Abstract
280 Background: Prostate cancer is characterized by heterogeneity of mechanisms which are poorly understood but pointing to epithelial plasticity as the key mechanism in progression to metastatic disease. ABI1, a member of WAVE complex and actin cytoskeleton regulator and adaptor protein, is proposed to act as tumor suppressor in prostate cancer, but the mechanism of tumor progression due to Abi1 loss is not clear. Methods: To address Abi1’s role in prostate cancer we used CRISPR-based gene editing and retroviral expression to manipulate Abi1 levels in prostate cancer cell lines. Levels of Abi1 expression in prostate organoid tumor cell lines were evaluated by Western blotting and/or RNA sequencing. Association of Abi1 loss with tumor grade was evaluated by immunohistochemistry. Results: Abi1 expression is downregulated in tumor organoid cell lines from metastatic bone and lymph node biopsies. Moreover, low Abi1 expression is associated with high-grade prostate tumors (GG3 or higher, p < 0.001). Disruption of Abi1 gene in a benign prostate epithelial cell line RWPE-1 resulted in a gain of invasive phenotype, which is characterized by loss of cell-cell adhesion markers and increased migratory ability of RWPE-1 Abi1 KO spheroids. Through RNA sequencing and protein expression analysis we discovered that Abi1 loss leads to activation of non-canonical WNT signaling and EMT pathways, which are rescued by re-expression of Abi1. Furthermore, increase in STAT3 phosphorylation upon Abi1 inactivation and evidence for high affinity interaction of FYN-SH2 domain with Abi1 pY421 support the model that Abi1 acts as a gatekeeper of the non-canonical WNT-EMT pathway activation downstream from FZD2 receptor. The gene expression profile of Abi1-EMT-WNT pathway overlaps with the reported gene signature of high-risk prostate tumors. Conclusions: Abi1 contributes to prostate cancer progression and epithelial plasticity through regulation of EMT-WNT pathways. Understanding of Abi1’s role may provide more mechanistic understanding of prostate cancer tumor progression.
Highlights
Prostate cancer development involves various mechanisms, which are poorly understood but pointing to epithelial mesenchymal transition (EMT) as the key mechanism in progression to metastatic disease
Low Abi1 expression is associated with high-grade prostate cancer and biochemical recurrence Our previous studies identified the loss of heterozygosity in ABI1 gene locus [37], the mechanism of ABI1 role as a tumor suppressor in prostate cancer is poorly understood
Staining of a test tumor tissue microarray (32 cases) with ABI1 antibody demonstrated a remarkable loss of ABI1 expression in tumors with high Gleason grade (Additional file 1: Figure S1A)
Summary
Prostate cancer development involves various mechanisms, which are poorly understood but pointing to epithelial mesenchymal transition (EMT) as the key mechanism in progression to metastatic disease. While indolent PCa is treatable, metastatic cancer invariably has a high mortality rate [2], warranting studies of PCa progression mechanisms and development of new therapeutic targets. Several growth control pathways have been implicated in high-risk prostate cancer. Aggressive prostate cancer has been linked to Androgen Receptor (AR) activation, which occurs through multiple mechanisms, including intra-tumor androgen production [4]. Bioinformatic inquiries over the last decade have resulted in a better understanding of signaling pathways and genetic alterations associated with prostate cancer initiation [7] and metastatic progression [8, 9]. Our previous studies implicated ABI1 downregulation in high-risk prostate tumors [10], but the mechanism underlying Abi tumor suppressor activity is unclear
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