Biology subjects

Martin, L. A.

Publications and source records attributed to Martin, L. A..

3 recordsLinked to original sources

bioRxiv2025

A patient-derived ovarian cancer organoid platform to study susceptibility to natural killer cells

Intratumoral heterogeneity drives therapy resistance and relapses in advanced stage cancers, such as ovarian cancer. Here, we present a live cell imaging assay using patient-derived ovarian cancer organoids for real time capture and quantification of natural killer cell-mediated apoptotic events in >500 organoids simultaneously. Our assay revealed significant inter- and intratumor response heterogeneity and identified a rare resistant organoid population, opening avenues to test immunomodulatory strategies that overcome resistance.

cancer biology↗

bioRxiv2025

Suppression of Ovarian Cancer Cell Proliferation is Associated with Upregulation of Cell-Matrix Adhesion Programs and Integrin-β4-Induced Cell Protection from Cisplatin.

The role of extracellular matrix adhesion components in modulation of the treatment sensitivity of ovarian cancer (OC) cells is not well understood. Analysis of ovarian cancer TCGA gene expression data sets revealed an inverse correlation between genes involved in cell-cycle progression and extracellular matrix interactions including laminin-binding receptor integrin {beta}4, a major component of extracellular matrix adhesion. Gene ontology analysis also showed that in patient populations with low integrin {beta}4 expression, cell cycle-related programs were activated, while in populations with high expression of integrin {beta}4, the activation of these cell cycle programs was lower. Suppression of proliferation with CDK4/6 inhibitor Palbociclib stimulated integrin {beta}4 expression and induced protection against cisplatin in cells naturally expressing low levels of integrin {beta}4. Additionally, ovarian cancer patient-derived organoids showed reduced cisplatin sensitivity when pretreated with Palbociclib. Our data also showed that integrin {beta}4 overexpression decreased ovarian cancer cell proliferation and at the same time, attenuated cisplatin response. Our investigations reveal that expression of integrin {beta}4 inversely correlates with cell cycle progression programs, whether observed in expression data of OC patient samples or in various OC cell lines. Consistently with these results, the overexpression of ITGB4 gene in ovarian cancer cell lines correlated with reduced cell proliferation rates and diminished sensitivity to cisplatin, supporting the idea that integrin {beta}4 and likely its matrix ligands play critical roles in the regulation of cellular growth and chemoresistance of ovarian cancer cells.

cancer biology↗

bioRxiv2024

Cell-of-origin epigenome underlies SS18::SSX-mediated transformation

Synovial sarcoma is an aggressive soft-tissue malignancy that is characterized by a pathognomonic t(X;18)(p11.2;q11.2) translocation, which produces the fusion oncogene named SS18::SSX. Despite recent advancements in our understanding of synovial sarcoma biology, the cell-of-origin remains undefined. A mesenchymal stromal cell (MSC) specific CreERT2 line was employed to express SS18::SSX in fibroblasts and related cell types, resulting in 100% penetrant synovial sarcoma development in mice, with a median latency period of 16.2 {+/-} 2.5 weeks. Murine tumours exhibited high concordance with human synovial sarcoma sub-types at the histological and molecular levels1. Genetic refinement of the cell-of-origin revealed that synovial sarcomas derive from a rare Hic1+ Pdgfra+ Lgr5+ fibroblastic population. Furthermore, longitudinal multi-omic profiling along the transformation continuum revealed the step-wise acquisition of a transformed phenotype initiated by the loss of a mature fibroblastic profile and subsequently, the gradual unmasking of an epigenetically embedded embryonic MSC program. Adult and embryonic MSCs exhibited overlapping H2AK119ub and H3K4me3/H3K27me3 (bivalent) histone marks, while SS18::SSX-mediated transformation culminated in the widespread loss of H3K27me3 at these genes and their consequent transcription. Collectively, these studies define a rare MSC context, conducive for SS18::SSX-mediated transformation, and demonstrate that SS tumorigenesis involves the induction and maintenance of an embryonic-like MSC phenotype.

cancer biology↗