Forcing Tumor Progression and Aggression

Valerie Weaver, Ph.D

Professor, Department of Surgery, Radiation Oncology and Bioengineering Director,

Center for Bioengineering &Tissue Regeneration,

Department of Surgery University of California, San Francisco

Forcing Tumor Progression and Aggression

Tissue development and homeostasis are regulated by tissue mechanics. Cells possess mechanotransduction machinery that detects force and translates these cues through the cytoskeleton and signaling platforms to regulate their growth, survival, migration and morphogenesis. Tumors show aberrantly increased tension and transformed cells are frequently more contractile. We have been studying what factors induce tumor tension and the relevance of perturbed tissue mechanics to malignancy. Our studies demonstrate that tissue inflammation induces tissue stiffening by stimulating stromal fibroblasts to deposit, remodel and crosslink the extracellular matrix (ECM). We determined that ECM stiffening occurs early during tumor progression and contributes to malignant transformation, tumor aggression as well as treatment resistance and tumor recurrence. We also found that oncogenic transformation and loss of key tumor suppressors elevate cell intrinsic tension and induce malignancy and tumor progression by inducing ECM remodeling and stiffening and elevating mechanosignaling. I will discuss data to support a role for both intrinsic and extrinsic force in solid tumor behavior and how this phenotype could provide insight to guide and improve cancer therapy and prevent tumor recurrence following treatment.