A groundbreaking study recently published in the prestigious journal Oncotarget has shed new light on the complex biology of metastatic prostate cancer, highlighting an unexpected protagonist: the R-spondin family member RSPO2. This comprehensive research, led by Aiden Deacon and corresponding author Justin Hwang from the University of Minnesota-Twin Cities, delves deeply into the functional distinctions and clinical implications of RSPO2 compared to its family counterparts in advanced prostate cancer cases. By unraveling the molecular intricacies of RSPO2, the study paves the way for novel therapeutic avenues against treatment-resistant forms of this prevalent malignancy.
Prostate cancer remains the most frequently diagnosed cancer among men in the United States, with metastatic progression marking a formidable clinical challenge. Despite initially effective androgen receptor (AR) targeted hormone therapies, many prostate tumors evolve mechanisms to bypass this dependency, engendering more aggressive and treatment-refractory disease states. The R-spondin (RSPO) family—comprising RSPO1, RSPO2, RSPO3, and RSPO4—serves as key modulators of the Wnt signaling pathway, an essential regulator of cellular proliferation, differentiation, and migration. While Wnt pathway disruption is well-documented in oncogenesis, the distinct roles of individual RSPO proteins in prostate cancer have remained underexplored until now.
Leveraging extensive genomic analyses encompassing thousands of metastatic prostate cancer tumor samples, the researchers revealed that RSPO2 alterations, particularly gene amplifications, occur at a striking frequency exceeding 20%. This rate surpasses not only changes in other RSPO family members but also surpasses prominent cancer genes such as CTNNB1 (encoding β-catenin) and APC which are canonical regulators within the Wnt signaling axis. These RSPO2 amplifications correlated with poor clinical outcomes, heightened tumor mutational burden, and elevated genomic instability, underscoring RSPO2’s pivotal oncogenic contribution in aggressive prostate cancer phenotypes.
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Functional assays utilizing prostate cancer cell lines established that RSPO2 overexpression drives increased cellular proliferation and activates epithelial-mesenchymal transition (EMT), a phenotypic switch whereby epithelial cells acquire mesenchymal properties. EMT is intimately linked to enhanced metastatic potential, therapeutic resistance, and poor prognosis in many cancers. Notably, RSPO2 induced upregulation of well-known EMT transcription factors including ZEB1, ZEB2, and TWIST1, which coordinate gene expression programs promoting cell motility and invasiveness. This mechanistic insight frames RSPO2 as an instrumental factor catalyzing tumor progression and dissemination.
Intriguingly, RSPO2 also exerts negative regulatory effects on androgen receptor signaling. Unlike other RSPO family members or canonical Wnt pathway components that may synergize with AR pathways, RSPO2 appears to suppress AR activity, potentially facilitating the emergence of AR-independent prostate cancer clones. This finding is critical because loss of AR reliance is a hallmark of castration-resistant prostate cancer, an incurable stage marked by resistance to standard hormone therapies. Consequently, RSPO2-mediated modulation may underpin this lethal transition, positioning RSPO2 as a unique molecular driver of therapy escape.
At a structural level, bioinformatic modeling using Alphafold2 has demonstrated distinctive three-dimensional conformations of RSPO2 compared to RSPO1, RSPO3, and RSPO4. These structural disparities encompass amino acid sequence variances and hydrophobicity profiles, as well as notable differences in root mean square deviation (RMSD) scoring—parameters vital for protein function and interaction specificity. Such molecular uniqueness intimates that selective pharmacological inhibition of RSPO2 is plausible, a notion of profound therapeutic relevance given the current paucity of targeted Wnt signaling inhibitors effective against RSPO2.
Presently, clinical strategies targeting the Wnt pathway are limited, and there exist no approved agents that selectively inhibit RSPO proteins. The intricate balance of Wnt signaling in normal tissue homeostasis complicates systemic targeting due to potential toxicity. However, the revelation of RSPO2 as a critical, structurally distinct oncogene in metastatic prostate cancer invites the design of novel molecules or biologics aimed precisely at this target, potentially offering a lifeline to patients whose tumors no longer respond to androgen deprivation or chemotherapy.
Furthermore, the study’s integration of genomic data with laboratory models exemplifies a powerful translational approach that bridges molecular discovery with clinical implications. By correlating RSPO2 gene amplifications with phenotypic aggressiveness and demonstrating causal impacts in vitro, the research provides robust evidence to justify pursuing RSPO2 inhibitors in clinical trials. This aligns with a broader oncology movement towards precision medicine, where understanding the unique genetic and proteomic landscapes of tumors informs rational drug development.
The implications of this work extend beyond prostate cancer biology. Given the conserved nature of RSPO proteins within Wnt signaling and the centrality of Wnt dysregulation in numerous malignancies, insights gleaned from RSPO2 could illuminate therapeutic strategies for a broad spectrum of cancers. The concept of exploiting subtle structural differences among highly homologous protein families to selectively target pathological variants could serve as a blueprint for future drug discovery endeavors across oncology.
Moreover, this research challenges existing paradigms by implicating a less-studied member of a gene family as a key driver of cancer aggressiveness and treatment resistance. It underscores the importance of dissecting gene family heterogeneity rather than treating them as functionally redundant units, a principle increasingly supported by advances in structural biology and high-throughput genomics. Such nuances may critically impact patient stratification and biomarker development, fostering the era of individualized cancer therapy.
As metastatic prostate cancer remains a leading cause of cancer-related mortality, especially when hormone therapies fail, the identification of RSPO2 as a molecular culprit opens promising investigative and clinical pathways. Future endeavors will likely focus on refining the biochemical mechanisms of RSPO2, elucidating its interaction networks, and developing selective inhibitors that harness these mechanistic insights. This study represents a significant stride towards transforming aggressive prostate cancer from a terminal diagnosis into a manageable condition through targeted molecular intervention.
In summary, this landmark study not only advances our understanding of the molecular underpinnings of therapy-resistant prostate cancer but also spotlights RSPO2 as a novel and druggable target within the Wnt signaling landscape. The convergence of genomic, biochemical, and structural data charts an exciting course towards next-generation therapeutics capable of overcoming current treatment barriers, heralding hope for millions affected by metastatic prostate cancer worldwide.
Subject of Research:
Advanced prostate cancer; R-spondin family genes; RSPO2 functional role; Wnt signaling pathway in cancer.
Article Title:
Dissecting the functional differences and clinical features of R-spondin family members in metastatic prostate cancer
News Publication Date:
25-Jul-2025
Web References:
Journal: Oncotarget Volume 16
DOI: 10.18632/oncotarget.28758
Image Credits:
© 2025 Deacon et al. Licensed under Creative Commons Attribution License (CC BY 4.0).
Keywords:
Prostate cancer, RSPO2, R-spondin family, Wnt signaling, epithelial-mesenchymal transition, androgen receptor resistance, gene amplification, structural biology, targeted therapeutics, metastatic cancer.
Tags: aggressive prostate cancerandrogen receptor-targeted therapiesmetastatic prostate cancer biologyMolecular mechanisms in cancernew gene RSPO2novel cancer therapeuticsOncotarget journal publicationprostate cancer research advancementsRSPO family proteinstreatment-resistant prostate cancerUniversity of Minnesota-Twin Cities studyWnt signaling pathway