Dataset Information

An in vitro vascularized micro-tumor model of human colorectal cancer recapitulates in vivo responses to standard-of-care therapy.

ABSTRACT: Around 95% of anti-cancer drugs that show promise during preclinical study fail to gain FDA-approval for clinical use. This failure of the preclinical pipeline highlights the need for improved, physiologically-relevant in vitro models that can better serve as reliable drug-screening and disease modeling tools. The vascularized micro-tumor (VMT) is a novel three-dimensional model system (tumor-on-a-chip) that recapitulates the complex human tumor microenvironment, including perfused vasculature, within a transparent microfluidic device, allowing real-time study of drug responses and tumor-stromal interactions. Here we have validated this microphysiological system (MPS) platform for the study of colorectal cancer (CRC), the second leading cause of cancer-related deaths, by showing that gene expression, tumor heterogeneity, and treatment responses in the VMT more closely model CRC tumor clinicopathology than current standard drug screening modalities, including 2-dimensional monolayer culture and 3-dimensional spheroids.

SUBMITTER: Hachey SJ

PROVIDER: S-EPMC8525497 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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An in vitro vascularized micro-tumor model of human colorectal cancer recapitulates in vivo responses to standard-of-care therapy.

Hachey Stephanie J SJ Movsesyan Silva S Nguyen Quy H QH Burton-Sojo Giselle G Tankazyan Ani A Wu Jie J Hoang Tuyen T Zhao Da D Wang Shuxiong S Hatch Michaela M MM Celaya Elizabeth E Gomez Samantha S Chen George T GT Davis Ryan T RT Nee Kevin K Pervolarakis Nicholas N Lawson Devon A DA Kessenbrock Kai K Lee Abraham P AP Lowengrub John J Waterman Marian L ML Hughes Christopher C W CCW

Lab on a chip 20210219 7

Around 95% of anti-cancer drugs that show promise during preclinical study fail to gain FDA-approval for clinical use. This failure of the preclinical pipeline highlights the need for improved, physiologically-relevant in vitro models that can better serve as reliable drug-screening and disease modeling tools. The vascularized micro-tumor (VMT) is a novel three-dimensional model system (tumor-on-a-chip) that recapitulates the complex human tumor microenvironment, including perfused vasculature, ...[more]

PMID: 33605955

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Project description:BackgroundIn vitro models of prostate cancer (PCa) are not always reliable to evaluate anticancer treatment efficacy. This limitation may be overcome by using viable tumor slice material. Here we report on the establishment of an optimized ex vivo method to culture tissue slices from patient-derived xenografts (PDX) of prostate cancer (PCa), to assess responses to PCa treatments.MethodsThree PDX models were used that are characterized by different androgen receptor (AR) expression and different homology directed DNA repair capacities, due to a breast cancer associated two (BRCA2) wild-type or mutated status. Tumors were removed from mice, sliced using a vibratome and cultured for a maximum of 6 days. To test the sensitivity to androgen antagonist, tumor slices from the AR-expressing and AR-negative PDX tumors were treated with the anti-androgen enzalutamide. For sensitivity to DNA repair intervention, tumors slices from BRCA2 wild-type and mutated PDXs were treated with the poly (ADP-ribose) polymerase-1 inhibitor olaparib. Treatment response in these tumor slices was determined by measuring slice morphology, cell proliferation, apoptosis, AR expression level, and secretion of prostate specific antigen (PSA).ResultsWe compared various culture conditions (support materials, growth media, and use of a 3D smooth rocking platform) to define the optimal condition to maintain tissue viability and proliferative capacity up to least 6 days. Under optimized conditions, enzalutamide treatment significantly decreased proliferation, increased apoptosis, and reduced AR-expression and PSA secretion of AR-expressing tumor slices compared to AR-negative slices, that did not respond to the intervention. Olaparib treatment significantly increased cell death in BRCA2 mutated tumors slices as compared to slices from BRCA2 wild type tumors.ConclusionsEx vivo treatment of PCa PDX tumor slices with enzalutamide and olaparib recapitulates responses previously observed in vivo. The faithful retention of tissue structure and function in this ex vivo model offers an ideal opportunity for treatment efficacy screening, thereby reducing costs and numbers of experimental animals.

Dataset Information

An in vitro vascularized micro-tumor model of human colorectal cancer recapitulates in vivo responses to standard-of-care therapy.

Publications

An in vitro vascularized micro-tumor model of human colorectal cancer recapitulates in vivo responses to standard-of-care therapy.

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