Abi1 loss drives prostate tumorigenesis through activation of EMT and noncanonical WNT signaling.

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.

Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer

“…Dysregulated ABI1, a protein involved in cellular cytoskeleton stabilization and signaling, may also contribute to the EMT process [45]. Downregulation of ABI1 is associated with loss of E-cadherin, the key protein involved in maintaining the adherens junction [45]. This may propel disease progression and metastatic spread of tumor through activation of EMT.…”

“…This may propel disease progression and metastatic spread of tumor through activation of EMT. ABI1 loss has also been associated with upregulated STAT3 activity [45]. STAT3 is a master regulator of EMT transcriptional programing that promotes cellular adhesion, migration, proliferation and differentiation Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 12 April 2021 doi:10.20944/preprints202104.0287.v1 [34,46,47].…”

“…ABI1 regulates STAT3 expression through SRC kinase FYN providing a novel, potential strategy for STAT3 targeting [45]. Enhanced STAT3 levels are associated with enzalutamide resistance [68].…”

“…Enhanced STAT3 levels are associated with enzalutamide resistance [68]. Therefore, loss or downregulation of ABI1 with overactive STAT3 signaling may contribute to enzalutamide resistance [45]. This suggests a potential role of ABI1 as a novel biomarker for early EMT events, as well as STAT3-mediated enzalutamide resistance.…”

Pan-cancer transcriptomic data of ABI1 transcript variants and molecular constitutive elements identifies novel cancer metastatic and prognostic biomarkers

“…Previous studies showed that the abnormal expression and phosphorylation of ABI1 are involved in the invasion and metastasis of various malignant tumors (colorectal cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma, breast cancer, leukemia, prostate cancer, and ovarian cancer, etc. ), being closely related to their prognosis [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26].…”