Biology subjects

Mes-Masson, A.-M.

Publications and source records attributed to Mes-Masson, A.-M..

10 recordsLinked to original sources

bioRxiv2025

BRCA mutation alters the stromal landscape in normal ovaries

For BRCA mutation (BRCA+) carriers, the risk of ovarian cancer can be as high as 59% compared with 1.4% for the general population. While the impact of BRCA mutations on epithelial cell transformation has been extensively studied, we hypothesize that these mutations cause structural changes that prematurely transform the ovary into a rich metastatic niche that supports the early onset of ovarian cancer. Analysis of collagen content and organization in human ovaries revealed increased coherence associated with fibrosis in premenopausal BRCA+ ovaries relative to those without a BRCA mutation. Brca1 deficiency and haploinsufficiency in murine ovarian fibroblasts triggered the expression of hallmarks of senescence, including Cdkn2a (p16) and acidic {beta}-galactosidase activity. Brca1-deficient fibroblasts also acquired an antigen-presenting myofibroblastic phenotype, characterized by expression of MHC-II molecules, -SMA and extracellular matrix components, suggesting the capacity to modulate immune activity and drive structural changes resembling fibrosis. These results provide insight into the mechanisms contributing to accelerated ovarian aging in BRCA+ carriers. TeaserBRCA mutation promotes fibroblast hyperactivity and senescence that changes the stromal architecture of the ovarian niche.

molecular biology↗

bioRxiv2025

Enhancing cryopreservation of ex vivo 3D tumor models using vitrification strategies

Microdissected tumor tissue explants (MDTs) are promising ex vivo models for oncology research but remain limited by poor preservation and the rapid loss of viability following resection. Here, we systematically optimized MDT cryopreservation using prostate-derived 49F and ovarian TOV112D tumor models. Before cryopreservation, we evaluated the effects of antioxidant supplementation, pre-cooling, and a short recovery period. MDTs were then preserved by either conventional slow-freezing or vitrification using ultra-rapid cooling. Following thawing, tissue morphology, apoptosis, and proliferative capacity were assessed relative to fresh controls. Vitrification improved morphological preservation and reduced apoptosis compared with slow-freezing, although recovery of proliferation differed between tumor models. Antioxidant supplementation enhanced post-thaw proliferation at optimal concentrations but induced toxicity at higher doses. Pre-cooling and a short pre-cryopreservation recovery period further improved post-thaw outcomes. Combining these parameters produced an optimized vitrification protocol that preserved up to 98% of the proliferative capacity of 49F MDTs and 69% of that of TOV112D MDTs relative to fresh controls. These findings establish optimized vitrification as a reproducible, high-yield strategy for preserving MDTs for downstream ex vivo oncology applications.

cancer biology↗

bioRxiv2025

Identification of a new inhibitor of Ran GTPase with therapeutic value in epithelial ovarian cancer

Compiled research studies suggest that the small GTPase Ran is critical in cancer initiation and progression. Compounds that block Ran activity would be valuable for cancer treatment. Yet, to date, there is no inhibitor proven to be efficient and specific to Ran. Here, by learning lessons from the discovery of KRAS G12C inhibitors, we generated a structural model of the switch II pocket of GDP-bound Ran to identify potential inhibitors of Ran by virtual screening. After in vitro verification, compound M26 was detected. Subsequent hit optimization lead us to identify compound M36 as an inhibitor of Ran with a promising therapeutic value. Binding of M36 to Ran was confirmed by cellular thermal shift assay. The specificity of M36 towards Ran was demonstrated by the evaluation of the active GTP-bound forms of a range of GTPases including Ran, RhoA, Cdc42 and Rac1; and by the expression of a dominant active mutant of Ran. Remarkably, similar to depletion of Ran by siRNA, M36 exhibits a specific toxicity in aneuploid ovarian cancer cells and represses DNA repair systems. In accordance with this, we demonstrated a synergistic relationship between M36 and the FDA approved PARP inhibitor Olaparib. In vivo, M36 presents acceptable pharmacokinetic properties and, more importantly, inhibits the tumor growth of an aggressive epithelial ovarian cancer xenograft model. Clinically relevant, M36 was able to induce cell death in ex vivo EOC patient derived micro-dissected tumor. Overall, our study is the first to provide a small-molecule compound inhibitor of Ran with a promising therapeutic potential.

cancer biology↗

bioRxiv2024

Localized translation of cell junction mRNAs is required for epithelial cell polarity

Epithelial cells exhibit a highly polarized organization along their apico-basal axis, a feature that is critical to their function and frequently perturbed in cancer. One less explored process modulating epithelial cell polarity is the subcellular localization of mRNA molecules. In the present study, we report that several mRNAs encoding evolutionarily conserved epithelial polarity regulatory proteins, including Zo-1, Afdn and Scrib, are localized to cell junction regions in Drosophila epithelial tissues and human epithelial cells. Targeting of these mRNAs is coincident with the robust junctional distribution of their encoded proteins, and we demonstrate that they are locally translated at cell junction regions. To identify RNA binding proteins (RBPs) potentially implicated in junctional mRNA regulation, we performed systematic immuno-labeling with a collection of validated RBP antibodies, identifying a dozen RBPs with consistent junctional distribution patterns, several of which directly bind junctional transcripts. Strikingly, depletion of these RBP candidates, including MAGOH, a core component of the exon-junction complex (EJC), perturbed the junctional distribution and localized translation of Zo-1 and Scrib mRNAs, as well as the junctional accumulation of their protein products. Functional disruption of MAGO, or its interaction partner Y14, in Drosophila follicular epithelial cells perturbs the distribution of junctional transcripts and proteins. Finally, tissue microarray analysis of ovarian cancer tumor specimens revealed that expression of MAGOH and ZO-1 is positively correlated and that both proteins are potential biomarkers of good prognosis. Altogether, this work reveals that localized mRNA translation at cell junction regions is important for modulating epithelial cell polarity. HIGHLIGHTSO_LICell junction mRNA targeting is conserved between tissues and species C_LIO_LIThese mRNAs undergo localized translation at areas of cell-cell contact C_LIO_LIA diversity of RBPs localize to cell junction regions and interact with junctional transcripts. C_LIO_LIDisruption of junctional RBPs impacts epithelial cell polarity and localized translation C_LIO_LIMAGOH and ZO-1 expression is correlated in ovarian tumor specimens and are potential biomarkers of good prognosis C_LI

molecular biology↗

bioRxiv2023

53BP1 mediates sensitivity to chemotherapy and is associated with poor clinical outcomes in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecological malignancy in North American women. At a cellular level, the current first-line chemotherapies cause DNA-damage and activate the DNA damage response signalling cascade. Here we explore the role of 53BP1, a central mediator of the DNA damage response, in HGSOC chemotherapy outcomes. Tissue 53BP1 protein levels were quantified in two independent HGSOC cohorts, the COEUR validation cohort (n = 173) and CHUM cohort (n = 56). Univariate and multivariate analyses showed that high nuclear 53BP1 levels in ovarian cancer cells were strongly associated with poor disease-specific survival in both cohorts. High 53BP1 was associated with poor progression-free survival (PFS) in the COEUR cohort, and trended towards poor PFS in the CHUM cohort. These findings were validated by whole-tumour TP53BP1 mRNA of the TCGA Firehose Legacy cohort (n = 591) in which high TP53BP1 mRNA levels were associated with poor overall survival on multivariate analysis. In HGSOC cell lines, 53BP1 levels were positively correlated with resistance to carboplatin using colony formation assay, and depletion of 53BP1 sensitized resistant cell lines to genotoxic therapies. These results suggest that 53BP1 is associated with poor prognosis in HGSOC and may mediate this relationship by modulating cellular sensitivity to chemotherapy. Statement of translational relevanceCurrent first-line chemotherapies in ovarian cancer cause DNA damage and activate the DNA damage response, culminating in the taking of cell fate decisions. 53BP1 is a central mediator in this signalling cascade, where it is involved at multiple levels: signal amplification, recruitment of effectors, DNA repair pathway choice, and cell cycle regulation. However, its role in ovarian cancer treatment outcomes remains unknown. In this study, we found that 53BP1 correlated with poor clinical outcomes in three ovarian cancer patient cohorts and mediated carboplatin sensitivity in ovarian cancer cells. These results reveal 53BP1 and the DNA damage response as important actors in ovarian cancer treatment response. Though further studies are necessary to gain a more complete understanding of their involvement in clinical outcomes, they appear as promising candidates for potential therapeutic targeting in ovarian cancer.

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↗

bioRxiv2023

Predicting developmental relationships of tumor resident and circulating T cells in ovarian cancer

Characterizing T cell populations and understanding their developmental relationships may help design more effective cancer immunotherapies. We coupled single-cell transcriptomics and T cell receptor (TCR) {beta} profiling of intratumoral and peripheral T cells in ovarian cancer patients to identify transcriptional programs and infer their relationship by trajectory and TCR overlap analyses. We proposed a model of differentiation pathway from an intermediate GZMH-expressing CD8 T cell subset found in the blood and tumor that progressively reinforces the exhaustion and tissue residency programs from a CCL4-expressing cluster towards XCL1- and CXCL13-expressing terminally exhausted cells. Inferred cell communication analysis suggests that interaction with CXCL13-expressing CD4 T cells, which we refer to as Tfh-like cells, sustains the effector function of this intermediate GZMH-expressing CD8 T cell subset. Moreover, our results suggest that Tfh-like cells attract cells expressing GPR183 through the production of its ligand 7,25 dihydroxycholesterol (7,25-HC). Finally, we demonstrated that GPR183 is highly expressed in a subset of pre-effector GZMK-expressing CD8 T cells and plasmacytoid dendritic cells. Collectively, our results suggest that Tfh-like cells expressing IL-21 help promote antitumor immunity against ovarian tumors by coordinating the action of immune cells responsive to 7,25-HC.

immunology↗

bioRxiv2022

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer

High grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation and CIN, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tumour tissues and 73 ovarian cancer cell lines, we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and is strongly associated with CIN and genome subclonality. Cell-based studies showed that high prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel which is the most common treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.

cancer biology↗

bioRxiv2019

Gravity-based microfiltration reveals unexpected prevalence of circulating tumor cell clusters in ovarian cancer

Circulating tumor cells (CTCs) are rare (few cells per milliliter of blood) and mostly isolated as single cell CTCs (scCTCs). CTC clusters (cCTCs), even rarer, are of growing interest, notably because of their higher metastatic potential, but very difficult to isolate. Here, we introduce gravity-based microfiltration (G{micro}F) for facile isolation of cCTCs while minimizing unwanted cluster disaggregation, with [~]85% capture efficiency. G{micro}F from orthotopic ovarian cancer mouse models, from 17 epithelial ovarian cancer (EOC) with either localized or metastatic disease, and from 13 metastatic colorectal cancer liver metastasis (CRCLM) patients uncovered cCTCs in every case, with between 2-100+ cells. cCTCs represented between 5-30% of all CTC capture events, and 10-80% of CTCs were clustered; remarkably, in 10 patients, most CTCs were circulating not as scCTCs, but as cCTCs. G{micro}F uncovered the unexpected prevalence and frequency of cCTCs including sometimes very large ones in EOC patients, and motivates additional studies to uncover their properties and role in disease progression.

bioengineering↗

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↗