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

Introduction PrimeSurface Research Papers

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

Adv Sci (Weinh). 2024 Oct;11(38):e2402757. https://doi.org/10.1002/advs.202402757

Copyright © Authors 2024
This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY).

Background

Desmoplasia in breast cancer is characterized by aberrant extracellular matrix (ECM) and vasculature, leading to impaired drug delivery within the tumor microenvironment. It is a key challenge to identify of personalized therapeutic strategies. While patient-derived tumor models and microphysiological systems are useful for evaluating treatment responses, current models fail to fully replicate the complexity of desmoplasia. Harnessing microphysiological models to discover new therapeutic approaches and improve clinical care for breast cancer patients is essential.

Research Achievements

In this study, tumoroids formed in PrimeSurfaceTM 96M plates using breast cancer cell lines and patient-derived breast cancer cells were cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction causing impaired drug delivery. Differences were observed in stromal hyaluronic acid (HA) deposition, vascular permeability, and interstitial fluid pressure among cell lines. Interleukin 8 secretion is found responsible for vascular dysfunction and loss of vascular HA. This developed MPS model can be personalized by using patient-derived cells and can be applied to discover new molecular therapies for the normalization of the tumor microenvironment.

【Fig.1】
Tumoroids assembled from breast cancer cell lines differentially remodel their surrounding stroma

Use of PrimeSurface™ in this study

Establish MPS model with MVNs incorporating tumoroids:

4000 tumor cells and 5000 fibroblasts (FBs) were cocultured using PrimeSurfaceTM 96M plates to form tumoroids for over 4 days.
Endothelial cells (ECs), FBs and tumoroids were co-injected with fibrin gel within the central channel of the microfluidic device and cultured for 7 days.
A monolayer of ECs was seeded on the gel surfaces in the side channels on day 4
Drug permeability evaluations were conducted using this device (MPS model)

* For details, please refer to the paper