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

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 α3/α6 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 .

Cell Lineage Infidelity in PDAC Progression and Therapy Resistance

“…There are many ongoing efforts in the field, including our own ( https://precode-project.eu/ ) trying to improve aspects of the organoid technology. For example, a recent report from the Jørgensen’ group ( Below et al, 2021 ) described a fully-synthetic hydrogel that supported tumour organoid propagation and co-cultivation with stromal elements, thus promising to be transformative for the field. Moreover, modifying medium formulations can “push organoids back” to a phenotype that more accurately resembles their origins ( Raghavan et al, 2021 ).…”

Reductionist Three-Dimensional Tumor Microenvironment Models in Synthetic Hydrogels

“…Additionally, the amount of RGD and/or other adhesion molecules in the gel can be titrated independently of the gel’s density and stiffness. This system has been used to model stromal cell interactions with melanoma cells by the Anseth group, demonstrating that the incorporation of fibroblasts decreased the proliferation and cluster size but increased the invasion of the melanoma cells [ 53 ], and to closely mimic the in situ, stiffness, and stromal cell cues on pancreatic ductal adenocarcinoma organoids by the Griffith and Jorgenson groups [ 54 ].…”

Human Endometrial Organoids: Recent Research Progress and Potential Applications

“…Based on this, the new synthetic scaffold uses eight-arm adhesion-linker pre-functionalized vinyl sulfone-activated PEG macromer (f-PEG-vs) based hydrogel system which is sensitive to matrix metalloproteinase (MMP). The system contains the fibrillar analogue FN-mimetic peptide PHSRN-K-RGD, collagen analogue the GFOGER peptide, and a BM-binding peptide which maintains cell secreted matricellular proteins to the greatest extent ( Below et al, 2022 ). The new system may provide some hints for whether a more accurate ECM for endometrial organoid and stromal cells growth and expansion can be established.…”