Sex differences in the MB49 syngeneic, murine model of bladder cancer

White‐Gilbertson, Shai; Davis, Megan M.; Voelkel‐Johnson, Christina; Kasman, Laura

doi:10.14440/bladder.2016.73

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…We found that even at low cell numbers, differential tumor growth in male mice was not significant between CSCs and parental cells, owing to the development of larger tumors from parental cells in male mice as compared to female littermates. These findings are in line with the report by White-Gilbertson and colleagues who showed sex-mediated disparity in growth of xenotransplanted bladder cancer cells (39). It is noteworthy that epidemiological and clinical studies have previously demonstrated that men are at a greater risk of developing lung cancer than women and relatively display poorer clinical outcomes (40).…”

Section: Discussionsupporting

confidence: 93%

Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From Gprc5a-Deficient Murine Lung Adenocarcinoma With Somatic Kras Mutations

et al. 2019

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Lung adenocarcinomas (LUADs) with somatic mutations in the KRAS oncogene comprise the most common molecular subtype of lung cancer in smokers and present with overall dismal prognosis and resistance to most therapies. Our group recently demonstrated that tobacco carcinogen-exposed mice with knockout of the airway lineage G-protein coupled receptor, Gprc5a , develop LUADs with somatic mutations in Kras . Earlier work has suggested that cancer stem cells (CSCs) play crucial roles in clonal evolution of tumors and in therapy resistance. To date, our understanding of CSCs in LUADs with somatic Kras mutations remains lagging. Here we derived CSCs (as spheres in 3D cultures) with self-renewal properties from a murine Kras -mutant LUAD cell line we previously established from a tobacco carcinogen-exposed Gprc5a −/− mouse. Using syngeneic Gprc5a −/− models, we found that these CSCs, compared to their parental isoforms, exhibited increased tumorigenic potential in vivo , particularly in female animals. Using whole-transcriptome sequencing coupled with pathways analysis and confirmatory PCR, we identified gene features ( n = 2,600) differentially expressed in the CSCs compared to parental cells and that were enriched with functional modules associated with an augmented malignant phenotype including stemness, tumor-promoting inflammation and anti-oxidant responses. Further, based on in silico predicted activation of GSK3β in CSCs, we found that tideglusib, an irreversible inhibitor of the kinase, exhibited marked anti-growth effects in the cultured CSCs. Our study underscores molecular cues in the pathogenesis of Kras -mutant LUAD and presents new models to study the evolution, and thus high-potential targets, of this aggressive malignancy.

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Section: Discussionsupporting

confidence: 93%

Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From Gprc5a-Deficient Murine Lung Adenocarcinoma With Somatic Kras Mutations

et al. 2019

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“…To assess the contribution of adaptive immunity to sex bias, we compared MB49 growth in male and female wild type (WT) mice, as well as mice with a deficiency of T cells ( Tcrb/Tcrd −/− ), B cells ( Ighm −/− ) or both ( Rag2 −/− ). Consistent with an earlier report 14 , MB49 grew more aggressively in WT male versus female mice ( Fig. 1a ).…”

Section: Cd8+ T Cell Immunity Is Required For Sex Differences In Murisupporting

confidence: 92%

“…Male bias in bladder cancer can be modeled successfully in mice with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced cancer 12,13 and a transplantable syngeneic bladder cancer cell line MB49 14 . To assess the contribution of adaptive immunity to sex bias, we compared MB49 growth in male and female wild type (WT) mice, as well as mice with a deficiency of T cells ( Tcrb/Tcrd −/− ), B cells ( Ighm −/− ) or both ( Rag2 −/− ).…”

Section: Cd8+ T Cell Immunity Is Required For Sex Differences In Murimentioning

confidence: 99%

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Kwon¹,

Chung²,

Kaneko³

et al. 2020

Preprint

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Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed. 24Abstract: Men and women show striking yet unexplained discrepancies in 25 incidence, clinical presentation, and therapeutic response across different types of 26 infectious/autoimmune diseases and malignancies 1,2 . For instance, bladder cancer 27 shows a 4-fold male-biased incidence that persists after adjustment for known risk 28 factors 3,4 . Here, we utilize murine bladder cancer models to establish that male-biased 29 tumor burden is driven by sex differences in endogenous T cell immunity. Notably, sex 30 differences exist in early fate decisions by intratumoral CD8 + T cells following their 31 activation. While female CD8 + T cells retain their effector function, male counterparts 32 readily adopt a Tcf1 low Tim3progenitor state that becomes exhausted over tumor 33 progression. Human cancers show an analogous male-biased frequency of exhausted 34 CD8 + T cells. Mechanistically, we describe an opposing interplay between CD8 + T cell 35 intrinsic androgen and type I interferon 5,6 signaling in Tcf1/Tcf7 regulation and formation 36 of the progenitor exhausted T cell subset. Consistent with female-biased interferon 37 response 7 , testosterone-dependent stimulation of Tcf1/Tcf7 and resistance to interferon 38 occurs to a greater magnitude in male CD8 + T cells. Male-biased predisposition for CD8 + 39T cell exhaustion suggests that spontaneous rejection of early immunogenic bladder 40 tumors is less common in males and carries implications for therapeutic efficacy of 41 immune checkpoint inhibitors 8,9 . 42Main: Sex is a biological variable with significant influence on immune function 1 . 43However, mechanisms underlying sex-biased incidence and mortality of various cancers 44 arising in non-reproductive organs remain elusive 2 . Indeed, bladder cancer shows a 4-45 fold male-biased incidence globally, which cannot be explained by established risk 46 factors: smoking, exposure to occupational hazards and urinary tract infection 3,4 . Here, 48 largely mediated by sex differences in T cell immunity. Flow cytometric and single cell 49 RNA-seq analyses of CD8 + tumor-infiltrating leukocytes (TILs) identified a striking male 50 bias in the formation of Tcf1 low Tim3progenitor cells 10 and in their transition to a 51 hypofunctional Tcf1 -Tim3 + exhausted state upon prolonged stimulation. In particular, 52androgen signaling was enriched in the progenitor exhausted subset. We found that 53 testosterone-induced Tcf1, an early molecular orchestrator of an exhaustion-associated 54 transcriptional landscape 11 in male CD8 + T cells, is also more resistant to pertinent 55 repression by female-biased type I interferon signaling 5 . Collectively, these findings 56 highlight sex differences in intratumoral CD8 + T cell fate as a potential mechanism 57 underlying bladder cancer sex bias and identify androgen as a possible target to modulate 58 CD8 + TIL exhaustion. 59CD8 + T cell immunity is required for sex differences in murine...

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“…The MB49 cell line is a useful in vivo murine model of bladder cancer that has several similarities to human disease (14). MB49 tumors in mice are sensitive to treatment with the antituberculosis vaccine bacillus Calmette–Guérin (15, 16), an immunotherapy for treatment of early-stage bladder cancer that is thought to activate the immune system to slow tumor growth.…”

mentioning

confidence: 99%

“…MB49 tumors in mice are sensitive to treatment with the antituberculosis vaccine bacillus Calmette–Guérin (15, 16), an immunotherapy for treatment of early-stage bladder cancer that is thought to activate the immune system to slow tumor growth. To evaluate different aspects of disease, MB49 cells can be administered to mice via various routes, including transurethral, s.c. or i.v., leading to development of tumors and spontaneous lung metastasis within 3 wk (14, 16–18). …”

mentioning

confidence: 99%

Using Visualization of t-Distributed Stochastic Neighbor Embedding To Identify Immune Cell Subsets in Mouse Tumors

Acuff

Linden

2017

The Journal of Immunology

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High-dimensional flow cytometry is proving to be valuable for the study of subtle changes in tumor-associated immune cells. As flow panels become more complex, detection of minor immune cell populations by traditional gating using biaxial plots, or identification of populations that display small changes in multiple markers, may be overlooked. Visualization of t-distributed stochastic neighbor embedding (viSNE) is an unsupervised analytical tool designed to aid the analysis of high-dimensional cytometry data. In this study we use viSNE to analyze the simultaneous binding of 15 fluorophore-conjugated Abs and one cell viability probe to immune cells isolated from syngeneic mouse MB49 bladder tumors, spleens, and tumor-draining lymph nodes to identify patterns of anti-tumor immune responses. viSNE maps identified populations in multidimensional space of known immune cells, including T cells, B cells, eosinophils, neutrophils, dendritic cells, and NK cells. Based on the expression of CD86 and programmed cell death protein 1, CD8+ T cells were divided into distinct populations. Additionally, both CD8+ T cells and CD8+ dendritic cells were identified in the tumor microenvironment. Apparent differences between splenic and tumor polymorphonuclear cells/granulocytic myeloid-derived suppressor cells are due to the loss of CD44 upon enzymatic digestion of tumors. In conclusion, viSNE is a valuable tool for high-dimensional analysis of immune cells in tumor-bearing mice, which eliminates gating biases and identifies immune cell subsets that may be missed by traditional gating.

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Sex differences in the MB49 syngeneic, murine model of bladder cancer

Cited by 10 publications

References 34 publications

Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From Gprc5a-Deficient Murine Lung Adenocarcinoma With Somatic Kras Mutations

Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From Gprc5a-Deficient Murine Lung Adenocarcinoma With Somatic Kras Mutations

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Using Visualization of t-Distributed Stochastic Neighbor Embedding To Identify Immune Cell Subsets in Mouse Tumors

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Sex differences in the MB49 syngeneic, murine model of bladder cancer

Cited by 10 publications

References 34 publications

Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From Gprc5a-Deficient Murine Lung Adenocarcinoma With Somatic Kras Mutations

Genome-Wide and Phenotypic Evaluation of Stem Cell Progenitors Derived From Gprc5a-Deficient Murine Lung Adenocarcinoma With Somatic Kras Mutations

Distinct CD8+T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Using Visualization of t-Distributed Stochastic Neighbor Embedding To Identify Immune Cell Subsets in Mouse Tumors

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Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome