Dataset Information

Bioengineered Submucosal Organoids for In Vitro Modeling of Colorectal Cancer.

ABSTRACT: The physical nature of the tumor microenvironment significantly impacts tumor growth, invasion, and response to drugs. Most in vitro tumor models are designed to study the effects of extracellular matrix (ECM) stiffness on tumor cells, while not addressing the effects of ECM's specific topography. In this study, we bioengineered submucosal organoids, using primary smooth muscle cells embedded in collagen I hydrogel, which produce aligned and parallel fiber topography similar to those found in vivo. The fiber organization in the submucosal organoids induced an epithelial phenotype in spheroids of colorectal carcinoma cells (HCT-116), which were embedded within the organoids. Conversely, unorganized fibers drove a mesenchymal phenotype in the tumor cells. HCT-116 cells in organoids with aligned fibers showed no WNT signaling activation, and conversely, WNT signaling activation was observed in organoids with disrupted fibers. Consequently, HCT-116 cells in the aligned condition exhibited decreased cellular proliferation and reduced sensitivity to 5-fluorouracil chemotherapeutic treatment compared to cells in the unorganized construct. Collectively, the results establish a unique colorectal tumor organoid model to study the effects of stromal topography on cancer cell phenotype, proliferation, and ultimately, chemotherapeutic susceptibility. In the future, such organoids can utilize patient-derived cells for precision medicine applications.

SUBMITTER: Devarasetty M

PROVIDER: S-EPMC5653148 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bioengineered Submucosal Organoids for In Vitro Modeling of Colorectal Cancer.

Devarasetty Mahesh M Skardal Aleksander A Cowdrick Kyle K Marini Frank F Soker Shay S

Tissue engineering. Part A 20171001 19-20

The physical nature of the tumor microenvironment significantly impacts tumor growth, invasion, and response to drugs. Most in vitro tumor models are designed to study the effects of extracellular matrix (ECM) stiffness on tumor cells, while not addressing the effects of ECM's specific topography. In this study, we bioengineered submucosal organoids, using primary smooth muscle cells embedded in collagen I hydrogel, which produce aligned and parallel fiber topography similar to those found in vi ...[more]

PMID: 28922975

Similar Datasets

Project description:Background & aimsPatient-derived tumor organoids recapitulate the characteristics of colorectal cancer (CRC) and provide an ideal platform for preclinical evaluation of personalized treatment options. We aimed to model the acquisition of chemotolerance during first-line combination chemotherapy in metastatic CRC organoids.MethodsWe performed next-generation sequencing to study the evolution of KRAS wild-type CRC organoids during adaptation to irinotecan-based chemotherapy combined with epidermal growth factor receptor (EGFR) inhibition. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 protein (Cas9)-editing showed the specific effect of KRASG12D acquisition in drug-tolerant organoids. Compound treatment strategies involving Aurora kinase A (AURKA) inhibition were assessed for their capability to induce apoptosis in a drug-persister background. Immunohistochemical detection of AURKA was performed on a patient-matched cohort of primary tumors and derived liver metastases.ResultsAdaptation to combination chemotherapy was accompanied by transcriptomic rather than gene mutational alterations in CRC organoids. Drug-tolerant cells evaded apoptosis and up-regulated MYC (c-myelocytomatosis oncogene product)/E2F1 (E2 family transcription factor 1) and/or interferon-α-related gene expression. Introduction of KRASG12D further increased the resilience of drug-persister CRC organoids against combination therapy. AURKA inhibition restored an apoptotic response in drug-tolerant KRAS-wild-type organoids. In dual epidermal growth factor receptor (EGFR)- pathway blockade-primed CRC organoids expressing KRASG12D, AURKA inhibition augmented apoptosis in cases that had acquired increased c-MYC protein levels during chemotolerance development. In patient-matched CRC cohorts, AURKA expression was increased in primary tumors and derived liver metastases.ConclusionsOur study emphasizes the potential of patient-derived CRC organoids in modeling chemotherapy tolerance ex vivo. The applied therapeutic strategy of dual EGFR pathway blockade in combination with AURKA inhibition may prove effective for second-line treatment of chemotolerant CRC liver metastases with acquired KRAS mutation and increased AURKA/c-MYC expression.

Dataset Information

Bioengineered Submucosal Organoids for In Vitro Modeling of Colorectal Cancer.

Publications

Bioengineered Submucosal Organoids for In Vitro Modeling of Colorectal Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets