TGF-betas in breast cancer progression

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

In FY22, we have continued to address the role of TGF-beta in regulating the cancer stem cell (CSC) compartment using a novel functional imaging approach that we developed to allow visualization of this minority cell population in real time and in situ. Our lentiviral-based CSC reporter uses a synthetic promoter in which expression of a fluorescent protein is driven by the stem cell master transcription factors Oct4 and Sox2. Using this approach, we have developed methods that allow extended cell fate mapping of individual CSCs in vitro and in vivo. In a collaboration with Dr. John Condeelis at the Albert Einstein College of Medicine we performed intravital imaging of the CSC population in primary breast tumor and at the lung metastatic site. The intravital imaging approach has allowed us to demonstrate that the CSCs are slow-moving, invasive cells in the primary tumor that are preferentially associated with the microanatomical structure (TMEM) that drives intravasation of tumor cells into the bloodstream. Importantly, we observed that contact with macrophages can induce a stem phenotype in non-stem tumor cells on contact with macrophages, thereby enhancing their aggressiveness and metastatic ability. Using ex vivo imaging of freshly excised organs, we have characterized CSC dynamics across the entire metastatic process, demonstrating peak CSC self-renewal during the earliest stages of metastatic colonization. Aspects of these dynamics can be successfully modeled in vitro for mechanistic analysis. We have shown that TGF-beta effects and TGF-beta signal transduction are different in stem vs. non-stem cells, and also that TGF-beta regulates the CSC compartment differently depending on whether TGF-beta is functioning as tumor suppressor or pro-progression factor. These results have important implications for the ongoing clinical development of TGF-beta pathway antagonists. We have developed fate-mapping approaches to address the effects of TGF-beta and components of the tumor microenvironment on phenotypic plasticity and CSC fate decisions. We are also integrating these analyses with genomic and single cell approaches to address underlying molecular mechanisms. Understanding how CSCs are regulated in vivo will be critical to development of more effective cancer therapies, as these cells are largely resistant to existing therapeutic approaches.