TGF-betas in breast cancer progression

Division Of Basic Sciences - Nci

Investigators

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Abstract

In FY23, we have continued to address characteristics of 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. Using ex vivo imaging of freshly excised lungs in a breast cancer xenograft model, 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 have been successfully modeled in vitro for mechanistic analysis, with a number of important findings. Based on our results, we propose that the CSC serves as a sensitive cellular sensor of microenvironmental quality, responding more rapidly than non-CSCs to changes in the cellular microenvironment. The transcription factors YAP/TAZ are key mediators of this sensor mechanism, integrating inputs from multiple upstream signals such as nutrient status and cell crowding. Targeting upstream regulators of YAP/TAZ can reduce CSC numbers and complements the effect of chemotherapy in reducing non-CSCs. We have further shown that TGF-beta signal transduction and biological outputs are different in stem vs. non-stem cells, with TGF-beta regulating 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.