RESUMEN
Lynch Syndrome is characterized by deficient mismatch repair (dMMR) components. We performed a meta-analysis of multiple RNA-sequencing datasets from patients with different dMMR variants (PMS2, MLH1, and MSH2) to better characterize the unique transcriptional profiles. Our results reveal enriched signaling pathways from tumor samples with germline mutations in the PMS2 gene including upregulation in pathways related to intrinsic and extrinsic prothrombin activation, fibrinolysis, and uPA/uPAR-mediated signaling. These pathways have been associated with tumor growth, invasiveness, and metastasis. This work provides support for further exploration into the role of PMS2 in tumor development, and as a potential therapeutic mechanism.
RESUMEN
Expression of CRIPTO, a factor involved in embryonic stem cells, fetal development, and wound healing, is tied to poor prognosis in multiple cancers. Prior studies in triple negative breast cancer (TNBC) models showed CRIPTO blockade inhibits tumor growth and dissemination. Here, we uncover a previously unidentified role for CRIPTO in orchestrating tumor-derived extracellular vesicle (TEV) uptake and fibroblast activation through discrete mechanisms. We found a novel mechanism by which CRIPTO drives aggressive TNBC phenotypes, involving CRIPTO-laden TEVs that program stromal fibroblasts, toward cancer associated fibroblast cell states, which in turn prompt tumor cell invasion. CRIPTO-bearing TEVs exhibited markedly elevated uptake in target fibroblasts and activated SMAD2/3 through NODAL-independent and - dependent mechanisms, respectively. Engineered expression of CRIPTO on EVs enhanced the delivery of bioactive molecules. In vivo , CRIPTO levels dictated TEV uptake in mouse lungs, a site of EV-regulated premetastatic niches important for breast cancer dissemination. These discoveries reveal a novel role for CRIPTO in coordinating heterotypic cellular crosstalk which offers novel insights into breast cancer progression, delivery of therapeutic molecules, and new, potentially targetable mechanisms of heterotypic cellular communication between tumor cells and the TME.