Background: Musashi-2 (MSI2) is a member of RNA-binding protein family that regulates mRNA translation of numerous intracellular targets and influences maintenance of stem cell identity. This study assessed MSI2 as a potential clinical biomarker in non-small cell lung cancer (NSCLC). Methods: The current study included 40 patients with NSCLC, of whom one presented with stage 1, 14 presented with stage II, 15 presented with stage III, and 10 patients had stage IV. All patients received standard of care treatments. All patient samples were obtained before treatment started. We used immunohistochemical (IHC) approach to measure MSI2 protein expression in matching specimens of normal lung versus tumor tissues, and primary versus metastatic tumors, followed by correlative analysis in relation to clinical outcomes. In parallel, clinical correlative analysis of MSI2 mRNA expression was performed in silico using publicly available datasets (TCGA/ICGC and KM plots). Results: MSI2 protein expression in patient samples was significantly elevated in NSCLC primary tumors versus normal lung tissue (P=0.03). MSI2 elevated expression positively correlated with a decreased progression free survival (PFS) (P=0.026) combined for all stages and with overall survival (OS) at stage IV (P=0.013). Elevated MSI2 expression on RNA level was confirmed in primary tumor versus normal tissue samples in TCGA dataset (P<0.0001), and positively correlated with decreased OS (P=0.02). No correlation was observed between MSI2 expression and age, sex, smoking, and treatment type. Conclusions: Elevated MSI2 expression in primary NSCLC tumors is associated with poor prognosis and can be used as a novel potential prognostic biomarker in NSCLC patients. Future studies in an extended patient cohort are warranted.

Non-small cell lung cancer (NSCLC) has a low survival rate, with metastasis contributing to the vast majority of deaths. Elevated expression of the protein Nedd9 (neural precursor cell expressed, developmentally down-regulated 9) has been reported in a large subset of lung cancers and other malignancies as a promotor of aggressive phenotypes and drug resistance. This study was performed to identify the mechanisms by which Nedd9 regulates invasion and metastasis of non-small cell lung cancer in the transgenic murine model. Aiming to address the research goals, we performed a set of in vivo and in vitro experiments with the help of such methods as magnetic resonance imaging (MRI), immunohistochemical staining of tissues and microscopy, western blotting. We found that Nedd9 constitutive null genotype enhanced tumor growth in an inducible Kras/Trp53 model, in which Kras mutation is induced specifically in the lung tissue by inhalation of adenovirus. Pathological examination of the tissues demonstrated that Nedd9 null genotype also was associated with higher invasive capacity in vivo, including direct invasion to the heart. We carried out a set of experiments to unveil the mechanism underlying the phenotype discovered. Overall, our data support the model in which Nedd9 provides critical support for early stages of the NSCLC growth, and progression beyond this early stage in the absence of Nedd9 requires extensive intracellular protein signaling reprogramming, allowing tumor cells to acquire mesenchymal properties, such as increased mobility and invasion due to a compensatory rearrangement of intracellular protein signaling pathways and activation of the epithelial-mesenchymal transition (EMT). These results are novel and have not been previously described in the literature. The biological mechanism by which Nedd9 regulates growth, invasion, and metastasis of NSCLC has been poorly investigated, and its study carries not only fundamental implicationdiscovery of novel mechanisms driving tumor development, but also significant practical importance: assessment of levels of Nedd9 activity in NSCLC patients can potentially serve as a biomarker of response to chemotherapy.

Oncogenic transformation alters the metabolism of cellular nutrients to sustain tumor growth. We here define a mechanism by which modifications in cholesterol metabolism control the formation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by means of conditional inactivation of Nsdhl in mice bearing a tumor-inducing Kras mutation (Kras G12D ) prevented PDAC formation in the context of a heterozygous Trp53 f/+ genotype without impairing normal pancreatic development. In mice with pancreatic Nsdhl ablation and homozygous loss of Trp53, the emerging tumors presented with the aggressive basal (mesenchymal) phenotype as opposed to the classic (glandular) PDAC. This paralleled significantly reduced expression of cholesterol metabolic pathway genes in human basal PDAC subtype. Mechanistically, we demonstrate that genetic or metabolic cholesterol deprivation stabilizes the transforming growth factor beta (TGFβ) receptor to activate pro-mesenchymal effectors in human and murine PDAC, providing a direct mechanism by which cholesterol metabolism can condition tumor differentiation.3 Introduction.

e21583 Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the world, and metastasis is the most common cause of death in lung cancer patients. Musashi-2 (MSI2) is a member of RNA-binding protein family and regulates mRNA translation of numerous intracellular targets, and influences multiple biological processes, including maintenance of stem cell identity. Previously we reported that MSI2 is upregulated in the metastasis-competent NSCLC murine and human cell lines, drives NSCLC metastasis, and is progressively elevated in lung cancer patient samples. This study assessed MSI2 as potential clinical biomarker in NSCLC. Methods: The current study included 40 patients with NSCLC, of whom 15 presented with stage II and III respectively (37,5% each), and 10 patients (25%) had stage IV. All patients received treatment in accordance with the NCCN guidelines, and did not participate in clinical trials. All patient samples were obtained before treatment started. We used immunohistochemical (IHC) approach to measure MSI2 expression on the protein level in matching specimens of normal versus tumor tissues, and primary tumor vs. metastasis, followed by correlative analysis in relation to clinical outcomes. In parallel, clinical correlative analysis of MSI2 mRNA expression was performed in silico using publicly available datasets (TCGA/ICGC) as of January 2020. Results: MSI2 protein expression in patient samples was significantly elevated in NSCLC primary tumors and metastatic sites versus normal tissue (p = 0.03). MSI2 elevated expression positively correlated with a decreased progression free survival (PFS) (p = 0.026) at all stages and overall survival at stage IV (p = 0.013). Elevated MSI2 expression on RNA level was observed in primary tumor versus normal tissue samples in TCGA (p < 0.0001), and positively correlated with decreased OS (p = 0.028). No correlation was observed between MSI2 expression and age, sex, smoking, and treatment type. Conclusions: Elevated MSI2 expression in primary NSCLC tumors is associated with poor prognosis and can be used as a novel potential prognostic biomarker in NSCLC patients. Future studies in an extended patient cohort are strongly warranted.