Brahmbhatt, S. | bioRxiv Science

bioRxiv2018

BAP1 Loss Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma

BackgroundMalignant Peritoneal Mesothelioma (PeM) is a rare but frequently fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM yet exist. In the search for novel therapeutic target candidates in PeM, we performed a comprehensive integrative multi-omics analysis of 19 treatment-naive PeM tumors.\n\nResultsThe analysis identified PeM tumors with BAP1 loss to form a distinct molecular subtype characterized by distinct expression patterns of genes involved in chromatin remodeling, DNA repair pathway, and immune checkpoint receptor activation. This PeM subtype could potentially benefit from immune checkpoint, PARP, or HDAC inhibition therapies.\n\nConclusionsOur findings uncover BAP1 as a trackable prognostic and predictive biomarker, and refine PeM disease classification. This integrated molecular characterization provides a comprehensive foundation for developing PeM precision medicine.

cancer biology↗

bioRxiv2017

Dual functions of Discoidin domain receptor coordinate cell-matrix adhesion and collective polarity in migratory cardiopharyngeal progenitors

Integrated analyses of regulated effector genes, cellular processes, and extrinsic signals are required to understand how transcriptional networks coordinate fate specification and cell behavior during embryogenesis. Migratory pairs of cardiac progenitors in the tunicate Ciona provide the simplest model of collective migration in chordate embryos. Ciona cardiopharyngeal progenitors (aka trunk ventral cells, TVCs) polarize as leader and trailer cells, and migrate between the ventral epidermis and trunk endoderm, which influences collective polarity. Using functional perturbations and quantitative analyses, we show that the TVC-specific and collagen-binding Discoidin-domain receptor (Ddr) cooperates with Integrin-{beta}1 to promote cell-matrix adhesion to the epidermis. We found that endoderm cells secrete a collagen, Col9-a1, that is deposited in the basal epidermal matrix and activates Ddr at the ventral membrane of migrating TVCs. A functional antagonism between Ddr/Int{beta}1-mediated cell-matrix adhesion and Vegfr signaling appears to modulate the position of cardiopharyngeal progenitors between the endoderm and epidermis. Finally, we show that Ddr activity promotes leader-trailer-polarized BMP-Smad signaling independently of its role in cell-matrix adhesion. We propose that dual functions of Ddr act downstream of cardiopharyngeal-specific transcriptional inputs to coordinate subcellular processes underlying collective polarity and directed migration.

developmental biology↗