Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma

Lineage transition in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of non-small cell lung cancer, as implicated by clinical observation of mixed ADC and SCC pathologies in adenosquamous cell carcinoma, remains a fundamental yet unsolved question. Here we provide in vivo evidence showing the transdifferentiation of lung cancer from ADC to SCC in mice: Lkb1-deficient lung ADC progressively transdifferentiates into SCC, via a pathologically mixed mAd-SCC intermediate. We find that reduction of lysyl oxidase (Lox) in Lkb1-deficient lung ADC decreases collagen disposition and triggers extracellular matrix remodelling and upregulates p63 expression, a SCC lineage survival oncogene. Pharmacological Lox inhibition promotes the transdifferentiation, whereas ectopic Lox expression significantly inhibits this process. Notably, ADC and SCC show differential responses to Lox inhibition. Collectively, our findings demonstrate the de novo transdifferentiation of lung ADC to SCC in mice and provide mechanistic insight that may have important implications for lung cancer treatment

Spectrum of Oncogenic Driver Mutations in Lung Adenocarcinomas from East Asian Never Smokers

PURPOSE:We previously showed that 90% (47 of 52; 95% CI, 0.79 to 0.96) of lung adenocarcinomas from East Asian never-smokers harbored well-known oncogenic mutations in just four genes: EGFR, HER2, ALK, and KRAS. Here, we sought to extend these findings to more samples and identify driver alterations in tumors negative for these mutations. EXPERIMENTAL DESIGN:We have collected and analyzed 202 resected lung adenocarcinomas from never smokers seen at Fudan University Shanghai Cancer Center. Since mutations were mutually exclusive in the first 52 examined, we determined the status of EGFR, KRAS, HER2, ALK, and BRAF in stepwise fashion as previously described. Samples negative for mutations in these 5 genes were subsequently examined for known ROS1 fusions by RT-PCR and direct sequencing. RESULTS:152 tumors (75.3%) harbored EGFR mutations, 12 (6%) had HER2 mutations, 10 (5%) had ALK fusions all involving EML4 as the 5' partner, 4 (2%) had KRAS mutations, and 2 (1%) harbored ROS1 fusions. No BRAF mutation were detected. CONCLUSION:The vast majority (176 of 202; 87.1%, 95% CI: 0.82 to 0.91) of lung adenocarcinomas from never smokers harbor mutant kinases sensitive to available TKIs. Interestingly, patients with EGFR mutant patients tend to be older than those without EGFR mutations (58.3 Vs 54.3, P = 0.016) and patient without any known oncogenic driver tend to be diagnosed at a younger age (52.3 Vs 57.9, P = 0.013). Collectively, these data indicate that the majority of never smokers with lung adenocarcinoma could benefit from treatment with a specific tyrosine kinase inhibitor

Evolution from genetics to phenotype: reinterpretation of NSCLC plasticity, heterogeneity, and drug resistance

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy is beneficial in most cases, but the development of drug resistance stands as an obstacle to good prognosis. Multiple mechanisms were explored such as genetic alterations, activation of bypass signaling, and phenotypic transition. These intrinsic and/or extrinsic dynamic regulations facilitate tumor cell survival in meeting the demands of signaling under different stimulus. This review introduces lung cancer plasticity and heterogeneity and their correlation with drug resistance. While cancer plasticity and heterogeneity play an essential role in the development of drug resistance, the manipulation of them may bring some inspirations to cancer prognosis and treatment. That is to say, lung cancer plasticity and heterogeneity present us with not only challenges but also opportunities

Oceanic redox condition during the late Ediacaran (551-541 Ma), South China

The late Ediacaran (551-541 Ma) oceanic environment could represent a significant preparation for the enrichment of redox sensitive elements during the early Cambrian and even for the evolution of life. However, the marine environment dur-ing the late Ediacaran has not been thoroughly characterized to date. To better understand late Ediacaran oceanic redox conditions, we investigated the Fe and S isotopic compositions of cherts from the slope (Yinjiang) and basin (Silikou) sections of the Nanhua basin in South China. The slope (Yinjiang) section is characterized by a wide range of delta Fe-56(T) values (-0.12 parts per thousand to 1.06 parts per thousand) and by continuously decreasing delta S-34(py) values from 40.4 parts per thousand to 4.1 parts per thousand. The variable delta Fe-56(T) values in the Yinjiang section primarily reflect the various oxidation degrees of dissolved Fe2+ in ferruginous seawater. The homogeneous delta Fe-56(T) signatures (0.02-0.40 parts per thousand) along the Silikou section and the decreasing trend of delta Fe-56(HR) values from 0.86 parts per thousand to near zero primarily depend on the mixing of Fe3+ hydroxide/oxide precipitates in a ferruginous water column, possibly followed by partial reduction, the authigenic framboidal pyrite trapped within an intermittent euxinic condition and detrital silicate Fe minerals. A 20-30%e discrepancy in delta S-34(py) values between the Yinjiang and Silikou sections may be ascribed to the formation of diagenetic pyrites and framboidal pyrites, respectively. Therefore, the continuously decreasing delta S-34(py) values in the Yinjiang and Silikou sections may reflect a significant increase of sulfate diffusion into sediments at the slope location and the enlarged marine sulfate reservoir at the basin location. These new results indicate that the deep water in the Nanhua basin is primarily characterized by a ferrug- inous condition with intermittent euxinic conditions in the basin location during the late Ediacaran. (C) 2018 Elsevier Ltd. All rights reserved

Advances in understanding mechanisms of long-term sperm storage-the soft-shelled turtle model

Long-term sperm storage is a special reproductive strategy, which can extend the time window between mating and fertilization in some animal species. Spermatozoa of the soft-shelled turtle, Pelodiscus sinensis, can be stored in the epididymis and oviduct for at least six months and one year, respectively. How spermatozoa can be stored in vivo for such a prolonged period is yet to be explained. We analyze the mechanisms that contribute to long-term sperm storage in P. sinensis, and compare them with other species from three different perspectives: the spermatozoon itself, the storage microenvironment and the interaction between the spermatozoon and microenvironment. Characteristics of soft-shelled turtle spermatozoa itself, such as the huge cytoplasmic droplet with its content of several large lipid droplets (LDs) and onion-like mitochondira, facilitate long-term sperm storage. The microenvironment of reproductive tract, involving in the secretions, structural barriers, exosomes, androgen receptors, Toll-like receptors and survival factor Bcl-2, are important for the maintenance of spermatozoa long-term storage. Sperm heads are always embedded among the oviductal cilia and even intercalate into the apical hollowness of the ciliated cells, indicating that the ciliated cells support the stored spermatozoa. RNA seq is firstly used to detect the molecular mechanism of sperm storage, which shows that autophagy, apoptosis and immune take part in the long-term sperm storage in this specie

Profiling Cellular Substrates of Lysine Acetyltransferases GCN5 and p300 with Orthogonal Labeling and Click Chemistry

p300 and GCN5 are two representative lysine acetyltransferases (KATs) in mammalian cells. It was recently reported that they possess multiple acyltransferase activities including acetylation, propionylation, and butyrylation of the ε-amino group of lysine residues of histones and non-histone protein substrates. Although thousands of acetylated substrates and acetylation sites have been identified by mass spectrometry-based proteomic screening, our knowledge about the causative connections between individual KAT members and their corresponding sub-acylomes remain very limited. Herein, we applied 3-azidopropionyl CoA (3AZ-CoA) as a bioorthogonal surrogate of acetyl-, propionyl- and butyryl-CoA for KAT substrate identification. We successfully attached the azide as a chemical warhead to cellular substrates of wild-type p300 and engineered GCN5. The substrates were subsequently labeled with biotin tag through the copper-catalyzed azide–alkyne cycloaddition (CuAAC). Following protein enrichment on streptavidin-coated resin, we conducted LC-MS/MS studies from which more than four hundred proteins were identified as GCN5 or p300 substrate candidates. These proteins are either p300- or GCN5-unique or shared by the two KATs and are extensively involved in various biological events including gene expression, cell cycle, and cellular metabolism. We also experimentally validated two novel substrates of GCN5, that is, IQGAP1 and SMC1. These results demonstrate extensive engagement of GCN5 and p300 in cellular pathways and provide new insights into understanding their functions in specific biological processes

The cytosolic isoform of triosephosphate isomerase, ZmTPI4, is required for kernel development and starch synthesis in maize (Zea mays L.)

Triosephosphate isomerase (TPI) is an enzyme that functions in plant energy production, accumulation, and conversion. To understand its function in maize, we characterized a maize TPI mutant, zmtpi4. In comparison to the wild type, zmtpi4 mutants showed altered ear development, reduced kernel weight and starch content, modified starch granule morphology, and altered amylose and amylopectin content. Protein, ATP, and pyruvate contents were reduced, indicating ZmTPI4 was involved in glycolysis. Although subcellular localization confirmed ZmTPI4 as a cytosolic rather than a plastid isoform of TPI, the zmtpi4 mutant showed reduced leaf size and chlorophyll content. Overexpression of ZmTPI4 in Arabidopsis led to enlarged leaves and increased seed weight, suggesting a positive regulatory role of ZmTPI4 in kernel weight and starch content. We conclude that ZmTPI4 functions in maize kernel development, starch synthesis, glycolysis, and photosynthesis

Prognostic value of Kinesin‐4 family genes mRNA expression in early‐stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy

Abstract Background The aim of this study was to investigate the potential prognostic value of Kinesin‐4 family genes mRNA expression in early‐stage pancreatic ductal adenocarcinoma (PDAC) patients after pancreaticoduodenectomy. Methods Kaplan‐Meier survival analysis method with log‐rank test and Cox proportional hazards regression analysis were performed to figure out the association between Kinesin‐4 family genes expression and PDAC patients overall survival time. Joint‐effect survival analysis and stratified survival analysis were carried out to assess the prognosis prediction value of prognosis‐related gene. Nomogram was constructed for the individualized prognosis prediction. In addition, we had used the gene set enrichment analysis and genome‐wide co‐expression analysis to further explore the potential mechanism. Results KIF21A expression level was significantly associated with PDAC patient clinical prognosis outcome and patient with a high expression of KIF21A would have a shorter overall survival time. The prognosis prediction significance of KIF21A was well validated by the joint‐effect survival analysis, stratified survival analysis, and nomogram. Meanwhile, the gene set enrichment analysis and genome‐wide co‐expression analysis revealed that KIF21A might involve in DNA damage and repair, transcription and translation process, post‐translation protein modification, cell cycle, carcinogensis genes and pathways. Conclusions Our current research demonstrated that KIF21A could serve as a potential prognostic biomarker for patient with early‐stage PDAC after pancreaticoduodenectomy