Brain metastatic incidence in HER2+ breast cancer patients with advanced disease is lethal. More than 50% of patients with residual disease develop brain metastases and survival rates in these patients' post-diagnosis and treatment is less than a year. Current standard of care - cytotoxic drugs, radiation, HER2 targeted therapies are ineffective, implicating emergence of altered signaling, epigenomic and metabolic dependencies in disseminated cancer cells with metastatic potential. To effectively eliminate brain metastases, understanding how residual disseminated cancer cells in the brain survive, stay latent, and initiate metastasis is critical. Towards addressing this significant knowledg...

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Brain metastatic incidence in HER2+ breast cancer patients with advanced disease is lethal. More than 50% of patients with residual disease develop brain metastases and survival rates in these patients' post-diagnosis and treatment is less than a year. Current standard of care - cytotoxic drugs, radiation, HER2 targeted therapies are ineffective, implicating emergence of altered signaling, epigenomic and metabolic dependencies in disseminated cancer cells with metastatic potential. To effectively eliminate brain metastases, understanding how residual disseminated cancer cells in the brain survive, stay latent, and initiate metastasis is critical. Towards addressing this significant knowledge gap, we isolated disseminated brain-tropic cells that stay latent, resist current standard of care and initiate brain metastasis. Leveraging these unique preclinical models and insights from unbiased transcriptomic and metabolic analyses, we aim to uncover the precise mechanisms that aid survival of metastasis initiating cells. Our investigations demonstrate that latent metastasis initiating cells uptake fatty acids from lipid rich environment, oxidize them to meet their cellular energy needs and store excess free fatty acids as lipid droplets to maintain cellular lipid and redox balance. Thus, our working hypothesis is that DRP1 driven mitochondrial fission augments fatty acid oxidation and promotes metabolic reprogramming, while DGAT2-dependent lipid homeostasis prevents lipo-toxicity enabling survival of latent HER2+ brain-tropic cells. The overall goal is to perturb mitochondrial plasticity and lipid homeostasis in latent cells to assess their impact on metastatic latency and recurrence. We anticipate successful completion of this project will uncover targetable survival dependencies of latent metastasis initiating cells and facilitate development of therapeutic strategies targeting brain metastasis initiating cells.

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