Hydrogel Models with Stiffness Gradients for Interrogating Pancreatic Cancer Cell Fate

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and has seen only modest improvements in patient survival rate over the past few decades. PDAC is highly aggressive and resistant to chemotherapy, owing to the presence of a dense and hypovascularized fibrotic tissue, which is composed of stromal cells and extracellular matrices. Increase deposition and crosslinking of matrices by stromal cells lead to a heterogeneous microenvironment that aids in PDAC development. In the past decade, various hydrogel-based, in vitro tumor models have been developed to mimic and recapitulate aspects of the tumor microenvironment in PDAC. Advances in hydrogel chemistry and engineering should provide a venue for discovering new insights regarding how matrix properties govern PDAC cell growth, migration, invasion, and drug resistance. These engineered hydrogels are ideal for understanding how variation in matrix properties contributes to the progressiveness of cancer cells, including durotaxis, the directional migration of cells in response to a stiffness gradient. This review surveys the various hydrogel-based, in vitro tumor models and the methods to generate gradient stiffness for studying migration and other cancer cell fate processes in PDAC.

Pancreatic Ductal Adenocarcinoma: Preclinical in vitro and ex vivo Models

“…Collagen matrices have a compression force more akin to healthy tissue while modified HA matrices reach compression forces up to 1.5 kPa which compares well to the pressure measured in PDAC tumors (Chang and Lin, 2021). A major drawback of using natural compounds is their batch-to-batch variability.…”

“…However, also due to its animal origin it is subject to significant batch-to-batch variations which negatively affect the reproducibility of organoid research. In addition, Matrigel is rather soft compared to the stiff collagen-I-rich stroma characteristic for PDAC (Chang and Lin, 2021). Attempts to move into a more homogenous matrix have not been successful yet but remain a target of intensive research.…”

Dual Functionalization of Gelatin for Orthogonal and Dynamic Hydrogel Cross-Linking

“…19,29,70 GelNB can also cross-link with tetrazinemodified macromers into click hydrogels. 24,71 Because gelatin is commonly used in hydrogel fabrication, dual modification of gelatin may provide additional functionality in hydrogel fabrication. 72−74 The abundant amine and acid groups on gelatin provide a diverse opportunity for modifying two chemical groups to provide additional functionality of the bioactive gelatin hydrogels.…”

“…Lee et al synthesized gelatin-hydroxyphenyl propionic acid through standard carbodiimide chemistry. The resulting gelatin derivatives were enzymatically cross-linked into hydrogels via adding HRP/H 2 O 2 . , In recent year, GelNB is also increasingly used because of its ability to form orthogonal cross-links via light or enzyme-mediated thiol-norbornene click reactions. ,, GelNB can also cross-link with tetrazine-modified macromers into click hydrogels. , …”

Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits

“…Alginate and polyethylene glycol, for instance, are relatively inert whereas collagens, laminin, and/or FN1 can contribute directly to cell signaling ( Miroshnikova et al, 2011 ) ( Caliari and Burdick, 2016 ). This ability to tailor matrix composition can be utilized to assist in decoupling the mechanical and biochemical signaling effects of the ECM on the growth of tumor organoids ( Chang and Lin, 2021 ). Indeed, seaweed-derived alginate, which lacks the native ligands that permit biological signaling with mammalian cells can be utilized to alter matrix mechanics without contributing to biological matrix signaling ( Rowley et al, 1999 ).…”