Manipulating the Tumor Microenvironment in Tumor Organoids Induces Phenotypic Changes and Chemoresistance

Anthony Dominijanni; Mahesh Devarasetty; Shay Soker

doi:10.1016/j.isci.2020.101851

Manipulating the Tumor Microenvironment in Tumor Organoids Induces Phenotypic Changes and Chemoresistance

iScience. 2020 Nov 23;23(12):101851. doi: 10.1016/j.isci.2020.101851. eCollection 2020 Dec 18.

Authors

Anthony Dominijanni¹, Mahesh Devarasetty¹, Shay Soker¹

Affiliation

¹ Wake Forest University School of Medicine, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, USA.

Abstract

Tumors comprised a tightly surrounded tumor microenvironment, made up of non-cellular extracellular matrix (ECM) and stromal cells. Although treatment response is often attributed to tumor heterogeneity, progression and malignancy are profoundly influenced by tumor cell interactions with the surrounding ECM. Here, we used a tumor organoid model, consisting of hepatic stellate cells (HSCs) embedded in collagen type 1 (Col1) and colorectal cancer cell (HCT-116) spheroids, to determine the relationship between the ECM architecture, cancer cell malignancy, and chemoresistance. Exogenous transforming growth factor beta (TGF-β) used to activate the HSCs increased the remodeling and bundling of Col1 in the ECM around the cancer spheroid. A dense ECM architecture inhibited tumor cell growth, reversed their mesenchymal phenotype, preserved stem cell population, and reduced chemotherapy response. Overall, our results demonstrate that controlled biofabrication and manipulation of the ECM in tumor organoids results enables studying tumor cell-ECM interactions and better understand tumor cell response to chemotherapies.

Keywords: Bioengineering; Biological Sciences; Cancer.

Abstract

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