Biology subjects

Villenet, C.

Publications and source records attributed to Villenet, C..

5 recordsLinked to original sources

bioRxiv2026

Predicting Head and Neck Squamous Cell Carcinoma outcomes using long-term Patient-Derived Tumor Organoids

Head and neck squamous cell carcinoma (HNSCC) remains associated with substantial morbidity and a 5-year overall survival rate of approximately 60%, reflecting persistent radio- and chemo-resistance and the lack of effective precision medicine strategies. Patient-Derived Tumor Organoids (PDTO) constitute promising functional models that may predict individual treatment response. In this study, we generated PDTO from surgically resected HNSCC of the oral cavity, oropharynx, larynx, and hypopharynx. A total of 20 long-term PDTO lines were established, maintaining growth over seven passages and successfully cryopreserved, capturing the molecular and clinical diversity of the patient cohort. These PDTO faithfully recapitulated histological features, major tumor marker expression, and the genomic and transcriptomic landscapes of their tumors of origin, with stability over time. Functional assays revealed heterogeneous responses to cisplatin and X-rays. Importantly, in vitro sensitivity of PDTO was associated with clinical outcome of patients at 24 months. Cisplatin response of PDTO predicted prognosis with 66.7% sensitivity and 100% specificity, while X-ray response showed 91.7% sensitivity and 75% specificity. Notably, all patients whose PDTO were classified as resistant to both cisplatin and X-rays experienced relapse and/or death within 24 months. Collectively, the successful long-term expansion and cryopreservation of HNSCC PDTO establish a stable and scalable preclinical resource that captures the molecular and clinical heterogeneity of the disease. This biobank provides a valuable platform for mechanistic studies and for the evaluation of innovative therapeutic strategies. This cohort represents one of the largest clinically annotated HNSCC PDTO collections to date, demonstrating a robust association between PDTO response to cisplatin and X-rays and patient prognosis. These findings support the predictive potential of PDTO-based functional assays and argue for their integration into standardized, rapid, and miniaturized precision oncology workflows for HNSCC.

cancer biology↗

bioRxiv2025

Oncogenic mutations convert MET from a pro-apoptotic tumor suppressor to an oncogenic driver

Dependence receptors can exert both oncogenic and tumor-suppressive activities. In cancers, downregulation of dependence receptors or overexpression of their ligands are well-established mechanisms that drive tumor progression. However, direct genetic alterations abolishing the pro-apoptotic function of dependence receptors have not been documented so far. MET, a receptor tyrosine kinase classically viewed as an oncogene, has also been proposed to act as a dependence receptor through its caspase-mediated cleavage, but whether this property impacts tumorigenesis remained unknown. In [~]3% of lung adenocarcinomas, MET mutations leading to exon 14 skipping (METex14Del) remove both the caspase site and the adjacent CBL-binding motif, thereby preventing generation of the pro-apoptotic p40MET fragment. METex14Del promotes sustained signaling, enhanced invasion, apoptosis resistance, and tumor growth in HGF-humanized mice. Genome editing revealed that combined --but not individual-- mutations of the caspase and CBL sites phenocopy METex14Del. Moreover, inducible re-expression of p40MET in METex14Del-expressing cells restored apoptosis and suppressed tumor formation. Altogether, our findings identify MET exon 14 skipping as the first oncogenic mutation that drives tumorigenesis by abolishing the tumor-suppressive pro-apoptotic function of a dependence receptor, thereby redefining the oncogenic potential of MET.

cancer biology↗

bioRxiv2025

Long-term patient-derived ovarian cancer organoids closely recapitulate tumor of origin and clinical response

There is an urgent need of precision medicine for ovarian cancer patients to identify patients who respond to chemotherapy and PARP inhibitors, a therapy targeting homologous recombination deficiency (HRD). Here we established a panel of 37 long-term patient-derived tumor organoids (PDTO) models of various histological subtypes from 224 patients and demonstrated that they mimic the histological and molecular characteristics of original tumors. Screening of chemotherapeutic drugs showed that PDTO exhibit heterogeneous responses, and that response of PDTO from high-grade serous ovarian carcinoma to carboplatin recapitulated patient response to first-line treatment. Additionally, the detection of HRD phenotype of PDTO using functional assay was associated with the results of the HRD test Genomic Instability Scar (GIScar). Although larger-scale investigations are needed to confirm the predictive potential of PDTO, these results provide further evidence of the potential interest of ovarian PDTO for functional precision medicine even if many challenges remain to be addressed.

cancer biology↗

bioRxiv2023

MET variants with activating N-lobe mutations identified in hereditary papillary renal cell carcinomas still require ligand stimulation

In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: in this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed ten uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.

cancer biology↗

bioRxiv2019

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

The molecular mechanisms underlying the caudal-to-rostral progression of Lewy body pathology in Parkinsons disease (PD) remain poorly understood. Here, we aimed to unravel transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological controls and PD donors. Using human postmortem brain datasets of non-neurological adults from the Allen Human Brain Atlas, we identified expression patterns related to PD progression, including genes found in PD genome-wide associations studies: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, and SCARB2. We confirmed these patterns in two datasets of non-neurological subjects (Genotype-Tissue Expression project and UK Brain Expression Consortium) and found altered patterns in two datasets of PD patients. Additionally, co-expression analysis across vulnerable regions identified two modules associated with dopamine synthesis, the motor and immune system, blood-oxygen transport, and contained microglial and endothelial cell markers, respectively. Alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in PD brains.

neuroscience↗