Defining the molecular mechanisms of fibroblast-mediated inflammation and its role in cancer progression and metastasis

Final Report Summary - CAF AND INFLAMMATION (Defining the molecular mechanisms of fibroblast-mediated inflammation and its role in cancer progression and metastasis)

Breast cancer continues to be one of the leading causes of cancer related mortality in women in the western world and inflammation is correlated with bad prognosis in breast cancer. Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. Cancer-Associated Fibroblasts (CAFs) are an activated sub-population of stromal fibroblasts, which have different characteristics in different tumor types and tissue locales. CAFs were shown to facilitate tumor growth by supporting tumor cell growth, enhancing angiogenesis and remodeling the extracellular matrix (ECM). We previously demonstrated that CAFs support tumorigenesis also by mediating inflammation in mouse and in human tumors. However, the role of CAFs in mediating tumor promoting inflammation in breast cancer is largely unknown and uncovering this role is a major aim of this project. We show that mammary fibroblasts can be educated by breast cancer cells to become activated to a pro-inflammatory state that supports malignant progression. Proteomic analysis of breast cancer cell–secreted factors identified the secreted pro inflammatory mediator osteopontin, which has been implicated in inflammation, tumor progression, and metastasis. Osteopontin was highly secreted by mouse and human breast cancer cells, and tumor cell–secreted Osteopontin activated CAF phenotypes in normal mammary fibroblasts in vitro and in vivo. Strikingly, silencing Osteopontin in tumor cells attenuated stromal activation, immune cell recruitment and inhibited tumor growth in vivo. Our findings establish a critical functional role for paracrine signaling by tumor-derived Osteopontin in reprograming normal fibroblasts into tumor-promoting CAFs. Moreover, by profiling the dynamic changes in CAFs isolated from distinct stages of mammary carcinogenesis, we have identified a novel pathway in mammary CAFs that links tissue damage with tumor-promoting inflammation called the NLRP3 inflammasome. The NLRP3 inflammasome is a multi-protein complex involved in sensing tissue damage and promoting the secretion of inflammatory cytokines. By utilizing a spontaneous model of murine breast carcinoma we study the role of CAF-derived NLRP3 inflammasome as a driver of tumor-promoting inflammation.
In addition, we studied the role of CAFs in facilitating lung metastasis of breast tumors. Mortality from breast cancer is almost exclusively a result of tumor metastasis, and therefore, understanding the mechanisms that facilitate the formation of a hospitable metastatic niche is a central challenge in cancer research. Very little is known about the role of CAF-mediated inflammation in facilitating lung metastasis and uncovering this role is a major focus of our research. We show that fibroblasts at the metastatic microenvironment are gradually activated even before the detection of lung metastases. This activation included elevated expression of αSMA and pro-inflammatory genes and activation of pro-fibrotic signaling which included collagen deposition. Notably, our data suggest a link between enhanced deposition of collagen and pulmonary metastasis. Moreover, we show that a subpopulation of lung CAFs are specifically recruited from the bone marrow, and that this subpopulation of CAFs has a distinct pro-inflammatory signature as compared with resident fibroblasts. Thus, fibroblasts at the metastatic site co-evolve with tumor progression and facilitate pulmonary metastasis of breast cancer.

Final Report Summary - CAF AND INFLAMMATION (Defining the molecular mechanisms of fibroblast-mediated inflammation and its role in cancer progression and metastasis)

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