Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model

Abstract

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.

Preliminary investigation of elevated collagen and blood‐clotting markers as potential noninvasive biomarkers for small cell lung cancer

“…Reciprocally, the process of EMT induces cellular changes that result in ECM remodeling creating a feedback loop that is tightly regulated in healthy tissues but is deregulated in cancer 43 . This cell interaction has recently been demonstrated in SCLC using a lung fibroblast coculture model 8 . Therefore, the consequences of ECM remodeling extend to the SCLC cells.…”

“…3 While the mechanisms of chemoresistance have not yet been fully elucidated, recent research has shown that processes such as epithelial to mesenchymal transition (EMT) are now known to play a role 4,5 and fibroblasts, and extracellular matrix (ECM) proteins such as collagens, laminins, fibronectin, and proteoglycans, 6 promote this transition. 7,8 Moreover, patients with SCLC often present with symptoms of advanced disease, including weight loss, fatigue, and poor wound healing, 1 with an increased risk of thromboembolism. 9 Although the mechanisms are not fully understood, the abnormal production of procoagulant factors, such as tissue factor, von Willebrand factor, or fibrinogen, may be involved, 9 and thromboembolism continues to be a significant cause of cancer-related mortality.…”

“…While the mechanisms of chemoresistance have not yet been fully elucidated, recent research has shown that processes such as epithelial to mesenchymal transition (EMT) are now known to play a role 4,5 and fibroblasts, and extracellular matrix (ECM) proteins such as collagens, laminins, fibronectin, and proteoglycans, 6 promote this transition 7,8 . Moreover, patients with SCLC often present with symptoms of advanced disease, including weight loss, fatigue, and poor wound healing, 1 with an increased risk of thromboembolism 9 .…”

Molecular mechanism underlying epithelial‐mesenchymal transformation and cisplatin resistance in esophageal squamous cell carcinoma

“…Additionally, epithelial cells can activate various EMT programs to varying degrees, and usually acquire many but not all of the characteristics related to complete mesenchymal cells. 15 This plasticity of cell phenotype may play an important role in the last step of the transfer cascade, namely the colonization of micro-metastatic deposits to form macroscopic tumors, as indicated by mouse and patient-derived xenograft (PDX) models. 16 Over the past two decades, the importance of the EMT program in tumor progression has been established, and an increasing number of studies have shown that the EMT program is activated during malignant progression.…”

“…It is worth noting that under all these pathological conditions, epithelial cells rarely activate the EMT program and EMT is typically reversible in normal epithelial cells and their tumor derivatives. Additionally, epithelial cells can activate various EMT programs to varying degrees, and usually acquire many but not all of the characteristics related to complete mesenchymal cells 15 . This plasticity of cell phenotype may play an important role in the last step of the transfer cascade, namely the colonization of micro‐metastatic deposits to form macroscopic tumors, as indicated by mouse and patient‐derived xenograft (PDX) models 16 …”