A groundbreaking study published on July 25, 2025, in Volume 16 of Oncotarget reveals the pivotal role of the RSPO2 gene in advancing metastatic prostate cancer. The research, led by Aiden Deacon and senior author Justin Hwang at the University of Minnesota-Twin Cities, offers fresh insights into the molecular mechanisms that fuel aggressive prostate tumors.
Prostate cancer remains the most prevalent cancer among men in the United States, posing a significant threat when it metastasizes beyond the prostate gland. While hormone therapies targeting the androgen receptor are standard treatments, many tumors eventually develop resistance, complicating patient management.
The research team conducted an extensive analysis of thousands of tumor samples, focusing on the R-spondin gene family (RSPO1, RSPO2, RSPO3, and RSPO4), which regulates the Wnt signaling pathway, a key driver in cancer progression.
Their findings highlighted RSPO2 as the most frequently altered gene within this family, surpassing even well-known cancer-related genes such as CTNNB1 and APC. Notably, RSPO2 gene amplification was present in over 20% of metastatic prostate cancer cases.
Patients harboring RSPO2 alterations exhibited markers of more aggressive disease, including increased mutation burden and heightened tumor complexity. Laboratory experiments further demonstrated that RSPO2 enhances cancer cell proliferation and promotes epithelial-mesenchymal transition (EMT), a process critical for tumor invasion and therapy resistance.
Unlike other genes within the Wnt pathway, RSPO2 uniquely suppressed androgen receptor activity, indicating its role in driving hormone-independent prostate cancer.
“In cell lines, RSPO2 overexpression led to upregulation of EMT pathways and key regulatory transcription factors such as ZEB1, ZEB2, and TWIST1,” explained the researchers.
Structurally, RSPO2 differs from other R-spondin proteins, suggesting potential for developing targeted inhibitors. Currently, no approved drugs exist that specifically block RSPO2, and therapies targeting the Wnt pathway remain limited. This study positions RSPO2 as a promising therapeutic target, particularly for patients resistant to hormone-based treatments.
By unveiling RSPO2’s crucial involvement in metastatic prostate cancer progression, this research opens avenues for novel treatment strategies aimed at combating therapy resistance and improving patient outcomes.
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