Live cell molecular analysis of primary prostate cancer organoids identifies persistent androgen receptor signaling

Prostate Cancer (PC) is a disease with remarkable tumor heterogeneity that often manifests in significant intra-patient variability with regards to clinical outcomes and treatment response. Commonly available PC cell lines do not accurately reflect the complexity of this disease and there is critical need for development of new models to recapitulate the intricate hierarchy of tumor pathogenesis. In current study, we established ex vivo primary patient-derived cancer organoid (PDCO) cultures from prostatectomy specimens of patients with locally advanced PC. We then performed a comprehensive multi-parameter characterization of the cellular composition utilizing a novel approach for live-cell staining and direct imaging in the integrated microfluidic Stacks device. Using orthogonal flow cytometry analysis, we demonstrate that primary PDCOs maintain distinct subsets of epithelial cells throughout culture and that these cells conserve expression of androgen receptor (AR)-related elements. Furthermore, to confirm the tumor-origin of the PDCOs we have analyzed the expression of PC-associated epigenetic biomarkers including promoter methylation of the GSTP1, RASSF1 and APC and RARb genes by employing a novel microfluidic rare-event screening protocol. These results demonstrate that this ex vivo PDCO model recapitulates the complexity of the epithelial tumor microenvironment of multifocal PC using orthogonal analyses. Furthermore, we propose to leverage the Stacks microfluidic device as a high-throughput, translational platform to interrogate phenotypic and molecular endpoints with the capacity to incorporate a complex tumor microenvironment.

Авторы
Heninger Erika1 , Kosoff David2 , Rodems T.S.1 , Sethakorn Nan2 , Singh Anupama1 , Gungurthi Harshitha1 , Carlson K.N.1 , Yang Bing 3 , Gilsdorf Cole1 , Pasch C.A.1 , Deming D.A.2 , Ellis Leigh4 , Beebe D.J.5 , Jarrard D.F. 3 , Lang J.M.1, 2, 6
Журнал
Издательство
Humana Press, Inc.
Номер выпуска
11
Язык
Английский
Страницы
1-13
Статус
Опубликовано
Том
38
Год
2021
Организации
  • 1 University of Wisconsin Carbone Cancer Center
  • 2 University of Wisconsin, Madison
  • 3 Department of Urology
  • 4 Samuel Oschin Comprehensive Cancer Institute
  • 5 Department of Pathology and Laboratory Medicine
  • 6 Wisconsin Institutes for Medical Research
Ключевые слова
prostate cancer; PdCo; primary culture; microfluidics; Epigenetic biomarker
Дата создания
11.07.2024
Дата изменения
11.07.2024
Постоянная ссылка
https://repository.rudn.ru/ru/records/article/record/154031/
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