Laforets, F. | bioRxiv Science

bioRxiv2025

Matrix structure and microenvironment dynamics correlate with chemotherapy response in ovarian cancer

Elevated extracellular matrix (ECM) in the tumor microenvironment (TME) is associated with chemoresistance and poor prognosis. We hypothesized that modifying the ECM may enhance response to chemotherapy. We measured chemotherapy-induced changes in the TME of two mouse models of high-grade serous ovarian cancer (HGSOC) that differed in chemotherapy response. Treatment of the chemo-sensitive tumors triggered dynamic transcriptional ECM and immune changes and structural modifications of ECM proteins. These changes, observed over twenty-days post-chemotherapy, had relevance to HGSOC patient responses to chemotherapy. Integrating transcriptomics with ECM structure metrics, we identified ECM targets, including lysyl oxidase (LOX), that might enhance chemotherapy in less responsive mouse tumors. Given alone or in combination with chemotherapy, a pan-LOX inhibitor (PXS-5505) modulated fibroblast and immune cell distribution and reduced tumor stiffness in HGSOC chemo-resistant mouse tumors. Moreover, pre-treatment with PXS-5505 improved response to chemotherapy. We conclude that pretreatment with ECM targeting agents may improve response to chemotherapy, by altering ECM structure and immune responses.

cancer biology↗

bioRxiv2020

Alteration of ribosome function upon 5-fluorouracil treatment favours cancer cell drug-tolerance

Partial response to chemotherapy leads to disease resurgence. Upon treatment, a subpopulation of cancer cells, called drug-tolerant persistent cells, display a transitory drug tolerance that lead to treatment resistance 1,2. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stemness and dormancy 2-4. 5-fluorouracil (5-FU), the most widely used chemotherapy in cancer treatment, is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways 5-9. Here, we show that 5-FU treatment leads to the unexpected production of fluorinated ribosomes, exhibiting altered mRNA translation. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts and human tumours. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs according to the nature of their 5-untranslated region. As a result, we found that sustained translation of IGF-1R mRNA, which codes for one of the most potent cell survival effectors, promoted the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favour the drug-tolerant cellular phenotype by promoting translation of survival genes. This could be exploited for developing novel combined therapies. By unraveling translation regulation as a novel gene expression mechanism helping cells to survive a drug-challenge, our study extends the spectrum of molecular mechanisms driving drug-tolerance.

cancer biology↗