Non-small cell lung cancer (NSCLC) has limited treatment options. Expression of the RNA-binding protein (RBP) Musashi-2 (MSI2) is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression, and drives NSCLC metastasis. We evaluated the mechanism of MSI2 action in NSCLC to gain therapeutically useful insights. Reverse phase protein array (RPPA) analysis of MSI2-depleted versus control Kras^LA1/+; Trp53^R172HΔG/+ NSCLC cell lines identified EGFR as a MSI2-regulated protein. MSI2 control of EGFR expression and activity in an NSCLC cell line panel was studied using RT-PCR, Western blots, and RNA immunoprecipitation. Functional consequences of MSI2 depletion were explored for cell growth and response to EGFR-targeting drugs, in vitro and in vivo. Expression relationships were validated using human tissue microarrays. MSI2 depletion significantly reduced EGFR protein expression, phosphorylation, or both. Comparison of protein and mRNA expression indicated a post-transcriptional activity of MSI2 in control of steady state levels of EGFR. RNA immunoprecipitation analysis demonstrated that MSI2 directly binds to EGFR mRNA, and sequence analysis predicted MSI2 binding sites in the murine and human EGFR mRNAs. MSI2 depletion selectively impaired cell proliferation in NSCLC cell lines with activating mutations of EGFR (EGFR^mut). Further, depletion of MSI2 in combination with EGFR inhibitors such as erlotinib, afatinib, and osimertinib selectively reduced the growth of EGFR^mut NSCLC cells and xenografts. EGFR and MSI2 were significantly co-expressed in EGFR^mut human NSCLCs. These results define MSI2 as a direct regulator of EGFR protein expression, and suggest inhibition of MSI2 could be of clinical value in EGFR^mut NSCLC.

Pancreatic neuroendocrine tumors (NETs) are rare well-differentiated neoplasms with limited therapeutic options and unknown cells of origin. The current classification of pancreatic neuroendocrine tumors is based on proliferative grading, and guides therapeutic strategies, however, tumors within grades exhibit profound heterogeneity in clinical manifestation and outcome. Manifold studies have highlighted intra-patient differences in tumors at the genetic and transcriptomic levels. Molecular classification might become an alternative or complementary basis for treatment decisions and reflect tumor biology, actionable cellular processes. Here, we provide a comprehensive review of genomic, transcriptomic, proteomic and epigenomic studies of pancreatic NETs to elucidate patterns shared between proposed subtypes that could form a foundation for new classification. We denote four NET subtypes with distinct molecular features, which were consistently reproduced using various omics technologies.

Background: The RNA-binding protein Musashi-2 (MSI2) controls the translation of proteins that support stem cell identity and lineage determination and is associated with progression in some cancers. We assessed MSI2 as potential clinical biomarker in colorectal cancer (CRC) and tubulovillous adenoma (TA) of colon mucosa. Methods: We assessed 125 patients, of whom 20 had polyps of the colon (TAs), and 105 had CRC. Among 105 patients with CRC, 45 had stages I-III; among metastatic CRC (mCRC) patients, 31 had synchronous and 29 metachronous liver metastases. We used immunohistochemistry to measure MSI2 expression in matching specimens of normal tissue versus TAs, primary CRC tumors, and metastases, correlating expression to clinical outcomes. We analyzed the biological effects of depleting MSI2 expression in human CRC cells. Results: MSI2 expression was significantly elevated in polyps versus primary tissue, and further significantly elevated in primary tumors and metastases. MSI2 expression correlated with decreased progression free survival (PFS) and overall survival (OS), higher tumor grade, and right-side localization (p = 0.004) of tumors. In metastases, high MSI2 expression correlated with E-cadherin expression. Knockdown of MSI2 in CRC cells suppressed proliferation, survival and clonogenic capacity, and decreased expression of TGFβ1, E-cadherin, and ZO1. Conclusion: Elevated expression of MSI2 is associated with pre-cancerous TAs in the colonic mucosa, suggesting it is an early event in transformation. MSI2 expression is further elevated during CRC progression, and associated with poor prognosis. Depletion of MSI2 reduces CRC cell growth. These data imply a causative role of MSI2 overexpression at multiple stages of CRC formation and progression.

Benzo[a]pyrene (BaP) is noted as one of the main cancer-causing pollutants in human beings and may damage the development of crop plants. The present work was designed to explore more insights into the toxic effects of BaP on Solanum lycopersicum L. at various doses (20, 40, and 60 MPC) spiked in Haplic Chernozem. A dose-dependent response in phytotoxicity were noted, especially in the biomass of the roots and shoots, at doses of 40 and 60 MPC BaP and the accumulation of BaP in S. lycopersicum tissues. Physiological and biochemical response indices were severely damaged based on applied doses of BaP. During the histochemical analysis of the localization of superoxide in the leaves of S. lycopersicum, formazan spots were detected in the area near the leaf’s veins. The results of a significant increase in malondialdehyde (MDA) from 2.7 to 5.1 times, proline 1.12- to 2.62-folds, however, a decrease in catalase (CAT) activity was recorded by 1.8 to 1.1 times. The activity of superoxide dismutase (SOD) increased from 1.4 to 2, peroxidase (PRX) from 2.3 to 5.25, ascorbate peroxidase (APOX) by 5.8 to 11.5, glutathione peroxidase (GP) from 3.8 to 7 times, respectively. The structure of the tissues of the roots and leaves of S. lycopersicum in the variants with BaP changed depending on the dose: it increased the intercellular space, cortical layer, and the epidermis, and the structure of the leaf tissues became looser.

Background: Neuroendocrine neoplasms are a rare and heterogeneous group of neoplasms. Small-sized (≤2 cm) pancreatic neuroendocrine tumors (PanNETs) are of particular interest as they are often associated with aggressive behavior, with no specific prognostic or progression markers. Methods: This article describes a clinical case characterized by a progressive growth of nonfunctional PanNET requiring surgical treatment in a patient with a germline FANCD2 mutation, previously not reported in PanNETs. The patient underwent whole exome sequencing and single-cell RNA sequencing. Results: The patient underwent surgical treatment. We confirmed the presence of the germline mutation FANCD2 and also detected the germline mutation WNT10A. The cellular composition of the PanNET was analyzed using single-cell sequencing, and the main cell clusters were identified. We analyzed the tumor genomics, and used the data to define the effect the germline FANCD2 mutation had. Conclusions: Analysis of the mutational status of patients with PanNET may provide additional data that may influence treatment tactics, refine the plan for monitoring such patients, and provide more information about the pathogenesis of PanNET. PanNET research using scRNA-seq data may help in predicting the effect of therapy on neuroendocrine cells with FANCD2 mutations.

Invasion and metastasis are well-known hallmarks of cancer, with metastatic disease accounting for 60% to 90% of cancer-related deaths