A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Christopher Below
  • Joanna Kelly
  • Alexander Brown
  • Jonathan Humphries
  • Colin Hutton
  • Jingshu Xu
  • Brian Lee
  • Celia Cintas
  • Xiaohong Zhang
  • Victor Hernandez-Gordillo
  • Linda Stockdale
  • Matthew Goldsworthy
  • Joe Geraghty
  • Lucy Foster
  • Derek O'Reilly
  • Barbara Schedding
  • Janet Askari
  • Jessica Burns
  • Nigel Hodson
  • Duncan Smith
  • Catherine Lally
  • Garry Ashton
  • David Knight
  • Antonia Banyard
  • Johannes A. Eble
  • Jennifer P Morton
  • Linda G Griffith
  • Claus Jorgensen (Corresponding)

Abstract

Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin–integrin α 36 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness—a hallmark of pancreatic cancer—was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro.

Bibliographical metadata

Original languageEnglish
Pages (from-to)110-119
Number of pages10
JournalNature Materials
Volume21
Issue number1
Early online date13 Sep 2021
DOIs
Publication statusPublished - 1 Jan 2022