A mechanical memory of pancreatic cancer cells

Abstract

Cells sense and respond to mechanical stimuli in healthy and pathological conditions. Although the major mechanisms underlying cellular mechanotransduction have been described, it remains largely unclear how cells store information on past mechanical cues over time. Such mechanical memory is extremely relevant in the onset of metastasis in which cancer cells migrate through tissues of different stiffness, e.g. from a stiffer tumor microenvironment to softer metastatic sites as commonly occurs for pancreatic cancer. Here, we used micropillar-based traction force microscopy to show that Suit-2.28 pancreatic cancer cells mechanically primed on a stiff matrix exerted higher traction forces even when transferred to a soft secondary matrix, as compared to soft-primed cells. This mechanical memory effect was mediated by the Yes-associated protein (YAP) and the microRNA-21 (miR-21) that are two mechanosensors initially identified as long-term memory keepers in mesenchymal stem cells. Soft-primed cells showed (i) a lower YAP nuclear translocation when transferred to a stiff secondary matrix and (ii) a loss of rigidity sensing through YAP, as compared to stiffprimed cells. The mechanical adaptation resulted in a differential expression of miR-21, inversely proportional to the priming rigidity. The long-term mechanical memory retained by miR-21 unveiled a previously unidentified mechanical modulation of drug resistance by past matrix stiffness. The higher expression of miR-21 in soft-primed cells correlated with the increased resistance to gemcitabine, as compared to stiff-primed and nonprimed pancreatic cancer cells. pancreatic cancer | cell mechanics | chemoresistance | gemcitabine Correspondence: stefano.

The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options

“…These are all genes involved in cell migr ECM adhesion, ECM remodeling, anti-apoptotic mechanisms an At this step, cells show less protein designated to maintain cell E-cadherin, causing a loss of tissue polarity, while they incre mentin, which is a marker of mesenchymal cells [68,121]. YAP/T can be similarly induced by the interaction of laminin 5 to α6β4 to maintain their stemness, as shown in epidermal stem cells [12 EMT is triggered by the accumulation of YAP and the transcriptional coactivator with the PDZ-binding motif, also known as WWTR1 (TAZ), within the nuclei [119][120][121][122][123]. YAP and TAZ need DNA-binding partners, as YAP and TAZ have no DNA binding ability.…”

Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces

“…Metastatic niche in a softer environment presents a higher intrinsic resistance to gemcitabine monotherapy, a standard first-line treatment for patients with metastatic pancreatic cancer. 393,394 In pancreatic cancer, YAP nuclear translocation and miR-21 expression mediate the mechanical memory in response to altered environmental stiffness. 393 Meanwhile, environmental stiffness can influence the gemcitabine chemoresistance of soft-primed pancreatic cancer cells.…”

“…393,394 In pancreatic cancer, YAP nuclear translocation and miR-21 expression mediate the mechanical memory in response to altered environmental stiffness. 393 Meanwhile, environmental stiffness can influence the gemcitabine chemoresistance of soft-primed pancreatic cancer cells. These findings could shed light on how the regulation of miRNA expression affects tumor metastasis in patients, while miR-21 serve as a potential therapeutic target in metastatic tumor cells.…”

Framing cancer progression: influence of the organ‐ and tumour‐specific matrisome

“…Changes in stiffness at the invasive front of a tumour can trigger epithelial‐to‐mesenchymal transition (EMT) and, thus, modifications in the cancer cell cytoskeleton . Several in vitro studies have shown that cancer cells can acquire so‐called mechanical memory on a stiff substrate by activating yes‐associated protein‐1 (YAP) signalling, leading to persistently higher actomyosin expression . Later, after reaching a softer 2D substrate, these cells exhibit larger‐than‐normal focal adhesions and increased migration speed .…”