Abstract 2580: Direct interaction between cancer cells and fibroblasts drives epithelial-to-mesenchymal plasticity (EMP) and contribute to chemotherapy resistance

The tumor microenvironment (TME), composed of immune cells and fibroblasts, blood vessels, signaling molecules and extracellular matrix, provides important cues that govern epithelial-to-mesenchymal transition (EMT) and facilitate the acquisition of aggressive traits such as chemotherapy resistance by cancer cells. Cancer cells exist in multiple hybrid epithelial/mesenchymal (E/M) states responsible for the ever-changing environment during tumor development and metastasis. How are these hybrid states generated and maintained is not fully understood. Using small cell lung carcinoma (SCLC) and normal lung fibroblasts model we show that direct interaction between SCLC 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. We also demonstrate that several core EMT-regulating transcription factors (EMT-TFs) are upregulated in cancer cells during direct contact with fibroblasts, including Yes-associated protein (YAP1), a major regulator of the Hippo pathway. Furthermore, we demonstrate that this upregulation of YAP1 in cancer cells which occurs significantly only during the direct interaction with fibroblast makes the cancer cells more resistant to chemotherapeutic agents resulting in more aggressive phenotypes. The cells become sensitive to chemotherapeutic agents when YAP1 is inhibited. 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 contribute to therapy resistance via YAP1 pathway, while interference with direct contact will result in slow recovery and a switch to the initial states. Citation Format: Nilu Dhungel, Ana- Maria Dragoi. Direct interaction between cancer cells and fibroblasts drives epithelial-to-mesenchymal plasticity (EMP) and contribute to chemotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2580.