Wnt-signaling pathway (WSP) alterations have been identified in patients with prostate cancer (PCa) and are implicated in disease progression and hormonal resistance. We utilized a multi-institutional dataset to characterize molecular alterations in the canonical and non-canonical WSP in PCa. Patients with PCa who underwent tissue-based genomic sequencing were investigated. Tumors with somatic activating mutations in CTNNB1 or RSPO2, or inactivating mutations in either APC or RNF43 were characterized as having aberrant canonical Wnt signaling (WSP-activated). Overall survival (OS) analyses were restricted to microsatellite stable (MSS) tumors lacking RNF43 G659fs* mutations. We also investigated non-canonical WSP by evaluation of ROR1, ROR2, and WNT5 in WSP-activated versus WSP wild-type (WSP-WT) tumors. Of 4,138 PCa samples, 3,684 were MSS. Among MSS tumors, 42.4% were from metastatic sites, of which 19.1% were WSP-activated, and 57.6% from the prostate, of which 10.1% were WSP-activated. WSP-activated tumors were more prevalent in metastatic sites than in primary PCa. WSP-activated PCa exhibited more SPOP mutations and higher expression of canonical WSP activators than WSP-WT tumors. ROR1 gene expression was elevated in WSP-activated tumors from both primary and metastatic sites. M2 macrophages predominated the tumor microenvironment in WSP-activated tumors. There was no significant difference in OS between WSP-activated and WSP-WT PCa patients. WSP-activated PCa demonstrated a more immunosuppressed tumor microenvironment and a pronounced upregulation of ROR1 gene expression, underscoring its potential involvement in the crosstalk between canonical and non-canonical Wnt signaling pathways. Implications: Our findings may provide rationale for developing novel therapeutic strategies targeting Wnt-activated PCa.
Molecular cancer research : MCR. 2024 Jun 24 [Epub ahead of print]
Sharon H Choi, Elizabeth Pan, Andrew Elliott, Himisha Beltran, Justine Panian, Christina Jamieson, Aditya Bagrodia, Brent Rose, Daniel Herchenhorn, Elisabeth Heath, Chadi Nabhan, Emmanuel S Antonarakis, Rana R McKay
UC San Diego Health System, La Jolla, CA, United States., University of California, San Diego, La Jolla, CA, United States., Caris Life Sciences (United States), Phoenix, AZ, United States., Dana-Farber Cancer Institute, Boston, MA, United States., University of California San Diego Medical Center, United States., University of California - San Diego School of Medicine, San Diego, California, United States., Brazilian National Cancer Institute, Rio de Janeiro, Rio de Janeiro, Brazil., Karmanos Cancer Center, Detroit, MI, United States., Caris Life Sciences (United States), Deerfield, United States., University of Minnesota, Minneapolis, United States.