Abstract
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.
Highlights
Bladder cancer holds the 10th position among the most common cancers worldwide [1]
The treatment of non–muscle-invasive bladder cancer (NMIBC) consists of transurethral resection of bladder tumors (TURBT), usually combined with a single intravesical administration of chemotherapy, or in high-risk cases, with additional treatment by Bacillus Calmette-Guerin (BCG) for up to three years [3,4]
Pathology assessment revealed that non-carcinogen exposed female hepatocyte growth factor (Hgf)-Cdk4R24C mouse bladder histology was normal (Fig 1B), whereas carcinogen treated Hgf-Cdk4R24C females displayed a urothelial cancer of Tis-T1 stage with squamous differentiation (Fig 1C) which was more advanced than for transgenic Hgf-Cdk4R24C males (Fig 1D) or Cdk4R24C littermates (Fig 1E)
Summary
Bladder cancer holds the 10th position among the most common cancers worldwide [1]. Around 70% of patients are diagnosed with NMIBC out of which one fifth are stage T1. Due to limited predictive biomarkers of progression of T1 tumors, the majority of patients with highrisk T1 bladder tumors present recurrences, and almost half of those progress to MIBC, resulting in a 15% mortality within 10 years from diagnosis [2]. The treatment of NMIBC consists of transurethral resection of bladder tumors (TURBT), usually combined with a single intravesical administration of chemotherapy, or in high-risk cases, with additional treatment by Bacillus Calmette-Guerin (BCG) for up to three years [3,4]. A phase II clinical trial of anti-PD1 therapy for BCG resistant and recurrent tumors resulted in a complete response rate of 31% [5]. Women have four times lower incidence of bladder cancer whilst presenting with a more advanced disease at diagnosis and higher disease-related morbidity than men [1,6,7,8]. It is crucial to differentiate gender-biased molecular markers both in preclinical and clinical studies when assessing novel therapeutics
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