Title: "The dynamic and reciprocal relationship between tissue tension and pro tumor immunity"

Abstract: Tumors show increased tissue level forces and a present with a chronically stiffened extracellular matrix (ECM), and transformed cells exhibit a perturbed oncogene-stimulated and ECM-tuned mechanophenotype. We have been studying how these aberrant cell and tissue level forces promote malignant transformation and drive tumor metastasis, and how they modulate tumor recurrence and treatment resistance in breast and pancreatic cancer and glioblastoma. We use two and three dimensional culture models with tuned extracellular matrix stiffness, as well as transgenic and syngeneic mouse models, human PDX models and human biospecimens, in which ECM crosslinking and stiffness and integrin mechanosignaling can be quantified and modified. Our studies have thus far revealed that the ECM in all tumors is progressively remodeled and stiffened by stromal fibroblasts and that this occurs prior to malignant transformation. We determined that ECM remodeling and stiffening is mediated very early during malignancy by stromal fibroblasts that are activated by factors including TGFb that are secreted by infiltrating pro inflammatory macrophages. The stromal-fibroblast stiffened ECM disrupts tissue organization, promotes cell growth and survival and drives cell invasion. A chronically stiffened tissue stroma drives angiogenesis, and activates STAT3 to induce key cytokines and chemokines that stimulate immune cell infiltration. The stiffened ECM thereafter modulates TGFb signaling in the myeloid cells to promote pro-tumor immunity that fosters tumor growth and dissemination. The stiffened ECM also drives an epithelial to mesenchymal transition and primes the metastatic niche to foster metastasis. I will discuss the dynamic and reciprocal interplay between tissue tension and innate and acquired immunity and how this forces tumor aggression and metastasis.


Valerie M. Weaver Lab

 

Stromal-epithelial interactions regulate tissue development and homeostasis. In particular, the extracellular matrix, which is the noncellular component of the microenvironment, influences cell growth, survival, migration and tissue-specific differentiation through a repertoire of cellular receptors including integrins, syndecans and discoidin receptors. My group is exploring the molecular mechanisms whereby these extracellular matrix receptors modulate cell fate. Specifically, we are investigating how mechanical and topological properties of the matrix, which are related to its composition and organization, regulate the function of matrix receptors to alter cell behavior. Our research program is broadly divided into two fields of inquiry. The first focuses on understanding how matrix composition and organization influences mammary tissue development and tumor progression, and the second aims to clarify the role of matrix force on embryonic and adult stem cell fate.

 

For further information and to view recent publications, please visit Professor Weaver's institutional profile page.