Interfacial Curvature in Confined Coculture Directs Stromal Cell Activity with Spatial Corralling of Pancreatic Cancer Cells.


Journal

Advanced biology
ISSN: 2701-0198
Titre abrégé: Adv Biol (Weinh)
Pays: Germany
ID NLM: 101775319

Informations de publication

Date de publication:
06 2021
Historique:
revised: 18 02 2021
received: 12 11 2020
pubmed: 24 3 2021
medline: 26 10 2021
entrez: 23 3 2021
Statut: ppublish

Résumé

Interfacial cues in the tumor microenvironment direct the activity and assembly of multiple cell types. Pancreatic cancer, along with breast and prostate cancers, is enriched with cancer-associated fibroblasts (CAFs) that activate to coordinate the deposition of the extracellular matrix, which can comprise over 90% of the tumor mass. While it is clear that matrix underlies the severity of the disease, the relationship between stromal-tumor cell assembly and cell-matrix dynamics remains elusive. Micropatterned hydrogels deconstruct the interplay between matrix stiffness and geometric confinement, guiding heterotypic cell populations and matrix assembly in pancreatic cancer. Interfacial cues at the perimeter of microislands guide CAF migration and direct cancer cell assembly. Computational modeling shows curvature-stress dependent cellular localization for cancer and CAFs in coculture. Regions of convex curvature enhance edge stress that activates a myofibroblast phenotype in the CAFs with migration and increased collagen I deposition, ultimately leading to a central "corralling" of cancer cells. Inhibiting mechanotransduction pathways decreases CAF activation and the associated corralling phenotype. Together, this work reveals how interfacial biophysical cues underpin aspects of stromal desmoplasia, a hallmark of disease severity and chemoresistance in the pancreatic, breast, and prostate cancers, thereby providing a tool to expand stroma-targeting therapeutic strategies.

Identifiants

pubmed: 33754491
doi: 10.1002/adbi.202000525
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2000525

Informations de copyright

© 2021 Wiley-VCH GmbH.

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Auteurs

Stephanie Nemec (S)

School of Materials Science and Engineering, UNSW Sydney, Sydney, NSW, 2052, Australia.

Joey Lam (J)

School of Chemistry Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW, 2052, Australia.

Jingxiao Zhong (J)

School of Aerospace, Mechanical and Mechatronic Engineering, The University of Sydney, Sydney, NSW, 2006, Australia.

Celine Heu (C)

Biomedical Imaging Facility, Mark Wainwright Analytical Center, UNSW Sydney, Sydney, NSW, 2052, Australia.

Paul Timpson (P)

The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, 2052, Australia.

Qing Li (Q)

School of Aerospace, Mechanical and Mechatronic Engineering, The University of Sydney, Sydney, NSW, 2006, Australia.

Janet Youkhana (J)

Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, School of Medical Sciences, UNSW Sydney, Sydney, NSW, 2052, Australia.

George Sharbeen (G)

Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, School of Medical Sciences, UNSW Sydney, Sydney, NSW, 2052, Australia.

Phoebe A Phillips (PA)

Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, School of Medical Sciences, UNSW Sydney, Sydney, NSW, 2052, Australia.

Kristopher A Kilian (KA)

School of Materials Science and Engineering, UNSW Sydney, Sydney, NSW, 2052, Australia.
School of Chemistry Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW, 2052, Australia.

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