The Non-Cell Autonomous Role of YAP Affects Blood Vessel Integrity and Immune Response in Tumors

Breast cancers are a family of malignancies arising from mammary epithelial cells. 4T1 cells are a triple negative breast cancer epithelial cell line, which metastasizes spontaneously in-vivo from a primary tumor in the mammary fat pad to multiple distant sites including lymph nodes, liver, lung and bone. In syngeneic, immune competent balb/c mice, the progressive spread of 4T1 metastases to the draining lymph nodes and other organs is similar to that of human mammary cancer and thus represents an accurate model for human breast cancer. Hippo signaling has been known to assume different roles in different cell contexts and microenvironments, due to its diversified interplay with many signaling transduction cascades. This is illustrated by reports demonstrating both tumor suppressive and oncogenic roles of YAP in breast cancer. We knocked-out Yap in 4T1 cells, using CRISPR/Cas9, to investigate YAP -dependent transcriptional programs and their effect on the in vivo tumor microenvironment. Surprisingly, the 4T1 Yap knock-out cells, generated larger tumors compared to wild type cells, with more mature blood vessels and reduced immune response. This suggests that tumors expressing YAP may be vulnerable to immune surveillance due to the formation of more permeable blood vessels. We plan to explore the impact of YAP on maintaining a tumor suppressive microenvironment during breast tumorigenesis.