Deciphering the Nanomechanical and Biochemical Signatures of Pancreatic Cancer

Abstract

Mechanical forces are ubiquitous within the human body and play vital roles in physiology and disease. Understanding the mechanisms through which these forces drive cell behaviour can provide insights into the pathogenesis and progression of diseases, such as cancer. Pancreatic cancer (PDAC) is a burden to healthcare systems across the globe, with poor survival rates and limited treatment options available. PDAC’s poor clinical outcomes are attributed to a lack of early-stage diagnostic and screening strategies, ill-defined symptoms, and an aggressive biological phenotype driven by biochemical and mechanical cues originating from the tumour microenvironment (TME). The pancreatic TME is a dynamic landscape consisting of cellular and non-cellular components, providing a supportive niche for cancer cell survival and migration. While significant efforts have been directed towards harnessing biochemical cues to help develop novel diagnostic and therapeutic solutions for PDAC, less attention has been given towards the use of mechanical cues. In this work, the nanomechanical and biochemical signatures in human PDAC tissue have been deciphered for the generation of novel pathways to diagnose and treat PDAC. A comprehensive approach using bioanalytical tools, such as BioAFM and Raman spectroscopy, and biomaterial-based platforms have been adopted to unravel these signatures and advance our understanding of the mechanical properties of the PDAC TME. For the first time, this study revealed that human pancreatic TME nanomechanical and compositional properties vary significantly over cancer progression and can be harnessed for translational healthcare applications. This work also introduces a biosynthetic hydrogel system to model the nanomechanical properties of the pancreatic TME, gaining insights to mechanosensing proteins. In-vitro investigations revealed that nanomechanics have influence on mechanosensory proteins in PDAC, paving the way for further mechanistic studies.