Myriam Sévigny

Cancer-associated fibroblasts (CAFs) promote tumorigenesis and represent potential therapeutic targets, highlighting the need for precise understanding of CAF heterogeneity. In colorectal cancer (CRC), CAF subsets and nomenclature vary widely, and many studies overlook the diversity of normal colon fibroblasts that shapes tumor mesenchyme. Here, we combine large-scale single-cell RNA-sequencing analysis with spatial validation and functional assays to construct a comprehensive reference map of human normal colon fibroblasts and mesenchymal subsets, guided by the well-characterized mouse colon. We define three major fibroblast populations, subepithelial myofibroblasts (SEMFs), mucosa-associated fibroblasts (MAFs), and submucosa-associated fibroblasts (SAFs), and characterize a previously underexplored muscle-embedded interstitial fibroblast (MIF) population. This reference enabled mapping of CRC-specific changes, revealing four cancer-specific CAF subsets, including inflammatory CAFs (iCAFs), matrix CAFs (mCAFs), and two precursor populations (pre-CAFs). We also identify robust CRC CAF markers including CTHRC1, infer transcriptional regulators, and define distinct developmental trajectories driving iCAF and mCAF activation. Together, our study provides a spatially and transcriptionally resolved reference map of fibroblasts in the normal colon and CRC, enabling mechanistic studies and informing CAF-targeted therapies.

Peutz‐Jeghers syndrome (PJS) is associated with early‐onset gastrointestinal polyposis caused by hereditary inactivating pathogenic variants in the tumor suppressor gene STK11 (LKB1). Due to lack of prophylactic therapies, management of PJS polyps requires frequent surveillance. Interestingly, studies in mouse models have revealed that stromal cells drive the polyp formation, but detailed understanding of the cell types and interactions involved has been lacking. Using single‐cell RNA sequencing of PJS mouse model polyps, we here identify a polyp‐enriched crypt top fibroblast (pCTF) cluster characterized by a transcriptional signature also enriched in PJS patient polyps. The pCTF signature was also noted in primary fibroblasts in vitro following acute STK11 loss. Targeted deletion of Stk11 in crypt top fibroblasts using Foxl1‐Cre led to upregulation of the pCTF signature genes and later to polyposis. pCTFs displayed similarity to inflammation‐associated fibroblasts, and polyposis was exacerbated by inflammation. Cell–cell communication analysis identified interleukin 11 (IL‐11) as a potential pCTF inducer, and consistent with this, IL‐11 was required for fibroblast reprogramming toward pCTFs following STK11 loss. Importantly, a neutralizing IL‐11 antibody efficiently reduced polyp formation in a PJS model indicating a key, targetable role for IL‐11 in polyp development. Together the results characterize pCTFs as a PJS polyp‐enriched fibroblast subset and identify IL‐11 as a key mediator of fibroblast reprogramming and a potential therapeutic target in PJS. © 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.

Background: Papillary thyroid cancer (PTC) is the predominant subtype of thyroid cancer ( THCA ), and it can cluster in families with an autosomal dominant (AD) inheritance pattern. The aim of this study was to identify novel genes and mechanisms underlying PTC susceptibility. Methods: Our previous investigation of 17 AD PTC families led us to conduct a deeper analysis on one family (Family Q) with whole-genome sequencing data from 3 PTC-affected individuals. In addition, 323 sporadic THCA cases from Avatar data and 12 familial adenomatous polyposis (FAP) individuals with secondary THCA were screened for pyruvate dehydrogenase phosphatase regulatory ( PDPR ) variants. CRISPR-Cas9 was used to create PDPR-deficient THCA (TPC1) and transformed normal thyroid cell lines (N-Thyori3-1) to study the metabolic consequences of PDPR loss. Results: We found truncating PDPR splice donor variants (NM_017990.4:c.361 + 1G>C) in all affected PTC Family Q members, and another PDPR splice donor variant (NM_017990.4:c.443 + 1G>C) in a sporadic PTC case. In addition, an ultra-rare missense variant was found in an FAP-PTC patient. The PDPR-deficient cells presented with elevated phosphorylation of pyruvate dehydrogenase and altered glucose metabolism, implying that PDPR plays an essential part in regulating glucose metabolism in thyroid cells. Conclusions: Our finding of novel truncating germline variants in PDPR in Family Q and additional cohorts suggests a role for PDPR loss in PTC predisposition. Also, somatic and RNA sequencing from the thyroid carcinoma (Firehouse Legacy) data showed that PDPR gene expression is much lower in THCA tumor tissue compared with matching normal tissue. Thus, PDPR appears to have a loss of function effect on THCA tumorigenesis.