Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, characterised by stromal remodelling, elevated matrix stiffness and high metastatic rate. Retinoids, compounds derived from vitamin A, have a history of clinical use in cancer for their anti-proliferative and differentiation effects, and more recently have been explored as anti-stromal therapies in PDAC for their ability to induce mechanical quiescence in cancer associated fibroblasts. Here, we demonstrate that retinoic acid receptor β (RAR-β) transcriptionally represses myosin light chain 2 (MLC-2) expression in pancreatic cancer cells. As a key regulatory component of the contractile actomyosin machinery, MLC-2 downregulation results in decreased cytoskeletal stiffness and traction force generation, impaired response to mechanical stimuli via mechanosensing and reduced ability to invade through the basement membrane. This work highlights the potential of retinoids to target the mechanical drivers of pancreatic cancer.

胰腺导管腺癌 (PDAC) 是最常见和最致命的胰腺癌，其特征是间质重塑、基质硬度升高和高转移率。类视黄醇是一种源自维生素 A 的化合物，因其抗增殖和分化作用而在癌症中具有临床应用历史，并且最近已被探索作为 PDAC 中的抗基质疗法，因为它们能够在癌症相关的成纤维细胞中诱导机械静止。在这里，我们证明视黄酸受体 β (RAR-β) 转录抑制胰腺癌细胞中肌球蛋白轻链 2 (MLC-2) 的表达。作为收缩肌动球蛋白机制的关键调节成分，MLC-2 下调导致细胞骨架刚度和牵引力生成降低，通过机械传感对机械刺激的反应受损，通过基底膜侵入的能力降低。这项工作突出了类视黄醇针对胰腺癌机械驱动因素的潜力。