Delineating the Impact of MAOA on Cellular Plasticity and Heterogeneity in Therapy Resistant Prostate Cancer - Project Summary: Prostate cancer (PC) is a leading cause of cancer-related death among men in the United States. PC mortality is primarily a consequence of disease progression to an aggressive metastatic castration-resistant state (mCRPC), often associated with the failure of anti-androgen receptor (AR) therapies, including highly potent AR signaling inhibitors (ARSIs) like enzalutamide (Enz). Acquired ARSI resistance remains nearly universal and represents a significant clinical obstacle for improving survival. Cellular plasticity, especially lineage plasticity, and resulting intratumor heterogeneity have been increasingly recognized as a cancer hallmark observed in up to 25% of advanced, therapy-resistant CRPC patients, as well as a key mechanism for acquired ARSI resistance, enabling PC cells to reprogram their AR-driven luminal cell identity to a non-AR-driven disease state, such as a neuroendocrine (NE) phenotype, with reduced or lost AR signaling to evade anti-AR therapies. There is a pressing clinical need to identify new, druggable molecular determinants of PC plasticity for developing effective targeted strategies to extend the benefits of anti-AR therapies. In our preliminary studies, we separated live AR-/low (lo)(PSA-/lo) and AR+(PSA+) cells from human bulk mCRPC cells with acquired Enz resistance, and expanding on our prior research in the last funding cycle we found upregulation of monoamine oxidase A (MAOA) in AR-/lo cells, which exhibit enormous cellular plasticity, stemness, and secretory function compared to AR+ counterparts. We showed that MAOA is critically required for maintaining cellular plasticity, aggressive behavior, and ARSI resistance in AR-/lo cells. We demonstrated elevated MAOA expression in non-luminal cells at the single-cell level in heterogeneous human CRPC tumors. Mechanistically, MAOA dictates both cell-autonomous and paracrine mechanisms via TWIST1-dependent POU3F2 and MDK, respectively, to promote cellular plasticity in AR-/lo cells. These new findings support our hypothesis that MAOA is a molecular driver of cellular plasticity and heterogeneity and thus renders cells unresponsive to anti-AR therapies in mCRPC. To test this hypothesis, Aim 1 will delineate the molecular mechanism by which MAOA confers cellular plasticity and heterogeneity in therapy-resistant AR-/lo mCRPC cells, specifically dissecting how MAOA activates TWIST1-dependent POU3F2 and MDK to promote cellular plasticity and elucidate upstream signals and regulators that induce MAOA under ARSIs. Aim 2 will define the functional and biological impact of MAOA in therapy-resistant AR-/lo mCRPC and NEPC using a series of in vitro and in vivo phenotypic and pharmacological assays coupled with human and mouse cell lines, organoids, cell line- and patient-derived xenograft mouse models, and syngeneic and transgenic mouse models. The mouse models are essential for modeling prostate tumor growth and progression under systemic anti-AR therapies like ARSIs, as no in vitro or other models can replicate the tumor’s dynamic, system-level ARSI response and resistance evolution within the tumor microenvironment. Successful completion of this project will provide a compelling rationale for repurposing clinical MAOA inhibitors for advanced, therapy-resistant PCs.
