TGF-betas in breast cancer progression

Division Of Basic Sciences - Nci

Investigators

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Abstract

In FY24, we completed a multi-year study to address the dynamic behavior of the cancer stem cell (CSC) compartment during early metastatic colonization in breast cancer models, as a basis for understanding the role of TGF-beta in this process. This study was enabled by 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 fluorescent CSC reporter responds to the presence of the stem cell master transcription factors Oct4 and Sox2. Using this approach, we have addressed population dynamics and molecular characteristics of CSCs in vitro and in vivo, coupled with single cell fate mapping in vitro. Ex vivo imaging of freshly excised lungs in breast cancer xenograft and allograft models revealed very different dynamics for CSCs and their more differentiated offspring (nonCSCs) within the tumor cell population. Aspects of these dynamics were successfully modeled in vitro for mechanistic analysis and we demonstrated that (a) CSC population expansion is strongly and selectively inhibited as culture density increases, and (b) CSCs respond faster and more extensively than nonCSCs to many changes in their local microenvironment. Based on our results, we proposed the novel concept that CSCs serve as sensitive cellular sensors of microenvironmental quality for the tumor as a whole, calibrating local tumor expansion dynamics to available resources. The transcriptional regulators YAP/TAZ and their TEAD protein effectors are key mediators of this sensor mechanism, integrating inputs from multiple upstream signals such as nutrient status and cell crowding. The enhanced sensitivity of the CSC to microenvironmental inputs is a result of elevated cell surface receptors for input signals, and a chromatin organization that selectively increases accessibility of TEAD binding sites, including those in enhancers of genes that regulate stemness, such as ID1 and KLF5. Weaponizing this information, we showed that targeting upstream regulators of YAP/TAZ can reverse the undesirable stimulatory effects of conventional chemotherapy in metastases in preclinical models. Having established some fundamental new aspects of CSC dynamics, we are now proceeding to address how TGF-beta regulates this tumor cell subpopulation. We have shown that TGF-beta signal transduction and biological outputs are different in CSCs vs nonCSCs. Furthermore, TGF-beta regulates the CSC compartment differently depending on whether TGF-beta functions as tumor suppressor or pro-progression factor in a given tumor model. These results have important implications for the ongoing clinical development of TGF-beta pathway antagonists. In depth analysis of underlying molecular and biological mechanisms is ongoing. 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. 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.