Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1120329/full |
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| author | Shruti D. Shah Bryan M. Gillard Michelle M. Wrobel Ellen Karasik Michael T. Moser Michalis Mastri Mark D. Long Norbert Sule Craig M. Brackett Wendy J. Huss Wendy J. Huss Barbara A. Foster |
| author_facet | Shruti D. Shah Bryan M. Gillard Michelle M. Wrobel Ellen Karasik Michael T. Moser Michalis Mastri Mark D. Long Norbert Sule Craig M. Brackett Wendy J. Huss Wendy J. Huss Barbara A. Foster |
| author_sort | Shruti D. Shah |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T17:43:07Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-04-10T17:43:07Z |
| publishDate | 2023-02-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-4ca92263d3fb4dc7be3b998b093ff8682023-02-03T07:07:22ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-02-011310.3389/fonc.2023.11203291120329Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancerShruti D. Shah0Bryan M. Gillard1Michelle M. Wrobel2Ellen Karasik3Michael T. Moser4Michalis Mastri5Mark D. Long6Norbert Sule7Craig M. Brackett8Wendy J. Huss9Wendy J. Huss10Barbara A. Foster11Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesIntroductionBladder 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.https://www.frontiersin.org/articles/10.3389/fonc.2023.1120329/fullBBN carcinogen-inducedbladder cancer molecular subtypeCIBERSORTmale and female sex disparityimmune-intact mouse modelimmune tumor microenvironment |
| spellingShingle | Shruti D. Shah Bryan M. Gillard Michelle M. Wrobel Ellen Karasik Michael T. Moser Michalis Mastri Mark D. Long Norbert Sule Craig M. Brackett Wendy J. Huss Wendy J. Huss Barbara A. Foster Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer Frontiers in Oncology BBN carcinogen-induced bladder cancer molecular subtype CIBERSORT male and female sex disparity immune-intact mouse model immune tumor microenvironment |
| title | Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer |
| title_full | Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer |
| title_fullStr | Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer |
| title_full_unstemmed | Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer |
| title_short | Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer |
| title_sort | syngeneic model of carcinogen induced tumor mimics basal squamous stromal rich and neuroendocrine molecular and immunological features of muscle invasive bladder cancer |
| topic | BBN carcinogen-induced bladder cancer molecular subtype CIBERSORT male and female sex disparity immune-intact mouse model immune tumor microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1120329/full |
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