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

TGFβ mechanotherapy hyaluronic acid microphysiological systems permeability tumor vascularization vascular glycocalyx

Journal

Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569

Informations de publication

Date de publication:
23 Jul 2024
Historique:
revised: 01 07 2024
received: 15 03 2024
medline: 23 7 2024
pubmed: 23 7 2024
entrez: 23 7 2024
Statut: aheadofprint

Résumé

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 reproduce key aspects of stromal and vascular dysfunction causing impaired drug delivery. Models containing SKBR3 and MDA-MB-468 tumoroids show 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 is found responsible for vascular dysfunction and loss of vascular HA. Interventions targeting IL8 or stromal HA normalize vascular permeability, perfusion, and IFP, and ultimately enhance drug delivery and TC death in response to perfusion with trastuzumab and cetuximab. Similar responses are observed in patient-derived models. These microphysiological systems can thus be personalized by using patient-derived cells and can be applied to discover new molecular therapies for the normalization of the tumor microenvironment.

Identifiants

pubmed: 39041892
doi: 10.1002/advs.202402757
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2402757

Subventions

Organisme : Swiss National Science Foundation
ID : P2EZP2_199914
Pays : Switzerland
Organisme : Swiss National Science Foundation
ID : P500PB_222131
Pays : Switzerland
Organisme : Swiss National Science Foundation
ID : SNSF-P400PB_186779
Pays : Switzerland
Organisme : Ludwig Center at MIT Koch Institute for Integrative Cancer Research
Organisme : NCI NIH HHS
ID : K00CA212227
Pays : United States
Organisme : NCI NIH HHS
ID : U01CA214381
Pays : United States
Organisme : NCI NIH HHS
ID : U54CA261694
Pays : United States
Organisme : Fondazione AIRC per la ricerca sul cancro ETS
ID : IG21479
Organisme : American-Italian Cancer Foundation
Organisme : Amgen

Informations de copyright

© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

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Auteurs

Giovanni S Offeddu (GS)

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Elena Cambria (E)

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Sarah E Shelton (SE)

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Kristina Haase (K)

European Molecular Biology Laboratory, European Molecular Biology Laboratory Barcelona, Barcelona, 08003, Spain.

Zhengpeng Wan (Z)

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Luca Possenti (L)

LaBS, Department of Chemistry, Materials and Chemical Engineering, Politecnico di Milano, Milan, 20133, Italy.
Data Science Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133, Italy.

Huu Tuan Nguyen (HT)

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Mark R Gillrie (MR)

Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, T2N 2T9, Canada.

Dean Hickman (D)

Amgen Research, Amgen Inc., 360 Binney Street, Cambridge, MA, 02142, USA.

Charles G Knutson (CG)

Amgen Research, Amgen Inc., 360 Binney Street, Cambridge, MA, 02142, USA.

Roger D Kamm (RD)

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Classifications MeSH