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. Significance: This work provides fundamental insights into Wnt signaling and prostate cancer cell biology and indicates that a subset of prostate cancer driven by autocrine Wnt signaling is sensitive to Wnt synthesis inhibitors.

The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer

“…Other classical tumorigenic pathways, such as Wnt signaling pathway (KEGG:04310, adjusted p-value = 3.48e-4) and TGF-beta signaling pathway (KEGG:04350, adjusted p-value = 3.30e-5) appear also enriched. In this regard, recent studies analyzed the involvement of Wnt signaling in the proliferation of prostate cancer cells (Ma et al 2022; Wei et al 2022), as well as the involvement and TGF-beta signaling (Natani et al 2022; Xi et al 2022).…”

HOXB3 drives WNT-activation associated progression in castration-resistant prostate cancer

“…Previous studies have shown that WNT-pathway activation is associated with higher Gleason grades and PSA levels [ 13 ]. In addition, aberrant activation of the WNT pathway is causative to multiple cancer progression, which may be caused by mutations of pathway components or dyshomeostasis of autocrine/paracrine signaling [ 31 , 34 , 35 ]. Among them, functional mutations in WNT pathway components have been demonstrated to be important for progression and NHT resistance in mCRPC patients.…”

“…In other word, upstream components of the pathway may be responsible for the high frequency of WNT signal activation besides somatic mutations. Emerging evidence show WNT3A [ 37 , 38 ], WNT16B [ 39 ] and WNT5A [ 34 ] are essential in PCA for its initial, development, progression and therapy resistance, which may be autocrine or paracrine from stroma. In this study, higher WNT3A was detected in HOXB3 + tumors and was associated with higher tumor grade and stage.…”

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

“…Recent work has shown that Wnt/β-catenin signaling not only promotes stem cell maintenance and invasive ability in mCRPC but also potentiates noncanonical Wnt5a -ROR1 signaling [ 255 ]. The non-canonical Wnt co-receptor ROR1 is elevated in several hematological and solid malignancies, particularly chemo-refractory disease [ 255 , 256 , 257 , 258 , 259 ]. Furthermore, the anti-ROR1 blocking antibody cirmtuzumab has shown efficacy in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) trials [ 247 ].…”