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Uncovering the Role of Cancer Associated Fibroblasts in Facilitating Breast Cancer Metastasis

Project description

Cancer-associated fibroblasts provide niche for breast cancer metastases

Mortality from breast cancer is a result of metastasis. Therefore, understanding tumour metastatic mechanisms is the key challenge in cancer research. It has become clear that the microenvironment of tumours is crucial in supporting tumour growth. Recent discoveries demonstrate the role that microenvironment and cancer-associated fibroblasts (CAFs) in particular play in tumour-promoting inflammation. The ERC-funded MetCAF project proposes to investigate the molecular changes in CAFs that facilitate the formation of a permissive metastatic niche. The study objectives include characterisation of the transcriptional changes in lung fibroblasts in the case of breast cancer lung metastasis. It will elucidate the origin of CAFs at the lung metastatic niche, their role in inflammation, and the role of CAF-mediated fibrosis in supporting lung metastasis.

Objective

Mortality from breast cancer is almost exclusively a result of tumor metastasis. Since advanced metastatic cancers are usually fatal, understanding the biology of tumor metastasis is the most significant challenge in cancer research today. It has become clear that the microenvironment of tumors is crucial in supporting tumor growth. Nevertheless, the role of the metastatic microenvironment in facilitating metastatic colonization is largely unknown. We recently uncovered a novel role for Cancer-Associated Fibroblasts (CAFs) in mediating tumor-promoting inflammation. However, the role of CAFs in the formation of a permissive metastatic niche that enables the growth of disseminated tumor cells is unresolved. I propose to systematically investigate, for the first time, the molecular changes in CAFs that facilitate metastases formation, which may lead to the discovery of novel targets for cancer therapeutics. To achieve this goal, I will integrate tumor biology knowledge and the unique expertise of my lab: we will combine novel mouse models of spontaneous lung metastasis of breast cancer, imitating the clinical setting, with multi-transgenic reporter mice that enable origin tracing and unbiased analysis of fibroblast sub-populations. By performing a comprehensive molecular and functional characterization of fibroblast co-evolution during metastases formation and analysis of breast cancer patient cohorts, we will uncover the dynamic changes in CAFs at the metastatic niche, identify the origin of metastatic CAFs, and elucidate the signaling pathways that govern their functional role in breast cancer metastasis.
Molecular understanding of the early stages of tumor metastasis is an essential prerequisite for the discovery of novel therapeutic targets. Achievement of the proposed goals will shed light on a central conundrum in cancer biology and open new horizons for the development of novel therapeutics that will transform cancer into a chronic, yet manageable disease.

Host institution

TEL AVIV UNIVERSITY
Net EU contribution
€ 1 281 958,75
Total cost
€ 1 281 958,75

Beneficiaries (1)