Crosstalk Between Neurons and Brain-Metastatic Breast Cancer Cells Facilitates Successful Metastatic Colonization

Rationale, Objective, and Aims: Brain metastasis, the spread of cancer to the brain, is a leading cause of death in breast cancer patients. Despite the application of multiple treatment modalities, breast cancer brain metastasis has an extremely grim prognosis with overall survival ranges from only 2 to 16 months, depending on the subtype of the tumor. Importantly, more and more breast cancer patients are diagnosed and die from brain metastasis due to improved survival from newly developed treatments. Despite ongoing research efforts, the factors that attract breast cancer cells to the brain are not fully understood. In particular, little is known about the role of neurons and neuronal activity in creating an optimal environment for metastatic breast cancer cells to flourish in the brain. Supporting this potential role of neurons, recent studies suggest that psychological stress promotes breast cancer aggressiveness and metastasis. The tropomyosin receptor kinase (Trk) pathway is one of the main regulatory signaling pathways in neurons. Neurotrophins and neurotransmitters such as glutamate, serotonin, and dopamine are released by neurons upon neuronal activity. Neurotrophins are growth factors that bind and activate Trk proteins. We recently showed increased neurotrophin secretion by cancer cells and subsequent Trk pathway activation as a crucial resistance mechanism to treatment in several cancers including glioblastoma and breast cancer. Our preliminary data also suggest that exogenous neurotransmitters significantly activate the Trk pathway in breast cancer cells. Using novel methodology, we propose to determine the role of the Trk pathway to mediate the interaction between neurons and metastatic breast cancer cells and subsequently promote tumor growth and therapeutic resistance. We will achieve this objective through pursuing these aims: In Aim 1, we will show that neuronal activity promotes breast cancer growth through activating the Trk pathway in cancer cells. In Aim 2, we will evaluate the impact of breast cancer brain metastasis on neurons and their activity, and in Aim 3, we will evaluate the therapeutic potential of clinically applicable Trk inhibitors against breast cancer brain metastasis. Applicability of the Research: The treatment of breast cancer brain metastases remains an unmet clinical need. Despite significant advances in the treatment of primary breast cancer, there is a remarkable lack of chemotherapeutic options against brain metastases. Given its increasing incidence and grim prognosis, new therapeutic strategies for the prevention and treatment of breast cancer brain metastasis are urgently needed. Our proposed studies would discover novel interactions between neurons and metastatic breast cancer cells that promote the establishment and growth of the metastatic disease. These findings could help develop new therapeutic strategies for the prevention and treatment of brain metastasis that can eventually be brought to the clinic. Establishing the Trk pathway as a crucial therapeutic target would rapidly lead to clinical trials for breast cancer patients, as Trk inhibitors have already been tested and Food and Drug Administration (FDA) approved by the for other indications. These clinically applicable inhibitors are highly brain penetrant and well tolerated, with minimal side effects. Altogether, these studies could significantly reduce breast cancer-related morbidity and mortality and improve the quality of life.