IntroductionBladder cancer is a heterogenous disease and the emerging knowledge on molecular classification of bladder tumors may impact treatment decisions based on molecular subtype. Pre-clinical models representing each subtype are needed to test novel therapies. Carcinogen-induced bladder cancer models represent heterogeneous, immune-competent, pre-clinical testing options with many features found in the human disease.MethodsInvasive bladder tumors were induced in C57BL/6 mice when continuously exposed to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in the drinking water. Tumors were excised and serially passed by subcutaneous implantation into sex-matched syngeneic C57BL/6 hosts. Eight lines were named BBN-induced Urothelium Roswell Park (BURP) tumor lines. BURP lines were characterized by applying consensus molecular classification to RNA expression, histopathology, and immune profiles by CIBERSORT. Two lines were further characterized for cisplatin response.ResultsEight BURP tumor lines were established with 3 male and 3 female BURP tumor lines, having the basal/squamous (BaSq) molecular phenotype and morphology. BURP-16SR was established from a male mouse and has a stromal-rich (SR) molecular phenotype and a sarcomatoid carcinoma morphology. BURP-19NE was established from a male mouse and has a neuroendocrine (NE)-like molecular phenotype and poorly differentiated morphology. The established BURP tumor lines have unique immune profiles with fewer immune infiltrates compared to their originating BBN-induced tumors. The immune profiles of the BURP tumor lines capture some of the features observed in the molecular classifications of human bladder cancer. BURP-16SR growth was inhibited by cisplatin treatment, while BURP-24BaSq did not respond to cisplatin.DiscussionThe BURP lines represent several molecular classifications, including basal/squamous, stroma-rich, and NE-like. The stroma-rich (BURP-16SR) and NE-like (BURP-19NE) represent unique immunocompetent models that can be used to test novel treatments in these less common bladder cancer subtypes. Six basal/squamous tumor lines were established from both male and female mice. Overall, the BURP tumor lines have less heterogeneity than the carcinogen-induced tumors and can be used to evaluate treatment response without the confounding mixed response often observed in heterogeneous tumors. Additionally, basal/squamous tumor lines were established and maintained in both male and female mice, thereby allowing these tumor lines to be used to compare differential treatment responses between sexes.
T here were an estimated 11 million cancer survivors in the United States in 2006 [1]. The number of US cancer survivors has increased, in part, because of earlier detection and better treatments. As cancer patients live longer, their well-being has become an increasingly important public health issue, which a number of agencies and organizations have begun to address. For example, in 2004, the Centers for Disease Control and Prevention (CDC), in conjunction with the Lance Armstrong Foundation, the American Cancer Society, and other partners, published an action plan that identifies and prioritizes the needs of cancer survivors and proposes strategies for addressing them [2]. The Institute of Medicine of the National Academies published a report in 2005 that recommends that each cancer survivor receives a survivorship plan that summarizes information about longterm care and maintenance of a healthy lifestyle [3].It is important to understand the behaviors and characteristics of cancer survivors, including their lifestyle, health status, health-related quality of life, use of preventive health services (eg, cancer screening and immunizations), and access to health care (eg, whether they have health insurance and a usual health care professional). However, there are few data sources available at the local and state level to monitor these behaviors and characteristics. Most reports provide information at the national level [4,5].The CDC's National Comprehensive Cancer Control Program (NCCCP) funds efforts by all 50 states, the District of Columbia, 7 tribes/tribal organizations, and 7 territories and US Pacific Island jurisdictions, to develop and implement comprehensive cancer-control programs [6]. Since most of the programs address issues associated with cancer survivorship [7,8], they need local, population-based data sources to plan and evaluate the impact of survivorshiprelated activities.The CDC's Division of Cancer Prevention and Control seeks to enhance state-level data for NCCCP-funded program planning. We used 2001 and 2002 Behavioral Risk Factor Surveillance System (BRFSS) data from North Carolina to describe the demographic and health characteristics of cancer survivors and the association of certain health behaviors, quality of life, use of preventive services, and access to health care with cancer survivorship. The results of this analysis will enhance the CDC's ability to help funded programs identify survivorship-related needs. MethodsThe BRFSS collects data annually, using telephone-based interviews of noninstitutionalized adults (defined as people aged ≥18 years) who are selected for participation by means
Patient derived models (PDMs) are a powerful tool to study preclinical responses. However, the benefits of each model have not been compared head-to-head when models are derived from the same surgical specimen. PDMs derived from surgical specimens were established as xenografts (PDX), organoids (PDO), and spheroids (PDS). PDMs were molecularly characterized by RNA sequencing. Differential gene expression was determined between the PDMs and surgical specimens. Surgical specimens had the most differentially expressed genes reflecting loss of immune and stromal compartments in PDMs. PDMs and surgical specimens were clustered using the Euclidian distance analysis to test model fidelity. PDMs upregulated a clear, patient-specific bladder cancer signal. Overall, the molecular profiles of PDXs were the most similar to the matching patient surgical specimen than the PDO and PDS from that patient. The epithelial mesenchymal transition (EMT) gene expression profile is maintained in the PDMs showing the persistence of EMT in both in vivo and in vitro model setting. The consensus molecular subtype was determined in order to compare PDMs to each other and their matching surgical specimen, and only surgical specimens with Basal/Squamous or Luminal Papillary molecular subtype established PDMs. Patient derived models reduce tumor heterogeneity and allow analysis of specific tumor compartments while maintaining the gene expression profile representative of the original tumor.
Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited treatment options. Checkpoint inhibitors, although approved as second-line therapy, have limited response rate that is indicative of intrinsic resistance to immune therapy. Efforts are being made to improve the response rate by designing novel drug combinations, one such being combination of chemotherapy and checkpoint inhibitors. Chemotherapy like the platinum-based therapy perturbs the tumor immune system, which contributes to the overall response to treatment. The tumor-immune system relationship is extremely dynamic, and the tumor post treatment constantly re-equilibrates the microenvironment to support its growth. The ability to capture the dynamic changes of the immune microenvironment will allow us to design treatments that can modulate the immune cells for a sustained antitumor effect. Here we have performed transcriptomic analysis of publicly available expression data provided by TCGA (The Cancer Genome Atlas) on MIBC. Using the deconvolution algorithm Cibersort, we generated tumor immune signatures for patients of MIBC. We observed that patients with high CD8+ T-cell expression signature are positively associated with improved survival. Moreover, we observed that patients with low CD8+ T-cell infiltration signature showed nonpolarized macrophage and resting CD4 T-cell expression signature, indicating that the patients' tumors have a “noninflamed” phenotype. To model the interplay between the tumor and the immune system, we constructed a network of bladder tumor-macrophage-CD4 T-cell (BMT network) crosstalk. The tumor expression data from the TCGA were used to build the tumor network, which was linked to the macrophage polarization network and CD4 T-cell differentiation network via “extracellular” cytokines. The change in the cytokine profile modulates the regulatory network of the macrophage polarization network and CD4 T-cell differentiation network. The BMT network is made dynamic by applying logic based Boolean formalism. The network structure of the BMT network was validated by comparing the network simulations to published experimental data. Network simulation with cisplatin treatment changed the immune profile of the BMT network depending on the initial condition of the network. The initial condition is described by the cytokine profile of the “extracellular” cytokine, and the immune profile is described by the macrophage polarized state and the CD4 T-cell differentiated cell. The BMT network generates a dynamic cytokine profile under different perturbation that allows us to predict the change in the tumor immune phenotypes in response to therapy and thus generate hypotheses on designing combination treatments to different immunotherapy. Citation Format: Shruti Shah, Barbara A. Foster, Donald E. Mager. Logical modelling of tumor-immune crosstalk network to predict the mechanism of immune evasion in muscle-invasive bladder cancer (MIBC) [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A10.
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