Personalized Vascularized Models of Breast Cancer Desmoplasia Reveal Biomechanical Determinants of Drug Delivery to the Tumor

Giovanni S. Offeddu#, Elena Cambria#, Sarah E. Shelton, Kristina Haase, Zhengpeng Wan, Luca Possenti, Huu Tuan Nguyen, Mark R. Gillrie, Dean Hickman, Charles G. Knutson, and Roger D. Kamm

Abstract: Desmoplasia in breast cancer leads to heterogeneity in physical properties of the tissue, resulting in disparities in drug delivery and treatment efficacy among patients, thus contributing to high disease mortality. Personalized in vitro breast cancer models hold great promise for high-throughput testing of therapeutic strategies to normalize the aberrant microenvironment in a patient-specific manner. Here, tumoroids assembled from breast cancer cell lines (MCF7, SKBR3, and MDA-MB-468) and patient-derived breast tumor cells (TCs) cultured in microphysiological systems including perfusable microvasculature reproduced key aspects of stromal and vascular dysfunction causing impaired drug delivery. Models containing SKBR3 and MDA-MB-468 tumoroids showed higher stromal hyaluronic acid (HA) deposition, vascular permeability, interstitial fluid pressure (IFP), and degradation of vascular HA relative to models containing MCF7 tumoroids or models without tumoroids. Interleukin 8 (IL8) secretion was found responsible for vascular dysfunction and loss of vascular HA. Interventions targeting IL8 or stromal HA normalized vascular permeability, perfusion, and IFP, and ultimately enhanced drug delivery and TC death in response to perfusion with Trastuzumab and Cetuximab. Similar responses were observed in patient-derived models. These microphysiological systems can thus be personalized by using patient-derived cells and applied to discover new molecular therapies for the normalization of the tumor microenvironment.

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*The U54 Metnet Grant ONLY funded Figure 5 of this publication