Radhika Narain1,2, Jonathon M. Muncie-Vasic3 and Valerie M. Weaver1,4,5,6,7 1Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California 94143, USA; 2Graduate Program in Bioengineering, University of California, San Francisco and University of California, Berkeley, Berkeley, California 94720, USA; 3Gladstone Institutes, San Francisco, California 94158, USA; 4Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California 94143, USA; 5Department of Radiation Oncology, University of California, San Francisco, San Francisco, California 94143, USA; 6Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, California 94143; 7UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA Corresponding author: valerie.weaverucsf.edu Abstract

Development and disease are regulated by the interplay between genetics and the signaling pathways stimulated by morphogens, growth factors, and cytokines. Experimental data highlight the importance of mechanical force in regulating embryonic development, tissue morphogenesis, and malignancy. Force not only sculpts tissue movements to drive embryogenesis and morphogenesis but also modifies the context of biochemical signaling and gene expression to regulate cell and tissue fate. Not surprisingly, experiments have demonstrated that perturbations in cell tension drive malignancy and metastasis by altering biochemical signaling and gene expression through modifications in cytoskeletal tension, transmembrane receptor structure and function, and organelle phenotype that enhance cell growth and survival, alter metabolism, and foster cell migration and invasion. At the tissue level, tumor-associated forces disrupt cell–cell adhesions to perturb tissue organization, compromise vascular integrity to induce hypoxia, and interfere with antitumor immunity to foster metastasis and treatment resistance. Exciting new approaches now exist with which to clarify the relationship between mechanotransduction, biochemical signaling, and gene expression in development and disease. Indeed, gaining insight into these interactions is essential to unravel molecular mechanisms that regulate development and clarify the molecular basis of cancer.