Abstract
Abstract The tumor microenvironment is a key regulator of tumor biology and response to therapeutic intervention, with intercellular communication between tumor and stromal cells known to regulate growth and progression. While two-dimensional cell culture is the most common method utilized for in vitro preclinical studies, it creates an artificial environment that does not take into account critical tissue components, including the tissue microenvironment (i.e., matrix proteins and stromal cell populations) and the three-dimensional tissue architecture/dimensionality. Recently, in vitro engineered tissues have been implemented as surrogates of human pathophysiology in biomedical and pharmaceutical research. Herein we utilize tissue engineering strategies to develop in vitro non-small cell lung tumor mimics that include key tissue components, including matrix proteins and stromal cell populations, utilizing patient-derived specimen. With the inclusion of stromal cell populations, these tumor mimics allow for evaluation of tumor-stromal interactions and could be utilized to determine the impact of these interactions on therapeutic response. Engineered tumor mimics were generated utilizing freshly isolated lung tumor specimen from consented patients undergoing surgical tumor resection. 5-mm-diameter tissue cores were produced and placed in a volume of extracellular matrix (ECM) within the bioreactor platform and maintained via a closed perfusion platform to provide nutrient circulation. Histologic and flow cytometric analyses were performed to evaluate cellular heterogeneity within the tumor mimics following culture. Primary human lung tumor specimens cultured ex vivo in the engineered tumor mimic platform maintain histologic architecture and representative cell populations, including endothelial cells (CD31+,10.46%), epithelial cells (EpCAM+,25.15%), fibroblasts (CD90+, 7.23%), CD8+ T cells (CD3+CD8+, 2.95%), and macrophages (CD14+CD64+CD11b+, 9.25%) following 14 days’ culture. Additionally, a tumor-promotive microenvironment is supported by this platform with maintenance of monocytic and granulocytic myeloid-derived suppressor cells (8.59% and 0.83 %, respectively) and tumor-promotive macrophages (M2 like, 81.3% of macrophages). Furthermore, the hypoxic biochemical microenvironment is recapitulated with carbonic anhydrase 9-positive cell populations maintained during culture. Moving forward, this platform will allow for extensive characterization of tumor-stromal interactions, response to therapeutic intervention, and therapeutic resistance in a patient-specific manner. Citation Format: Kayla F. Goliwas, Yong Wang, Joel L. Berry, Victor J. Thannickal, James M. Donahue, Jessy S. Deshane. Engineered three-dimensional lung tumor mimics maintain tissue heterogeneity allowing for investigation of tumor-stromal interactions [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B23.
Published Version
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