Biology subjects

Lafontaine, J.

Publications and source records attributed to Lafontaine, J..

5 recordsLinked to original sources

bioRxiv2026

The Smac mimetic drug Xevinapant sensitizes triple negative breast cancer to radiotherapy-induced cell death in a TNFα dependent manner

Purpose: There is an unmet need in the treatment of triple-negative breast cancer (TNBC), as recurrence rates remain high; thus, novel treatment strategies are warranted to improve outcomes for patients. Smac mimetics (SMs) are small molecules that inhibit the inhibitors of apoptosis. In this study, we investigated the properties of the SM Xevinapant (AT406) as a radiosensitizer in TNBC. Methods: TNBC cell lines were treated with Xevinapant (AT406) in the presence or absence of ionizing RT and cell viability and apoptosis measured in vitro. Clonogenic assays were performed to confirm radiosensitization. We also assessed xevinapant radiosensitization in the presence of the Tumor Necrosis Factor (TNF) cytokine, which has been shown to enhance SM-induced apoptosis. Radiosensitization mechanisms were further validated by western blotting, flow cytometry and cell cycle analysis. Results: We show that Xevinapant increased cell death in a panel of irradiated TNBC cell lines. In clonogenic assays, Xevinapant sensitized MDA-MB-231 cells to RT-induced cell death, and this was significantly enhanced in the presence of TNF, with a dose-enhancing factor (DEF) of 1.57. We also show that Xevinapant radiosensitization is mediated by TNF-dependent apoptosis. Conclusions: Xevinapant is a radiosensitizer that enhances RT-induced cell death in TNBC cells, and TNF is central to this process through activation of apoptosis. These results are promising for combining RT with Xevinapant to improve local control in TNBC.

cancer biology↗

bioRxiv2026

CRISPR-enabled genetic screens identify synthetic lethal targets across frequently altered cancer drivers

Synthetic lethality (SL) provides a treatment paradigm for targeting cancer with alterations in driver genes that are not conventionally druggable, including loss-of-function (LoF) mutations in tumor suppressor genes and gain-of-function (GoF) alterations in oncogenes. We undertook a series of genome-wide CRISPR screens using functionally validated isogenic cell lines and also conducted a large-scale SL analysis using data from the cancer dependency map (DepMap). We charted SL interactions across 15 genetic alterations characteristic of diseases with high incidence and unmet clinical need: FBXW7, CCNE1, CDK12, ARID1A, KMT2D, DNMT3A, TET2, KEAP1, STK11, IDH1, SF3B1, SRSF2, U2AF1, chromosome 18q loss, and chromosome 13q loss. We show validation of several SL interactions between tractable targets with cancer drivers, including ARID1A and the hexosamine biosynthetic pathway aminotransferase GFPT1, STK11 with CAMK protein kinase family members including MARK2, FBXW7 and the CDK1 regulatory kinase PKMYT1, and CCNE1 amplification and the anaphase promoting complex or cyclosome (APC/C). In summary, this study offers a rich resource of genetic interactions across cancer drivers enabling the discovery of new biological insights and drug targets for future therapeutic development.

cancer biology↗

bioRxiv2025

Hypoxic-Core (HyCo) Spheroids Recapitulate Hallmarks of Clinical Hypoxia: A Simple Chip-Based Method for Translational Oncology

Hypoxia influences the biology and response of cancers. No user-friendly device allows the study of hypoxia on highly-controlled clinically-relevant tumor models. Here, we describe how hypoxic-core (HyCo) spheroids generated using our unique non-perfused microfluidic device recapitulate key clinical hallmarks of hypoxia in vitro. Our PDMS-made system can generate up to 240 spheroids naturally exhibiting a diffusion-driven hypoxic core in only 4 days, here from two sarcoma cell lines. Compared to smaller normoxic spheroids from the same cell lines, known hypoxia-related genes are upregulated in HyCo spheroids. In addition, HyCo spheroids display hallmark hypoxia-induced resistance to radiotherapy and chemotherapy, along with increased invasiveness. Finally, to demonstrate applications of our HyCo spheroids and on-chip framework in drug development, we used our HyCo-derived gene expression dataset to select a drug candidate (diethyl-pythiDC) and confirmed its effect on spheroid invasiveness. Our results suggest that HyCo spheroids can be efficiently used as translational tools to integrate hypoxia in cancer research, without complex workflows or setups. TeaserOn-chip spheroids with a natural hypoxic-core emulate clinical cancer hypoxia hallmarks essential for novel therapy development.

cancer biology↗

bioRxiv2023

A senescence-like state is beneficial for ovarian cancer treatment

High-grade serous ovarian carcinoma (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that tissue-derived primary HGSOC epithelial cultures reflecting the original disease primarily undergo therapy-induced senescence in response to DNA damage and first-line carboplatin/paclitaxel chemotherapy. Unlike previous observations using cell lines, primary HGSOC cell TIS displays a stable senescence proliferation arrest and p16INK4A expression, and is accompanied by persistent DNA damage, an inflammatory secretome, and senolytic sensitivity, suggesting new avenues for selective pharmacological manipulation of these cells. Whether cell senescence induced by cancer therapy is beneficial or detrimental to clinical outcomes remains unknown. Single cell comparison of pre- and post-chemotherapy patient HGSOC tissue samples revealed changes in physio-pathological senescence biomarkers supporting a post-treatment senescence-like state. Importantly, patients with stronger senescence signatures post-chemotherapy displayed better 5-year survival suggesting that senescence accounts, at least in part, for beneficial cellular responses to treatment. Given that ovarian cancer epithelial cells almost universally retain the capacity to undergo senescence and that senescence appears beneficial in this context, HGSOC senescence-centric therapeutic avenues should be further explored. Author SummaryWhether cancer therapy-induced cell fate decisions like senescence are good or bad for patient treatment outcome is unknown. We find that ovarian cancer cells almost universally retain senescence competence and that senescence in treated cancer tissues correlate with good clinical outcomes. This reveals that senescence is a relevant drug target in ovarian cancer.

cancer biology↗

bioRxiv2018

Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that primary HGSOC cultures undergo therapy-induced senescence (TIS) in response to DNA damage induced by chemotherapy. HGSOC-TIS displays most senescence hallmarks including persistent DNA damage, senescence-associated inflammatory secretome, and selective sensitivity to senolytic Bcl-2 family inhibitors, suggesting avenues for preferential synergistic clearance of these cells. Comparison of pre- and post-chemotherapy HGSOC patient tissue samples revealed changes in senescence biomarkers suggestive of post-treatment \"in patient\" TIS, and a stronger TIS response in post-chemotherapy tissues correlated with better 5-year survival rates for patients. Together, these data suggest that the induction of cellular senescence in HGSOC cells accounts at least in part for beneficial cellular responses to treatment in patients providing a new therapeutic target.\n\nOne Sentence SummaryCellular senescence is a central beneficial response to chemotherapy in high-grade serous ovarian cancer both in vitro and in patient.

cancer biology↗