Abstract LT016: Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance

Abstract

Abstract Metastatic dissemination of cancer cells to vital secondary organs pose a lifelong lethal threat unless they can successfully be eliminated by the immune system. Interestingly, despite their ability to evade immunity at primary organs, the vast majority of disseminated cancer cells are killed at secondary organs, suggesting that the process of dissemination renders cancer cells sensitive to immunity. Understanding how dissemination renders cancer cells sensitive to immunity would therefore provide exciting new opportunities to target metastases, but the relationship between dissemination and the immune response is not clear. In our effort to study this relationship, we manipulated cancer cells’ expression of myocardin related transcription factors A and B (MRTFA/B), which are central in regulation of actin cytoskeleton and are indispensable for metastatic invasion, dissemination and colonization. Surprisingly, despite MRTFA/B’s established roles in promoting metastasis, we found that MRTFA/B expression in cancer cells downregulated metastatic colonization in fully immuno-competent mouse models. MRTFA/B mediated decrease in colonization was completely reversed upon immune cell depletion suggesting that the immune cells exploit MRTFA/B expression in cancer cells for cytotoxicity. Among various cancer cell parameters involved in immune cell activation, T- and NK cell activation most prominently correlated with MRTFA/B driven mechanical compliance of cancer cells. Mechanical compliance, also known as stiffness, of antigen presenting cells and synthetic substrates are well-known to activate T- and NK cells through biophysical and mechano-chemical signal transduction. As such, perturbing cancer cells’ stiffness downregulated the immune response and cytotoxicity. Thus, we termed this process mechanosurveillance. Our work on mechanosurveillance will help us understand how disseminated cancer cells are targeted by immunity and how they evade it at secondary organs. Importantly the concept of mechanosurveillance will help guide the use of existing therapeutics that alter tissue stiffness and immune boosting therapies to combat metastases. Citation Format: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calò, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er. Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT016.