Biology subjects

FENOUIL, T.

Publications and source records attributed to FENOUIL, T..

3 recordsLinked to original sources

bioRxiv2025

Lineage of origin-specific developmental programs drive the behaviors of malignant cells in an avian embryo model of human Medulloblastoma subgroups

Tumoral cells of medulloblastoma (MB) subgroups (SHH, G3 and G4) display a close transcriptomic proximity to early neuronal progenitors that migrate to form the embryonic cerebellum. With the aim of exploring functional proximities between MB cells and their physiological counterparts, we established a model of transplantation of human MB cells into the cerebellum of chick embryos in vivo and ex ovo. Light-sheet imaging of embryos grafted with cell lines and patient biopsies of MB SHH, G3 and G4 revealed the formation of primary tumors within a few days, whose topography matched that of the different MB subgroups on patients MRI. We found that transplanted MB cells adopted morphological and migratory features specific of their respective lineage of origin. Combining transcriptomic and functional approaches, we found that MB G3 tumoral cells exploit the canonical SLIT migration developmental signaling at disease emergence. This signaling is maintained in MB G3 patients and is associated with tumor aggressivity and poor prognosis.

cancer biology↗

bioRxiv2025

Dynamic dysregulation of Tenascin-X/Tenascin-C balance controlled by Transforming Growth Factor-beta leads to tumor cell proliferation during pancreatic carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to late diagnosis and poor therapeutic efficiency. Throughout PDAC progression, a dense extracellular matrix (ECM) is deposited around neoplastic cells and accompanies tumor development and aggressiveness. This significant stroma, both in terms of quantity and through its impact on tumor cells, is now considered as a target for innovative therapies to improve patient survival. Among ECM proteins, Tenascins (TNs) are a family of four glycoproteins (TNC, TNW, TNR and TNX) sharing a common modular structure, but exhibiting different expression patterns and functions depending on the physiological and physio-pathological contexts. In PDAC, TNC is up-regulated and is considered as a pro-tumorigenic actor, whereas TNXs role remains to be elucidated. Herein, we demonstrated that unlike TNC, TNX is drastically decreased in PDAC, and that this loss is correlated with reduced patient survival. Dysregulation of the TNX/TNC balance is attributable to Transforming Growth Factor-beta (TGF-{beta}) upregulation during pancreatic carcinogenesis. Interestingly, we found that TNX is first highly deposited in low grade lesions before being clearly decreased in later stages suggesting an elaborate stromal remodelling during PDAC development. Finally, low TNX and high TNC deposition around precursor lesions are correlated with increased preneoplastic cell proliferation. Altogether, our results (i) demonstrate the importance of Tenascin ratios during pancreatic carcinogenesis, (ii) suggest an anti-proliferative role for TNX unlike its pro-tumoral counterpart, TNC and (iii) underscore TNX and TNC as valuable targets for the development of new drugs for pancreatic cancer and/or solid tumor treatment. Statement of significanceThe tumor microenvironment plays a prominent but contradictory role in pancreatic cancer. Our study highlights the role of a TGF-{beta}-controlled TNX/TNC balance and designates TNX as an inhibitor of tumor cell proliferation.

cancer biology↗

bioRxiv2024

Translational control of cell plasticity drives 5-FU tolerance

All routine clinical treatments for colorectal cancer include 5-fluorouracil (5-FU), which cannot counteract recurrence and metastases formation. As the pyrimidine analog 5-FU can impact multiple pathways including both DNA and RNA metabolism, studying its mode of actions could lead to improved therapies. Using a dedicated reporter system for lineage-tracing and deep translatome profiling we demonstrate that 5-FU causes some colorectal cancer cells to tolerate the drug, due to a durable translational reprogramming that sustains cell plasticity. This period of drug tolerance coincides with specific translational activation of genes coding for proteins with major pro-tumoral functions. We unravel a major unexpected translational overexpression of the pro-inflammatory and pro-tumoral IL-8 cytokine, alongside other anti-apoptotic, senescence-associated secretory phenotype and cancer-related senescence phenotype genes. Given the adverse prognostic implications of elevated IL-8 levels across various cancers, our findings suggest IL-8 targeting could counteract 5-FU resistance.

cancer biology↗