A Novel Scaffold-Based Hybrid Multicellular Model for Pancreatic Ductal Adenocarcinoma-Toward a Better Mimicry of the in vivo Tumor Microenvironment

Priyanka Gupta; Pedro A Pérez-Mancera; Hemant Kocher; Andrew Nisbet; Giuseppe Schettino; Eirini G Velliou

doi:10.3389/fbioe.2020.00290

A Novel Scaffold-Based Hybrid Multicellular Model for Pancreatic Ductal Adenocarcinoma-Toward a Better Mimicry of the in vivo Tumor Microenvironment

Front Bioeng Biotechnol. 2020 Apr 24:8:290. doi: 10.3389/fbioe.2020.00290. eCollection 2020.

Authors

Priyanka Gupta¹, Pedro A Pérez-Mancera², Hemant Kocher³, Andrew Nisbet⁴, Giuseppe Schettino^{5

6}, Eirini G Velliou¹

Affiliations

¹ Bioprocess and Biochemical Engineering Group (BioProChem), Department of Chemical and Process Engineering, University of Surrey, Guildford, United Kingdom.
² Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
³ Centre for Tumour Biology and Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
⁴ Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom.
⁵ Department of Physics, University of Surrey, Guildford, United Kingdom.
⁶ Medical Radiation Science Group, The National Physical Laboratory, Teddington, United Kingdom.

Abstract

With a very low survival rate, pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. This has been primarily attributed to (i) its late diagnosis and (ii) its high resistance to current treatment methods. The latter specifically requires the development of robust, realistic in vitro models of PDAC, capable of accurately mimicking the in vivo tumor niche. Advancements in the field of tissue engineering (TE) have helped the development of such models for PDAC. Herein, we report for the first time a novel hybrid, polyurethane (PU) scaffold-based, long-term, multicellular (tri-culture) model of pancreatic cancer involving cancer cells, endothelial cells, and stellate cells. Recognizing the importance of ECM proteins for optimal growth of different cell types, the model consists of two different zones/compartments: an inner tumor compartment consisting of cancer cells [fibronectin (FN)-coated] and a surrounding stromal compartment consisting of stellate and endothelial cells [collagen I (COL)-coated]. Our developed novel hybrid, tri-culture model supports the proliferation of all different cell types for 35 days (5 weeks), which is the longest reported timeframe in vitro. Furthermore, the hybrid model showed extensive COL production by the cells, mimicking desmoplasia, one of PDAC's hallmark features. Fibril alignment of the stellate cells was observed, which attested to their activated state. All three cell types expressed various cell-specific markers within the scaffolds, throughout the culture period and showed cellular migration between the two zones of the hybrid scaffold. Our novel model has great potential as a low-cost tool for in vitro studies of PDAC, as well as for treatment screening.

Keywords: 3D model; endothelial cells; multicellular tumor model; pancreatic cancer; pancreatic stellate cells; polyurethane scaffold; scaffold-assisted tumor model.