Mechanism-guided targeting of angiocrine signals to limit metastatic progression
Blood vessels disseminate throughout our body to supply nutrients and maintain the steady-state function of different organ systems in adults. In the context of metastasis, blood vessel-lining endothelial cells (EC), via the secretion of angiocrine factors, orchestrate a supportive stromal niche to facilitate tumor cell colonization. Yet, the exact molecular mechanisms that underline multidirectional stromal communication remain understudied. Employing models of lung and liver metastasis, research project C06 aims to elucidate cellular and molecular mechanisms that result in the formation of a conducive metastatic niche. In particular, we interrogate crosstalk between EC and stromal cells at a single-cell resolution during metastatic progression. The project aims to exploit EC-derived angiocrine factors as therapeutic modalities to reprogram the tumor microenvironment, thereby enhancing the efficacy of current clinically approved drugs such as immune checkpoint inhibitors. The project further develops LRG1 as a target to limit multiorgan metastases. Overall, the findings are expected to not only shed novel insights into the temporal evolution of metastatic niche but also provide a mechanism-guided rationale for combining vascular modulatory agents with clinically approved drugs.