Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in the world due to its insensitivity to current therapies and its propensity to metastases from the primary tumor mass. This is largely attributed to its complex microenvironment composed of unique stromal cell populations and extracellular matrix (ECM). The recruitment and activation of these cell populations causes an increase in deposition of ECM components, highly influencing the behavior of malignant cells through disrupted forms of signalling. As PDAC progresses from premalignant lesion to invasive carcinoma, this dynamic landscape shields the mass from immune defenses and cytotoxic intervention. This microenvironment influences an invasive cell phenotype through altered forms of mechanical signaling, capable of enacting biochemical changes within cells through activated mechanotransduction pathways. The effects of altered mechanical cues on malignant cell mechanotransduction have long remained enigmatic, particularly in PDAC, whose microenvironment significantly changes over time. A more complete and thorough understanding of PDAC’s physical surroundings (microenvironment), mechanosensing proteins, and mechanical properties may help in identifying novel mechanisms that influence disease progression, and thus, provide new potential therapeutic targets.Copyright © 2020. Published by Elsevier B.V.