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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.

Purpose: The relationship between anxiety or depressive comorbidities, their chronology of onset, and the severity of anorexia nervosa (AN) is not well-studied. We hypothesize that the existence of a comorbidity, particularly before the onset of AN, is associated with greater severity of AN.Methods: One hundred seventy-seven subjects were assessed. The prevalence of major depressive disorder (MDD), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), and social phobia (SP) as well as their chronology of onset were studied. The assessment criteria of AN severity were the overall clinical condition, body mass index (BMI) on admission, lowest BMI, intensity of the eating symptoms, age at the onset of AN, illness duration, number of hospitalizations, and quality of life.Results: Patients with AN had the greatest clinical severity when they had a comorbid disorder over their lifetime, such as MDD, GAD, or SP. These comorbidities along with OCD were associated with a higher level of eating symptoms and a more altered quality of life. A profile of maximum severity was associated with a higher prevalence of MDD and GAD. Concerning the chronology of onset, the age at the start of AN was later in cases of MDD or GAD prior to AN.Conclusion: There seems to be an association between severity of AN and both MDD and GAD. The chronology of onset of the comorbidity did not seem to be associated with the severity.