肿瘤微环境（TME）是影响癌细胞上皮间质转化（EMT）和促进癌细胞获得侵袭性获得重要信号的来源。现在认为，EMT不是一个二元程序，并且癌细胞很少转化成完全的间质表型。相反，癌细胞存在于多个混合的上皮/间质（E/M）状态，负责细胞种群的异质性，这对肿瘤发展和转移过程中不断变化的环境非常有利。如何产生和维持这些中间状态还不完全清楚。在这里，我们展示了小细胞肺癌细胞和肺成纤维细胞之间的直接相互作用诱导了一种杂交EMT表型，在这种表型中，几个与细胞外基质（ECM）受体相互作用和ECM重塑有关的间质基因被上调，而如E-cadherin之类的上皮基因保持不变或略微增加。我们还证明，在癌细胞与成纤维细胞直接接触期间，许多EMT调控转录因子（EMT-TFs）以及Hippo通路的主要调节因子之一Yes-associated protein（YAP1）在癌细胞中被上调。此外，我们展示这些变化是短暂的，在相互作用被破坏后会逆转到初始状态。总的来说，我们的研究结果提供了证据，表明肿瘤细胞与TME中的成纤维细胞之间的直接接触会引发信号级联，从而造就了癌细胞的混合E/M状态。这些杂交状态在相互作用期间得以维持，并可能有助于治疗耐药和免疫逃避，而干扰直接接触将导致缓慢恢复并切换回初始状态。Copyright © 2023 Dhungel, Youngblood, Chu, Carroll and Dragoi.

The tumor microenvironment (TME) is the source of important cues that govern epithelial-to-mesenchymal transition (EMT) and facilitate the acquisition of aggressive traits by cancer cells. It is now recognized that EMT is not a binary program, and cancer cells rarely switch to a fully mesenchymal phenotype. Rather, cancer cells exist in multiple hybrid epithelial/mesenchymal (E/M) states responsible for cell population heterogeneity, which is advantageous for the ever-changing environment during tumor development and metastasis. How are these intermediate states generated and maintained is not fully understood. Here, we show that direct interaction between small cell lung carcinoma cells and lung fibroblasts induces a hybrid EMT phenotype in cancer cells in which several mesenchymal genes involved in receptor interaction with the extracellular matrix (ECM) and ECM remodeling are upregulated while epithelial genes such as E-cadherin remain unchanged or slightly increase. We also demonstrate that several core EMT-regulating transcription factors (EMT-TFs) are upregulated in cancer cells during direct contact with fibroblasts, as is Yes-associated protein (YAP1), a major regulator of the Hippo pathway. Further, we show that these changes are transient and reverse to the initial state once the interaction is disrupted. Altogether, our results provide evidence that tumor cells' direct contact with the fibroblasts in the TME initiates a signaling cascade responsible for hybrid E/M states of cancer cells. These hybrid states are maintained during the interaction and possibly contribute to therapy resistance and immune evasion, while interference with direct contact will result in slow recovery and switch to the initial states.Copyright © 2023 Dhungel, Youngblood, Chu, Carroll and Dragoi.