Abstract
Three-dimensional (3D) cancer models are invaluable tools designed to study tumour biology and new treatments. Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of cancer, has been progressively explored with bioengineered 3D approaches by deconstructing elements of its tumour microenvironment. Here, we investigated the suitability of collagen-nanocellulose hydrogels to mimic the extracellular matrix of PDAC and to promote the formation of tumour spheroids and multicellular 3D cultures with stromal cells. Blending of type I collagen fibrils and cellulose nanofibres formed a matrix of controllable stiffness, which resembled the lower profile of pancreatic tumour tissues. Collagen-nanocellulose hydrogels supported the growth of tumour spheroids and multicellular 3D cultures, with increased metabolic activity and matrix stiffness. To validate our 3D cancer model, we tested the individual and combined effects of the anti-cancer compound triptolide and the chemotherapeutics gemcitabine and paclitaxel, resulting in differential cell responses. Our blended 3D matrices with tuneable mechanical properties consistently maintain the growth of PDAC cells and its cellular microenvironment and allow the screening of anti-cancer treatments.
Highlights
The tumour microenvironment (TME) is a complex and dynamic niche that integrates the extracellular matrix (ECM), multiple cell populations and an array of secreted factors and signalling molecules [1]
We demonstrated the effect of blending type I collagen with nanocellulose to form hydrogels of adjustable stiffness for 3D tissue models [35]
Imaging of the matrix structure revealed that collagen hydrogels have larger pores than those of the collagen-nanocellulose hydrogels (Supplementary Figure 1)
Summary
The tumour microenvironment (TME) is a complex and dynamic niche that integrates the extracellular matrix (ECM), multiple cell populations and an array of secreted factors and signalling molecules [1]. Despite our improved understanding about the role of the TME in cancer progression, pancreatic ductal adenocarcinoma (PDAC) has one of the highest cancer-related mortality rates, with a 5-year survival rate of 10% [2,3,4]. This is caused by the late diagnosis of the disease, multi-drug resistance, and lack of targeted therapies, which diminishes the efficacy of existing treatments and hinders the development of new treatments. The continuous advancement of ECM-like biomaterials, such as hydrogels, that closely reproduce the specific features of tumour tissues is critical for biomimetic 3D matrices to model the pancreatic TME
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