FGFR1-NCAM Interactions Promote Neuron-Mediated Outgrowth of ER+ Breast Cancer Brain Metastasis

University Of Colorado Denver, Aurora CO

Investigators

Abstract

Abstract Brain metastasis (BM) confers the worst survival outcomes for patients with breast cancer (BC). While most breast cancer brain metastasis (BCBM) research focuses on triple-negative and HER2+ subtypes, which have higher rates of BM, estrogen receptor positive (ER+) breast cancer, the most frequently diagnosed subtype, accounts for a large fraction of BCBM. Aside from being severely understudied, ER+ BCBM occurs in the unique clinical setting of age and low estrogen (E2). Preliminary data from our lab demonstrates that while models of ER+ BCBM in young mice require supplementation of E2, as is the standard across the field, BCBM were able to outgrow independent of E2 supplementation in older mice, suggesting that the aged brain provides a distinct niche that supports E2-independent outgrowth of ER+ BCBM. Prior studies have identified FGFR1 aberrations as drivers of endocrine resistance and predictors of increased risk for BCBM. Published and preliminary studies show that FGFR1-amplification alone is not sufficient to drive tumor progression in post-menopausal mouse models; rather, FGFR1-kinase signaling activation through the microenvironment promotes tumor progression under low E2. Our preliminary studies show that ER+ patient-derived xenografts (PDX) with FGFR1-amplification have greater ability to colonize the brain, and FGFR1 downregulation decreased the ability of FGFR1+ ER+ BC cells to grow in organotypic brain slices and in the brain in vivo, suggesting that brain-induced activation of FGFR1 may play a role in the promotion of ER+ BCBM. Recent studies have shown that growth of BCBM cells depends on their ability to form pseudo-synapses with glutamatergic neurons, and that neuronal activity can drive BM outgrowth of multiple cancers. Binding of FGFR1 to NCAM (neural cell adhesion molecule) promotes synaptic plasticity and activates FGFR1 downstream signaling in neurons. Our preliminary studies indicate that treatment of ER+ BC with exogenous NCAM induces rapid kinase and downstream oncogenic pathway activation, and that FGFR1 downregulation reduces synapse density in ER+ BC cells co-cultured with brain slices. Thus, the hypothesis of this proposal is that that FGFR1 contributes to ER+ BCBM in the aged and E2- depleted brain microenvironment by i) binding to neuronal NCAM and activating downstream oncogenic signaling and ii) promoting neuronal activity-mediated signaling in ER+ BM. Aim1 will define how interactions between FGFR1 in ER+ BC and NCAM in neurons promote cancer growth downstream of FGFR1. Aim 2 will determine the impact of FGFR1 on the functionality of synapses between ER+ BC and neurons. The long-term goal of this proposal is to study novel interactions between ER+ BC and neurons through FGFR1. This study will identify how FGFR1 in ER+ BC promotes BM outgrowth through neuronal-specific interactions, providing insight into drivers of ER+ BCBM that can inform future therapies and clinical biomarkers.