Autocrine Canonical Wnt Signaling Primes Noncanonical Signaling through ROR1 in Metastatic Castration-Resistant Prostate Cancer
Abstract
Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes β-catenin, have been implicated in prostate cancer development and progression to metastatic castration-resistant prostate cancer (mCRPC). However, nongenomic drivers and downstream effectors of Wnt signaling in prostate cancer and the therapeutic potential of targeting this pathway in prostate cancer have not been fully established. Here we analyzed Wnt/β-catenin signaling in prostate cancer and identified effectors distinct from those found in other tissues, including aryl hydrocarbon receptor and RUNX1, which are linked to stem cell maintenance, and ROR1, a noncanonical Wnt5a coreceptor. Wnt/β-catenin signaling–mediated increases in ROR1 enhanced noncanonical responses to Wnt5a. Regarding upstream drivers, APC genomic loss, but not its epigenetic downregulation commonly observed in prostate cancer, was strongly associated with Wnt/β-catenin pathway activation in clinical samples. Tumor cell upregulation of the Wnt transporter Wntless (WLS) was strongly associated with Wnt/β-catenin pathway activity in primary prostate cancer but also associated with both canonical and noncanonical Wnt signaling in mCRPC. IHC confirmed tumor cell WLS expression in primary prostate cancer and mCRPC, and patient-derived prostate cancer xenografts expressing WLS were responsive to treatment with Wnt synthesis inhibitor ETC-1922159. These findings reveal that Wnt/β-catenin signaling in prostate cancer drives stem cell maintenance and invasion and primes for noncanonical Wnt signaling through ROR1. They further show that autocrine Wnt production is a nongenomic driver of canonical and noncanonical Wnt signaling in prostate cancer, which can be targeted with Wnt synthesis inhibitors to suppress tumor growth.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 07, 2022
- Source ID
- 10.1158/0008-5472.can-21-1807
Entities
People
- Adam G Sowalsky
- Amanda R. Yuan
- Carla Calagua
- David J Einstein
- Eliezer Van Allen
- Fen Ma
- Huihui Ye
- Joshua W. Russo
- Keshan Wang
- Larysa Poluben
- Manoj K. Bhasin
- Meng Xiao He
- Seiji Arai
- Steven P Balk
- Xin Yuan
- Yu Liu
- Zhongkai Gu
Organizations
- Dana–Farber Cancer Institute
- Emory University School of Medicine
- Gunma University Hospital
- Harvard Medical School
- Huazhong University of Science and Technology
- National Cancer Institute
- National Institutes of Health
- National Science Foundation
- United States Department of Defense
- University of California, Los Angeles