Friday, April 4, 2025
4/4/2025
Decipher the Molecular Mechanisms of Breast Cancer Bone Metastasis - Breast cancer (BCa) metastases are associated with extremely high mortality; hence, the development of effective prevention and treatment strategies for metastatic breast cancer is critical. Bone is typically the first and most frequent site of breast cancer metastatic expansion, and the resulting metastases can cause severe pain, immobility, fractures, and nerve damage. Additionally, our recent studies underscore the important role bone metastases can play in spreading cancer cells to other organs, thus making the bone metastatic process a very attractive target for the prevention and treatment of metastatic breast cancer. Presently, current treatments for bone metastases, such as bisphosphonates, have shown limited success, largely because these drugs predominantly target bone turnover and remodeling instead of directly eradicating cancer cells in the bone environment. Moreover, tumor cells can at times survive adjuvant therapies given to patients after surgery and eventually cause late-onset relapse in bone. It is therefore imperative to establish new therapeutic strategies to improve the outcome of patients with breast cancer bone metastases. Our preliminary studies are helping to unravel the transition of biological behaviors from the early phase of bone metastases (termed microscopic-bone metastasis or micro-BoM) to established BoM (termed macro-BoM). At the micro-BoM stage, the colonized metastatic tumor cells grow slowly and undergo amino acid and lipid metabolism to collect and accumulate necessary resources to sustain their survival. Our mechanistic studies have suggested that in the micro-BoM stage, the transcriptional coactivators YAP/TAZ are regulated by a bone- specific calcium-signaling-related mechanism, and YAP/TAZ activation orchestrates a repertoire of metabolic gene expression. Furthermore, we have developed delicate strategies that allow us to treat the microscopic bone lesions. The overall objectives of this proposal are to understand the underlying molecular mechanisms by which YAP/TAZ activation drives the advancing of BCa BoM. Our central hypothesize is that YAP/TAZ orchestrates an evolution of metabolic behaviors in micro-BoM and targeting of YAP/TAZ could potentially impede cellular adaptation processes and arrest the progression of micro-BoM. Our long-term goals are to decipher the crosstalk between YAP/TAZ activation in bone-colonized tumor cells and the bone microenvironment and uncover new therapeutic targets to treat both the microscopic and fully established BoM. To achieve these goals, we propose the following two aims: 1) determine the molecular mechanisms driving the dynamical activation of YAP/TAZ in BCa BoM; 2) determine the functional role of YAP/TAZ-activation-driven metabolic reprograming in BCa micro- BoM. A major impact of this study will be the identification of previously undescribed mechanisms underlying the adaptation and progression of microscopic BoM that can inform the development of new biomarkers and novel therapeutic interventions for advanced or metastatic BCa.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).