Abstract：
Epithelial-stromal interplay through chemomechanical cues from cells and matrix propels cancer progression. Elevated tissue stiffness in potentially malignant tissues suggests a link between matrix stiffness and enhanced tumor growth. In this study, employing chronic oral/esophageal injury and cancer models, it is demonstrated that epithelial-stromal interplay through matrix stiffness and Hedgehog (Hh) signaling is key in compounding cancer development. Epithelial cells actively interact with fibroblasts, exchanging mechanoresponsive signals during the precancerous stage. Specifically, epithelial cells release Sonic Hh, activating fibroblasts to produce matrix proteins and remodeling enzymes, resulting in tissue stiffening. Subsequently, basal epithelial cells adjacent to the stiffened tissue become proliferative and undergo epithelial-to-mesenchymal transition, acquiring migratory and invasive properties, thereby promoting invasive tumor growth. Notably, transcriptomic programs of oncogenic GLI2, mechano-activated by actin cytoskeletal tension, govern this process, elucidating the crucial role of non-canonical GLI2 activation in orchestrating the proliferation and mesenchymal transition of epithelial cells. Furthermore, pharmacological intervention targeting tissue stiffening proves highly effective in slowing cancer progression. These findings underscore the impact of epithelial-stromal interplay through chemo-mechanical (Hh-stiffness) signaling in cancer development, and suggest that targeting tissue stiffness holds promise as a strategy to disrupt chemo-mechanical feedback, enabling effective cancer treatment.
摘要：
上皮-基质通过来自细胞和基质的化学机械线索相互作用推动癌症进展。潜在恶性组织中组织硬度升高表明基质硬度与肿瘤生长增强之间存在联系。在这项研究中,采用慢性口腔/食道损伤和癌症模型，研究表明，通过基质硬度和Hedgehog（Hh）信号传导的上皮-基质相互作用是复合癌症发展的关键。上皮细胞与成纤维细胞积极相互作用，在癌前阶段交换机械反应信号。具体来说,上皮细胞释放SonicHh，激活成纤维细胞产生基质蛋白和重塑酶，导致组织变硬。随后，与硬化组织相邻的基底上皮细胞变得增殖并经历上皮到间质转化，获得迁移和侵入特性，从而促进侵袭性肿瘤的生长。值得注意的是,由肌动蛋白细胞骨架张力机械激活的致癌GLI2的转录组学程序，管理这个过程，阐明了非规范GLI2激活在协调上皮细胞增殖和间质转化中的关键作用。此外，针对组织硬化的药物干预被证明在减缓癌症进展方面非常有效。这些发现强调了上皮-基质相互作用通过化学-机械（Hh-刚度）信号在癌症发展中的影响。并表明靶向组织硬度有望作为破坏化学机械反馈的策略，能够有效治疗癌症。
