Function and Therapeutic Implications of NRG3 in Breast Cancer Brain Metastasis

The goal of this project is to uncover the mechanisms driving brain metastasis occurrence in breast cancer models that are clinically less associated with brain metastasis at diagnosis. Metastasis stands as the utmost obstacle to Breast Cancer treatment. While both genomic and epigenetic increase in complexity during metastasis, bone has been identified as the primary site of metastasis relapse in luminal breast cancer. More recently, we began to better appreciate the complexity of the metastatic cascade during breast cancer progression. In fact, we realized that cancer cells can expand from various metastatic sites to initiate new lesions which contribute to accelerating disease progression. Despite these clinical observations, the mechanisms driving these secondary metastasis processes remain largely unexplored. More recently, we have identified a poorly studied neuron-associated ligand, Neuregulin 3 (NRG3), as a bone metastasis-related factor. NRG3 was induced in bone metastasis via epigenetic mechanisms and demonstrated to enhance the seeding potential of breast cancer cells. Surprisingly, we found that in the brain, the ecosystem surrounding secondary micrometastases derived from bone-reprogrammed cancer cells was also NRG3-enriched, arguing for key roles of NRG3 in the brain metastasis initiation process. The ability of luminal models to transition from “bone-only” to brain metastasis-initiating cells suggests that NRG3 could enhance the brain metastasis potential of cancer cells. As brain metastasis is associated with worse survival outcomes in bone metastasis patients, we hypothesize that the bone-mediated NRG3 promotes brain metastasis by remodeling the brain microenvironment and establishing a pro-survival niche. To test our hypothesis, we will (i) elucidate the role of neuron-derived NRG3 on CTC chemoattraction from bone to brain, (ii) investigate the mechanisms of the “NRG3 niche” establishment in bone metastasis-derived BrM, and (iii) assess the therapeutic potential of NRG3 inhibition using experimental and spontaneous preclinical models. Ultimately, this paradigm-shifting proposal will narrow down a large gap of knowledge on the metastasis-to-metastasis seeding process and establish a new foundation for brain metastasis prevention and treatment in patients with bone metastasis as the primary site of distant relapse. Project Number: 1R01CA303558-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Igor Bado | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $642,242 | Activity Code: R01 | Study Section: Tumor Host Interactions Study Section[THI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366698