Biology subjects

Chanez, B.

Publications and source records attributed to Chanez, B..

4 recordsLinked to original sources

bioRxiv2026

Transcriptomic FOLFIRINOX sensitivity signatures stratify overall survival and reveal directional reclassification after neoadjuvant FOLFIRINOX in borderline resectable and locally advanced pancreatic cancer

Background: Transcriptomic FOLFIRINOX-component sensitivity signatures have been clinically evaluated in resected and advanced PDAC, but their relevance and longitudinal stability in the neoadjuvant BR/LA setting are unknown. Patients and methods: We retrospectively studied 77 patients with borderline resectable or locally advanced PDAC treated with neoadjuvant FOLFIRINOX followed by resection. Pretreatment sensitivity to 5-fluorouracil, oxaliplatin and irinotecan was determined using previously developed locked transcriptomic classifiers and integrated into a regimen-level FOLFIRINOX classification. The primary molecular cohort comprised 53 patients whose pretreatment biopsies had [≥]10% tumour cellularity. Cox models assessed associations with survival. Longitudinal changes were assessed in 35 paired tumours. Results: Thirty-one pretreatment tumours were classified as FOLFIRINOX-sensitive (FFX-Sens), and 22 were not classified as FOLFIRINOX-sensitive (FFX-Res). FFX-Sens status was associated with longer overall survival (OS; hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.25-0.93; p=0.029). In the complete-case model adjusted for baseline carbohydrate antigen 19-9 (CA19-9) and tumour size (n=50), the association with OS persisted (adjusted HR 0.47, 95% CI 0.23-0.96; p=0.037), whereas the adjusted association with disease-free survival was not statistically significant (adjusted HR 0.55, 95% CI 0.28-1.10; p=0.090). Among paired tumours, 15 changed from FFX-Sens to FFX-Res and four in the opposite direction (exact McNemar p=0.019). The OS association also persisted after adjustment for postoperative pathological factors (adjusted HR 0.40; p=0.015). Conclusions: Pretreatment FOLFIRINOX sensitivity was associated with OS under neoadjuvant FOLFIRINOX, while matched pretreatment and residual-tumour analyses revealed significant directional reclassification after treatment. These findings extend the clinical evaluation of validated drug-specific FOLFIRINOX sensitivity classifiers to the neoadjuvant setting and provide a longitudinal assessment of their stability during treatment. They support prospective evaluation of both pretreatment stratification and molecular reassessment of residual disease.

cancer biology↗

bioRxiv2026

Co-translational O-glycosylation driven by GALNTs spatial reprogramming fosters pancreatic cancer growth

Signal-driven relocation of GalNAc-transferases (GALNTs) from the Golgi to the ER, termed GALA, promotes tumour growth, but its effects on glycosylation are unclear. Unlike N-glycosylation, which is co-translational, O-glycosylation initiates post-translationally in the Golgi. Here we show that GALA subverts this arrangement in pancreatic ductal adenocarcinomas (PDAC) and in murine pancreatic tumours, where it stimulates growth. Quantitative glycoproteomics on a cellular model reveals a substantial expansion of the O-glycoproteome, consisting in thousands of sites across hundreds of proteins, ER-resident proteins, cell-surface receptors, secreted factors, and extracellular matrix components. Profiling of murine tumours and patient-derived xenografts confirms widespread activation and cross-species conservation of glycosylation patterns. Structural analysis reveals that GALA-specific residues have solvent accessibility as low as N-glycosylation sites, and below Golgi O-glycosylation or phosphorylation sites, indicating that ER O-glycosylation occurs co-translationally. By inverting the normal temporal sequence of folding and glycosylation, cancer cells generate alternative glycoforms that foster tumour growth.

cancer biology↗

bioRxiv2026

Circulating colorectal tumor cells remodel their surfaceome to increase their viability and metastatic potential in the bloodstream

Circulating tumor cells (CTCs) are the potential seeds of distant metastases; however, little is known about how they survive in the bloodstream. Using a large cohort of colorectal cancer (CRC) patients, we found that the pseudokinase receptor PTK7 is highly expressed in primary tumors and metastatic lesions. Consistent with previous reports, high PTK7 expression is associated with reduced disease-free survival and increased metastatic dissemination. Surprisingly, PTK7 is absent from most CTCs and undergoes a cell-autonomous ONtumor/OFFCTC/ONmetastasis switch that can be recapitulated in a xenografted mouse model, in in vitro systems, and a fluidic platform. PTK7-negative cancer cells exhibit increased expression of YAP1-driven genes, senescence-like features, and enhanced resistance to hemodynamic stress following loss of cell-cell and cell-matrix adhesion. This adaptive phenotype depends on metalloproteases, notably ADAM17, whose cleavage activity remodels the CTCs surfaceome. Functionally, the PTK7 OFFCTC state confers enhanced metastatic potential in vivo, and can be pharmacologically suppressed using metalloprotease inhibitors. Collectively, our findings identify a reversible, cell-autonomous, protease-driven surfaceome remodeling program that enables metastatic adaptation during hematogenous dissemination. Highlights / statement of significanceBy investigating potential markers for circulating colorectal tumor cells with strong metastatic potential, we describe a reversible and cell-autonomous remodeling of the circulating tumor cell surfaceome in patients that confers resistance to anoikis and stress induced by entry into the bloodstream. One Sentence SummaryThe dynamic regulation of PTK7 serves as a surrogate marker for tumor cell plasticity, aggressiveness, survival in the bloodstream, and efficiency in forming metastases. Trial registrationCTC colon Cohort: registered on https://ClinicalTrials.gov identifier NCT03256084; date of registration 2017-07-17 B-Org cohort: registered on https://ClinicalTrials.gov NCT05384184; date of registration 2019-06-06 Ethics statement for animal experimentsStudies on animals were conducted in accordance with the current ethical standards of the European Community (Directive 2010/63/EU), the Ethics Committee for Animal Experimentation (CEEA#14) and the French Ministry of Higher Education and Research, which approved and authorized the entire procedure described in this paper (project number APAFIS #35294).

cancer biology↗

bioRxiv2024

A common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice

ObjectiveGenome wide association studies have identified an exon 6 CTRB2 deletion variant that associates with increased risk of pancreatic cancer. To acquire evidence on its causal role, we developed a new mouse strain carrying an equivalent variant in Ctrb1, the mouse orthologue of CTRB2. DesignWe used CRISPR/Cas9 to introduce a 707bp deletion in Ctrb1 encompassing exon 6 (Ctrb1{Delta}exon6). This mutation closely mimics the human deletion variant. Mice carrying the mutant allele were extensively profiled at 3 months to assess their phenotype. ResultsCtrb1{Delta}exon6 mutant mice express a truncated CTRB1 that accumulates in the ER. The pancreas of homozygous mutant mice displays reduced chymotrypsin activity and total protein synthesis. The histological aspect of the pancreas is inconspicuous but ultrastructural analysis shows evidence of dramatic ER stress and cytoplasmic and nuclear inclusions. Transcriptomic analyses of the pancreas of mutant mice reveals acinar program down-regulation and increased activity of ER stress-related and inflammatory pathways. Heterozygous mice have an intermediate phenotype. Agr2 is one of the most up-regulated genes in mutant pancreata. Ctrb1{Delta}exon6 mice exhibit impaired recovery from acute caerulein-induced pancreatitis. Administration of TUDCA or sulindac partially alleviates the phenotype. A transcriptomic signature derived from the mutant pancreata is significantly enriched in normal human pancreas of CTRB2 exon 6 deletion variant carriers from the GTEx cohort. ConclusionsThis mouse strain provides formal evidence that the Ctrb1{Delta}exon6 variant causes ER stress and inflammation in vivo, providing an excellent model to understand its contribution to pancreatic ductal adenocarcinoma development and to identify preventive strategies. SUMMARY BOX What is already known about this subject?- CTRB2 is one of the most abundant proteins produced by human pancreatic acinar cells. - A common exon 6 deletion variant in CTRB2 has been associated with an increased risk of pancreatic ductal adenocarcinoma. - Misfolding of digestive enzymes is associated with pancreatic pathology. What are the new findings?- We developed a novel genetic model that recapitulates the human CTRB2 deletion variant in the mouse orthologue, Ctrb1. - Truncated CTRB1 misfolds and accumulates in the ER; yet, mutant mice display a histologically normal pancreas at 3 months age. - CTRB1 and associated chaperones colocalize in the ER, the cytoplasm, and the nucleus of acinar cells. - Transcriptomics analysis reveals reduced activity of the acinar program and increased activity of pathways involved in ER stress, unfolded protein response, and inflammation. - Mutant mice are sensitized to pancreatic damage and do not recover properly from a mild caerulein-induced pancreatitis. - TUDCA administration partially relieves the ER stress in mutant mice. How might it impact on clinical practice in the foreseeable future?- The new mouse model provides a tool to identify the mechanisms leading to increased pancreatic cancer risk in CTRB2 exon 6 carriers. - The findings suggest that drugs that cause ER stress relief and/or reduce inflammation might provide preventive opportunities.

cancer biology↗