Skip to main content

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

Publication ,  Conference
Nath, D; Li, X; Mondragon, C; Post, D; Chen, M; Hryniewicz-Jankowska, A; Caza, T; White, J; Kuznetsov, V; Hehnly, H; Khanna, R; Gleicher, S ...
Published in: Journal of Clinical Oncology
March 1, 2019

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.

Duke Scholars

Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

March 1, 2019

Volume

37

Issue

7_suppl

Start / End Page

280 / 280

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Nath, D., Li, X., Mondragon, C., Post, D., Chen, M., Hryniewicz-Jankowska, A., … Kotula, L. (2019). Abi1 loss drives prostate tumorigenesis through activation of EMT and noncanonical WNT signaling. In Journal of Clinical Oncology (Vol. 37, pp. 280–280). American Society of Clinical Oncology (ASCO). https://doi.org/10.1200/jco.2019.37.7_suppl.280
Nath, Disharee, Xiang Li, Claudia Mondragon, Dawn Post, Ming Chen, Anita Hryniewicz-Jankowska, Tiffany Caza, et al. “Abi1 loss drives prostate tumorigenesis through activation of EMT and noncanonical WNT signaling.” In Journal of Clinical Oncology, 37:280–280. American Society of Clinical Oncology (ASCO), 2019. https://doi.org/10.1200/jco.2019.37.7_suppl.280.
Nath D, Li X, Mondragon C, Post D, Chen M, Hryniewicz-Jankowska A, et al. Abi1 loss drives prostate tumorigenesis through activation of EMT and noncanonical WNT signaling. In: Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2019. p. 280–280.
Nath, Disharee, et al. “Abi1 loss drives prostate tumorigenesis through activation of EMT and noncanonical WNT signaling.Journal of Clinical Oncology, vol. 37, no. 7_suppl, American Society of Clinical Oncology (ASCO), 2019, pp. 280–280. Crossref, doi:10.1200/jco.2019.37.7_suppl.280.
Nath D, Li X, Mondragon C, Post D, Chen M, Hryniewicz-Jankowska A, Caza T, White J, Kuznetsov V, Hehnly H, Khanna R, Gleicher S, Jamaspishvili T, Berman DM, Zhang F, Kung SHY, Fazli L, Bratslavsky G, Pandolfi PP, Kotula L. Abi1 loss drives prostate tumorigenesis through activation of EMT and noncanonical WNT signaling. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2019. p. 280–280.

Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

March 1, 2019

Volume

37

Issue

7_suppl

Start / End Page

280 / 280

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences