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Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis.

ABSTRACT: We have discovered a previously uncharacterized tumor suppressor function of Numb in the homeostasis of the normal bladder mucosa. Targeted ablation of Numb in the basal layer of the urothelium drives spontaneous bladder tumorigenesis, driving progression from preneoplastic to preinvasive and overtly invasive tumors, and accelerates tumorigenesis in the presence of oncogenic insults. Using 3D-Matrigel organoid cultures to recapitulate bladder tumorigenesis in vitro, we found that Numb deficiency enhances the proliferative and invasive potential of both mouse and human bladder cancer cells. Integrative transcriptomic and functional analyses revealed that downregulation of the canonical Hippo pathway, resulting in enhanced YAP transcriptional activity, underlies the biological aggressiveness of Numb-deficient bladder cancer. These molecular events are dependent on the activation of RhoA/ROCK signaling subsequent to Numb loss. Thus, a dysfunctional Numb–RhoA/ROCK–Hippo/YAP regulatory network is at play in aggressive Numb-deficient bladder cancers, opening avenues for the development of targeted therapies. Furthermore, retrospective cohort studies revealed that a Numb-deficient status correlates with worse overall survival in post-cystectomy muscle-invasive bladder cancer (MIBC) patients and increased risk of progression to MIBC in non-muscle-invasive bladder cancer (NMIBC) patients. The Numb-deficient status was associated with a 27-gene prognostic signature that has the potential to identify high-risk NMIBC patients who are eligible for targeted RhoA/ROCK/YAP therapies.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE256272 | GEO | 2024/10/11

REPOSITORIES: GEO

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Project description:Bladder cancer, one of the most prevalent malignancies worldwide, remains hard to classify due to a staggering molecular complexity. Despite a plethora of diagnostic tools and therapies, it is hard to outline the key steps leading up to the transition from high-risk non–muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC). Carcinogen-induced murine models can recapitulate urothelial carcinogenesis and natural anti-tumor immunity. Herein, we have developed and profiled a novel model of progressive NMIBC based on 10 weeks of OH-BBN exposure in hepatocyte growth factor/cyclin dependent kinase 4 (R24C) (Hgf-Cdk4R24C) mice. The profiling of the model was performed by histology grading, single cell transcriptomic and proteomic analysis, while the derivation of a tumorigenic cell line was validated and used to assess in vivo anti-tumor effects in response to immunotherapy. Established NMIBC was present in females at 10 weeks post OH-BBN exposure while neoplasia was not as advanced in male mice, however all mice progressed to MIBC. Single cell RNA sequencing analysis revealed an intratumoral heterogeneity also described in the human disease trajectory. Moreover, although immune activation biomarkers were elevated in urine during carcinogen exposure, anti-programmed cell death protein 1 (anti-PD1) monotherapy did not prevent tumor progression. Furthermore, anti-PD1 immunotherapy did not control the growth of subcutaneous tumors formed by the newly derived urothelial cancer cell line. However, treatment with CpG-oligodeoxynucleotides (ODN) significantly decreased tumor volume, but only in females. In conclusion, the molecular map of this novel preclinical model of bladder cancer provides an opportunity to further investigate pharmacological therapies ahead with regards to both targeted drugs and immunotherapies to improve the strategies of how we should tackle the heterogeneous tumor microenvironment in urothelial bladder cancer to improve responses rates in the clinic.

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Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis.

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