RSPO1 (R-Spondin 1)

The analysis identified 11 variants affecting both BRCA1 and BRCA2 carriers, most of which increase risk, including the following: IRS1, RSPO1, SYNPO2, BABAM1, MRPL34, PLEKHM1, and TIPARP...The only SNP reaching genome-wide significance (p < 5 × 10-8) was in BNC2. The article summarizes the growing number of genetic modifiers of ovarian cancer risk among BRCA1/2 carriers and highlights their potential to improve individualized risk assessment, enhance patient stratification, support personalized prevention and surveillance strategies, deepen the understanding of disease biology, and identify potential therapeutic targets.

Additionally, Wnt/β-catenin signaling inversely correlates with YAP/TAZ-mediated signaling, leaving higher YAP/TAZ activity in AXIN1-mutant versus CTNNB1-mutant cells. Thus, AXIN1 mutations drive physiologically relevant Wnt/β-catenin activation, providing a permissive environment for YAP/TAZ signaling, thereby distinguishing them from CTNNB1 mutations.

Mechanistically, RSPO4 exerted suppressive effects on Wnt signaling in an LGR4/5- and ZNRF3- dependent manner, through promoting LRP6 degradation and ZNRF3 stabilization. Our study revealed a novel role of RSPO4 as a tumor suppressor through antagonizing Wnt signaling, which provides important implications for development of diagnostic biomarkers and targeted therapy.

This study identifies a relatively high incidence of RSPO3 rearrangements in aCRC and a strong association with clinical features. Furthermore, we find that RSPO3 fusions are associated with poorer OS.

Our findings also highlight technical challenges in NUMT detection across genome builds and databases, with significant discrepancies observed between reference genomes and population frequency estimates. We propose that this homozygous RSPO1-NUMT insertion may represent a previously unrecognized predisposing factor for LUAD development and progression through modulation of RSPO1 expression and subsequent WNT pathway activation, potentially influencing tumor vascularization, drug response, and disease progression.

RSPO1 enhances Wnt signaling by specifically stabilizing FZD5/8...We further demonstrated that DVL proteins promote ligand-independent endocytosis of FZD but are dispensable for Wnt-induced FZD5/8 endocytosis and degradation. Our results reveal a novel negative regulatory mechanism of Wnt signaling at the receptor level and illuminate the mechanism by which RSPO-ZNRF3/RNF43 regulates Wnt signaling in human cells, which may provide new insights into regenerative medicine and cancer therapy.

This ternary arrangement and forced dimerization of ZNRF3 likely underpin how LGR4 and RSPO2 potentiate Wnt/β-catenin signaling by sequestering ZNRF3 from Wnt receptors and facilitating its auto-inactivation. This study provides a structural basis for understanding the regulatory mechanism of Wnt/β-catenin signaling through the LGR4-RSPO2-ZNRF3 pathway and may offer opportunities for future drug development targeting this axis.

Importantly, we generated a functional RNF43-DCP by producing a hexavalent GUR-1.6.12.2 molecule, which exhibited inhibitory activity against Wnt signaling in cells by competing with R-spondin, a RNF43 ligand that potentiates signaling. The RNF43 binders presented here offer new opportunities for the research and development of anticancer therapies targeting Wnt signaling with improved selectivity.

TNFR1-mediated signaling regulates specification and function of colonic mesenchyme, performing an integral role in the maintenance of the crypt stem cell population.

ESCC exhibited amplifications of MCL1, RECQL4, NKX2-1, PARP10, RSPO1, MUCL, and WTIP, while GAC showed deletions of APC and PRKG1, along with amplifications of ARRDC1 and NRARP. The patient achieved stable disease without recurrence following chemoradiotherapy and Sintilimab immunotherapy. This case underscores the role of genetic alterations in dual primary cancers and demonstrates the feasibility of precision treatment.

This large-scale Proteome-Wide MR study introduced novel targets for BMD and osteoporosis at transcriptional and translational levels, presenting new prospects for drug repurposing and development.

In mediation analysis, decreased chymotrypsin B2 (CTRB2) levels mediated 1.03% (95% CI [confidence interval] 0.02%-2.03%) of the effects of body mass index on acute pancreatitis...We also found increased klotho beta (KLOTB) levels mediated the effects of waist-hip ratio (7.01%, 95% CI 3.30%-10.71%) and visceral adipose tissue (8.98%, 95% CI 4.55%-13.41%) on chronic pancreatitis, and decreased receptor tyrosine kinase-like orphan receptor 1 (ROR1) levels mediated the effects of body mass index (10.39%, 95% CI 3.36%-17.42%) and visceral adipose tissue (6.29%, 95% CI 1.00%-11.58%) on pancreatic carcinoma. The MR suggests that circulating CTRB2, RSPO3, KLOTB, and ROR1 proteins may mediate associations between obesity and pancreatic diseases.