Tumors develop a desmoplastic response that creates a tissue microenvironment that is complicit in malignant transformation and metastasis. Tumor desmoplasia is characterized by fibrosis that is mediated by elevated extracellular matrix deposition, remodeling and cross-linking that stiffen the tumor stroma. 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 becomes progressively remodeled and stiffened by the resident stromal fibroblasts and revealed that this occurs prior to malignant transformation. The stromal-fibroblast stiffened ECM disrupts tissue organization, promotes tumor cell growth, survival and invasion, induces angiogenesis, and promotes a pro-tumor immunity that drives tumor aggression and metastasis. We recently found that the fibrotic stroma drives the metabolic rewiring of the tumor cells and determined that this associates with elevated expression of key enzymes that regulate the cellular glycoproteome. A stiffened fibrotic stroma stimulated sialoglycan expression through tension-induced integrin signaling. The elevated mechanosignaling induced in the tumor cells by the stiffened stroma increased the level of secreted proteoglycans deposited at the tumor-ECM interface where a high density of protumorigenic immune suppressive infiltrating myeloid cells were detected. The association between a stiff, fibrotic tumor stroma, elevated secreted proteoglycans and a pro tumor immune infiltrate was very predominant in the more aggressive human breast tumors. I will discuss the dynamic and reciprocal interplay between tissue tension, metabolic reprogramming and glycoprotein regulation and innate and acquired immunity in tumor aggression and progression.
