Abstract

Tumors show increased tissue level force and present with a remodeled, stiffened extracellular matrix (ECM). Moreover, transformed cells exhibit a perturbed oncogene-stimulated and ECM -tuned mechanophenotype that further stimulates ECM remodeling and stiffening. My group has been exploring how the aberrant cell and tissue level forces arise and by what means they contribute to malignancy and metastasis, as well as tumor recurrence and treatment resistance. We use two and three dimensional culture models with tuned ECM stiffness, as well as transgenic and syngeneic mouse models, human PDX models and human biospecimens, in which ECM crosslinking and stiffness and integrin mechanosignaling are manipulated and quantified. Our work has thus far revealed that the tumor ECM is progressively remodeled, and stiffened, primarily by stromal fibroblasts prior to malignant transformation. We determined that infiltrating pro-tumorigenic myeloid cells secrete factors that stimulate stromal fibroblasts to remodel and crosslink the ECM very early during tumor evolution. The stromal-fibroblast stiffened ECM thereafter disrupts tissue organization, promotes cell growth and survival and drives cell invasion. The stiffened tumor stroma additionally drives angiogenesis, and activates STAT3 to increase expression of cytokines and chemokines that stimulate immune cell infiltration. The stiffened ECM thereafter differentially modulates TGF  signaling in the myeloid cells to alter their metabolism and drive their synthetic ECM phenotype that accelerates tumor aggression and metastatic dissemination by impairing CD8 T cell anti-tumor immunity. During my presentation I will discuss the dynamic and reciprocal interplay between tissue tension and innate and acquired immunity, and how this forces tumor aggression and metastasis.