)-lysosome-targeting chimera (LYTAC) molecule effectively inhibited abnormal vascular growth in vascular retinal diseases. These examples highlight the practical relevance and potential in advancing drug discovery efforts. In this review we provide a comprehensive overview of the latest advances in aptamer-based TPD strategies, including proteolysis-targeting and lysosome-targeting chimeras, emphasizing their applications, potential therapeutic benefits, as well as the challenges that must be overcome to fully harness their clinical potential. © 2025 The Pathological Society of Great Britain and Ireland.
A Tc1- and Th1-T-lymphocyte-rich tumor microenvironment is a hallmark of MSI colorectal cancer.
Huang Z, Mandelkow T, Debatin NF … +28 more , Lurati MCJ, Ebner J, Raedler JB, Bady E, Müller JH, Simon R, Vettorazzi E, Menz A, Möller K, Gorbokon N, Sauter G, Lennartz M, Luebke AM, Höflmayer D, Krech T, Lebok P, Fraune C, Hinsch A, Jacobsen F, Marx AH, Steurer S, Minner S, Dum D, Weidemann S, Bernreuther C, Clauditz TS, Burandt E, Blessin NC
J Pathol · 2025 Jun · PMID 40181205 · Full text
Microsatellite instability is a strong predictor of response to immune checkpoint therapy and patient outcome in colorectal cancer. Although enrichment of distinct T-cell subpopulations has been determined to impact the...
Microsatellite instability is a strong predictor of response to immune checkpoint therapy and patient outcome in colorectal cancer. Although enrichment of distinct T-cell subpopulations has been determined to impact the response to immune checkpoint therapy and patient outcome, little is known about the underlying changes in the composition of the immune tumor microenvironment. To assess the density, composition, degree of functional marker expression, and spatial interplay of T-cell subpopulations, 79 microsatellite instable (MSI) and 1,045 microsatellite stable (MSS) colorectal cancers were analyzed. A tissue microarray and large sections were stained with 19 antibodies directed against T cells, antigen-presenting cells, functional markers, and structural proteins using our BLEACH&STAIN multiplex-fluorescence immunohistochemistry approach. A deep learning-based framework comprising >20 different convolutional neuronal networks was developed for image analysis. The composition of Type 1 (T-bet), Type 2 (GATA3), Type 17 (RORγT), NKT-like (CD56), regulatory (FOXP3), follicular (BCL6), and cytotoxic (CD3CD8) or helper (CD3CD4) T cells showed marked differences between MSI and MSS patients. For instance, the fraction of Tc1 and Th1 was significantly higher (p < 0.001 each), while the fraction of Tregs, Th2, and Th17 T cells was significantly lower (p < 0.05) in MSI compared to MSS patients. The degree of TIM3, CTLA-4, and PD-1 expression on most T-cell subpopulations was significantly higher in MSI compared to MSS patients (p < 0.05 each). Spatial analysis revealed increased interactions between Th1, Tc1, and dendritic cells in MSI patients, while in MSS patients the strongest interactions were found between Tregs, Th17, Th2, and dendritic cells. The additional analysis of 12 large sections revealed a divergent immune composition at the invasive margin. In summary, this study identified a higher fraction of Tc1 and Th1 T cells accompanied by a paucity of regulatory T-cell, Th17, and Th2 T-cell subpopulations, along with a distinct interaction profile, as a hallmark of MSI compared to MSS colorectal cancers. © 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.
Histologic and molecular features shared between antibody-mediated rejection of kidney allografts and chronic histiocytic intervillositis support common pathogenesis.
Albersammer L, Leon J, Martinovic J … +16 more , Dagobert J, Lebraud E, Bessières B, Loeuillet L, Eloudzeri M, Vivanti AJ, Dumery G, Marchaudon V, Antal C, Korganow AS, Quibel T, Costedoat-Chalumeau N, Tsatsaris V, Benachi A, Zuber J, Rabant M
J Pathol · 2025 Jun · PMID 40178007 · Full text
Chronic histiocytic intervillositis (CHI) is an inflammatory condition of the placenta, characterised by an abnormal, mainly macrophagic infiltrate within the intervillous space. Recent research suggests that CHI results...
Chronic histiocytic intervillositis (CHI) is an inflammatory condition of the placenta, characterised by an abnormal, mainly macrophagic infiltrate within the intervillous space. Recent research suggests that CHI results from a 'maternal-foetal rejection' mechanism, because at least some CHI cases fulfil the criteria for antibody-mediated rejection (AMR) of kidney allografts according to the Banff classification [i.e. presence of anti-human leukocyte antigen (HLA) paternal antibodies activating the complement or foetal-specific antibodies (FSA), a macrophage-rich infiltrate, and positive C4d immunostaining]. To gain further insights into CHI pathogenesis, we aimed to refine the phenotype of the inflammatory infiltrate using a multiplex immunofluorescence technique and to compare the mRNA signatures between CHI and AMR of kidney allografts. Twelve patients with C4d+ FSA+ CHI were included in the study and compared to a control group of 5 patients without inflammatory lesions on placental examination. We developed a multiplex immunofluorescence panel to identify CD4+ and CD8+ T lymphocytes, CD68+/CD206- and CD68+/CD206+ macrophages, and NK cells in the villi and intervillous space. Molecular signatures were studied using NanoString® technology and the B-HOT panel recommended by the Banff classification for kidney allografts. Multiplex immunofluorescence revealed that the infiltrate in the intervillous space was mainly composed of CD68+/CD206- macrophages as well as a higher proportion of CD8+ lymphocytes in patients with CHI compared to controls. Densities of NK cells and CD4 T cells were very low. Molecular signatures showed an overexpression of HLA class II genes, an IFN-γ signature, and cytokine gene sets in C4d+ FSA+ CHI patients, also involved in kidney AMR. These results reinforce the paradigm of maternal-foetal rejection. © 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.
MicroRNA-371-373 cluster and methylome analysis suggests that a subset of 'somatic-type' malignancies arising in germ cell tumors may originate in yolk sac tumor components.
Lobo J, Tavares NT, Fonseca D … +15 more , Jerónimo C, Henrique R, Wyvekens N, Yang Y, Snuderl M, Maclean F, Gordetsky J, Fletcher CD, Hirsch MS, Hornick JL, Idrees MT, Collins K, Warmke L, Ulbright TM, Acosta AM
J Pathol · 2025 Jun · PMID 40152072 · Full text
Somatic-type malignancies (SMs) arising in germ cell tumors (GCTs) are aggressive neoplasms resistant to systemic treatment. Most are diagnosed in metastatic sites after chemotherapy; however, they have also been well-do...
Somatic-type malignancies (SMs) arising in germ cell tumors (GCTs) are aggressive neoplasms resistant to systemic treatment. Most are diagnosed in metastatic sites after chemotherapy; however, they have also been well-documented in primary testicular GCTs. Historically, SMs were thought to originate in components of teratoma that acquire molecular alterations equivalent to those that characterize their true somatic counterparts. However, recent studies have shown that SMs typically lack the hallmark molecular alterations seen in similar somatic tumors. Additionally, clinicopathologic and molecular data suggest that a subset may derive from yolk sac tumor (YST) rather than teratoma. In this study, we evaluated the relationship between conventional histological types of GCTs and SMs by comparing expression of microRNA (miR)-371-373 and genomic methylation profiles. A total of 96 samples (including multiple paired conventional GCT-SM samples from individual tumors) were assessed for miR-371-373 expression by RT-qPCR and genomic DNA methylation using a clinically validated assay. Expression of miR-371-373 was higher in conventional GCTs than in SMs (considered as a single category encompassing all histological subtypes). However, miR-371-373 expression was heterogeneous among SMs, with significantly higher levels in sarcomatoid YST (SYST) and glandular neoplasms than in other SMs. Genomic DNA methylation analysis showed that SMs (considered as a single category) did not form a distinct cluster. Instead, they grouped into multiple clusters that did not show perfect correspondence with histology and often included conventional GCTs. Genome-wide methylation assessment showed a higher abundance of hypermethylated regions in SMs than in conventional GCTs. Analysis of paired conventional GCT and 'somatic-type' components that did not meet size criteria for SMs dissected from individual tumors demonstrated separation according to histology, suggesting that epigenetic processes play a role in the transition from conventional GCT to 'somatic-type' phenotypes. Gene-level and pathway-level analyses identified MAPK/RAS signaling, mitosis/proliferation, differentiation towards neural tissue/neuroectoderm, epithelial-to-mesenchymal transition, and DNA repair as key differentially regulated processes in components with somatic-type histology, suggesting mechanisms of progression from conventional to 'somatic' phenotypes in GCT. These results support the hypothesis that a subset of SMs derive from YST and suggest that some subtypes (such as SYST) may represent 'intermediate' phenotypes. Additionally, analysis of differentially methylated promoter regions in SM identified genes and biologic processess that may underlie 'somatic tranformation' in GCTs. © 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.
Multi-omics analyses reveal distinct molecular characteristics and transformation mechanisms of stage I-III micropapillary lung adenocarcinoma.
Qu Y, Feng X, Chen H … +9 more , Tan F, Shao A, Pang J, Xue Q, Zheng B, Zheng W, Ou Q, Gao S, Shao K
J Pathol · 2025 Jun · PMID 40151900 · Publisher ↗
The micropapillary (MIP) pattern is a high-grade histological subtype of lung adenocarcinoma (LUAD) with poor prognosis. In this study, surgically resected tumor samples from 101 patients with stage I-III MIP-LUAD (MIP ≥...
The micropapillary (MIP) pattern is a high-grade histological subtype of lung adenocarcinoma (LUAD) with poor prognosis. In this study, surgically resected tumor samples from 101 patients with stage I-III MIP-LUAD (MIP ≥30%) were microdissected to separate MIP components from non-MIP components, all of which underwent RNA and DNA whole-exome sequencing (WES). The genomic and transcriptomic landscapes of MIP and non-MIP components within MIP-enriched tumor tissues demonstrated remarkable similarities, notably marked by high epidermal growth factor receptor (EGFR) alteration frequencies. However, when compared to MIP-naïve LUAD tissues, MIP components showed higher chromosomal instability and revealed 18 enriched alterations, encompassing EGFR mutations, EGFR amplifications, and CDKN2A/CDKN2B deletions, which all linked to upregulation of cell proliferation pathways and downregulation of immune pathways. Shared mutations were observed in 97.8% (91/93) of patients with paired DNA WES data for MIP and non-MIP components within the same tissues, suggesting a common origin. The recurrence-free survival analysis identified MACF1, PCLO, ADGRV1, and Fanconi Anemia pathway mutations as negative indicators. In all, we conducted an in-depth analysis of the molecular characteristics and transformation mechanisms of MIP-LUAD, employing microdissection techniques to investigate the genomic and transcriptomic levels within a substantial cohort, providing insights for precision medicine of this aggressive cancer subtype. © 2025 The Pathological Society of Great Britain and Ireland.
Phosphodiesterase 5 inactivation in vascular smooth muscle cells aggravates aortic aneurysm and dissection.
Feng Y, Xue Y, Feng X … +13 more , Li Z, Ren L, Guo W, Hou Y, Shu T, Zhang W, Yang Y, Zhou Y, Song K, Xiong J, Liu B, Wang J, Zhao H
J Pathol · 2025 Jun · PMID 40145405 · Publisher ↗
Aortic aneurysm and dissection (AAD) are vascular disorders with high mortality. Previous evidence has suggested an elevated risk of AAD associated with the use of phosphodiesterase 5A (PDE5A) inhibitors. PDE5A, a cGMP-h...
Aortic aneurysm and dissection (AAD) are vascular disorders with high mortality. Previous evidence has suggested an elevated risk of AAD associated with the use of phosphodiesterase 5A (PDE5A) inhibitors. PDE5A, a cGMP-hydrolyzing enzyme, is enriched in vascular smooth muscle cells (SMCs), but the role of SMC-specific PDE5A in the pathogenesis of AAD is still unclear. In this study, PDE5A expression in human and mouse aortic tissues was analyzed by single-cell RNA sequencing (scRNA-seq), western blotting, immunofluorescence, and immunohistochemistry staining. SMC-specific PDE5A knockout (PDE5A) and PDE5A-overexpressing (PDE5A) mice were constructed and utilized, along with an AAD mouse model induced by a high-fat diet and angiotensin II (Ang II) infusion. In vivo imaging and histological analyses were performed to assess aortic pathologies. PDE5A expression was reduced in human and mouse AAD aortic tissues, primarily in SMCs. Pharmacological inhibition or genetic knockout of PDE5A in SMCs exacerbated aortic wall dilatation and elastin fiber degradation, increasing AAD incidence. In contrast, the AAD phenotype was rescued in challenged PDE5A mice. Mechanistically, PDE5A expression influenced myosin light chain (MLC) phosphorylation, a key regulator of SMC contractility. In AAD tissues from PDE5A mice, increased cGMP-dependent protein kinase (PKG) activation and decreased MLC phosphorylation indicate enhanced aortic relaxation. In conclusion, our findings suggest that PDE5A downregulation or inhibition plays a causative role in exacerbating AAD likely by potentiating cGMP/PKG-mediated aortic SMC relaxation. Our findings highlight the need for caution in the clinical use of PDE5 inhibitors in patients at risk of aortic diseases. © 2025 The Pathological Society of Great Britain and Ireland.
A breast cancer PDX collection enriched in luminal (ER) tumors and young premenopausal patients to identify new therapeutic strategies for high-risk patients.
Defilippi P, Nigrelli F, Arina P … +2 more , Taverna D, Salemme V
J Pathol · 2025 Jun · PMID 40145404 · Full text
Breast cancer includes a group of neoplasms originating from mammary gland epithelial cells caused by a variety of genetic alterations, with different responses to treatments and outcomes. In clinical practice, estrogen...
Breast cancer includes a group of neoplasms originating from mammary gland epithelial cells caused by a variety of genetic alterations, with different responses to treatments and outcomes. In clinical practice, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression guides the distinction between luminal A (ER, PR, HER2), luminal B (ER, PR, HER2), and triple-negative (ER, PR, HER2), each with a distinct biological behavior and clinical and therapeutic implications. Approximately 11% of breast cancers are diagnosed in young premenopausal women aged 20-49 years. Patient-derived xenografts (PDXs) offer a powerful solution to integrate personalized medicine and novel therapeutic agents. Dr Belletti's group recently developed a PDX biobank composed of 26 PDX lines highly enriched in luminal A and B and young premenopausal breast cancer patients. The bank faithfully recapitulates the characteristics of the original tumors. A major focus of their research was to exploit these PDXs to assess the resistance to CDK4/6 inhibitors (CDK4/6i), which are critical in managing advanced luminal breast cancers. Their effort addresses a significant gap in existing PDX models, which are limited for these patient subgroups, thereby enabling deeper insights into tumor biology and therapeutic responses in these understudied populations. © 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.
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