Metastases are responsible for majority cancer related deaths. Disseminated tumor cells (DTCs) gain a diverse array of metastatic traits in order to adapt to and survive within different microenvironments, making them very difficult to therapeutically target. Remarkably, regardless of the secondary organ, DTCs survive and thrive in perivascular niches. Using xenograft and syngeneic models of metastasis in mouse, we found that upon extravasation, neuronal cell adhesion molecule L1 (L1CAM) expressed by DTCs engages the vascular basal lamina in order to amplify integrin β1 and integrin linked kinase (ILK) signaling in DTCs. ILK promotes actin polymerization for cell spreading and subsequent activation of mechanotransduction effector transcription factors YAP and MRTF. We found that activation of YAP and MRTF coincides with DTCs ability to dislodge resident pericytes from the perivascular niche and is an essential step in the metastatic colonization regardless of dormancy state. Therefore, these results provided us a unifying molecular mechanism that governs cancer progression from metastatic seeding to overt colonization. Ongoing studies will determine how mechanotransduction and pericyte-DTC interactions can be manipulated to prevent metastatic colonization by potentiating the immune response and exposing their biophysical vulnerabilities.

Citation Format: Ekrem Emrah Er, Maria Tello-Lafoz, Jing Hu, Morgan Huse, Joan Massagué. Metastatic colonization in the perivascular niche: A mechanotransduction perspective [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 209.