Development Of Adenocarcinoma Research Articles

Comprehensive analysis of the lncRNAs-related immune gene signatures and their correlation with immunotherapy in lung adenocarcinoma.

Long non-coding RNAs (lncRNAs)-related immune genes (lrRIGs) play a crucial role in the development and progression of lung adenocarcinoma (LUAD). However, reliable prognostic signatures based on lrRIGs have not yet been identified. We screened lrRIGs associated with the prognosis of LUAD using The Cancer Genome Atlas (TCGA) database and then established a novel prognostic nine-gene signature composed of CD79A, INHA, SHC3, LIFR, TNFRSF11A, GPI, F2RL1, SEMA7A and WFDC2 through bioinformatic approaches. A risk score derived from this gene signature was used to divide LUAD patients into the low- and high-risk groups. The latter was confirmed to have markedly worse overall survival (O.S.). A nomogram was developed using the risk score and other independent prognostic elements, demonstrating excellent performance in predicting the O.S. rate of LUAD patients. We observed that the infiltration of diverse immune cell subtypes and response to immunotherapy and chemotherapy significantly differed between the low- and high-risk groups. Overall, stratification based on this gene signature could be used to guide better therapeutic management and improve outcomes for LUAD patients.

Increased circulating Th17 cell populations in patients with pancreatic ductal adenocarcinoma.

T-helper 17 (Th17) cells are a subset of CD4+ helper T cells that produce interleukin 17 (IL-17) and play a crucial role in the pathogenesis of inflammatory and autoimmune diseases. Few studies have been conducted to determine the role of Th17 cells in the tumorigenesis and development of pancreatic ductal adenocarcinoma (PDAC); however, its role is still unclear. In this study, the percentage of circulating Th17 cells and serum levels of IL-17A and IL-23 were analyzed using flow cytometry and ELISA, respectively, in 40 PDAC patients, 30 chronic pancreatitis (CP) patients and 30 healthy controls (HC). In addition, the mRNA expression levels of IL-17A, STAT3 and RORγt in tissue samples were quantified by qRT-PCR. The results showed that the percentage of circulating Th17 cells and the concentrations of serum IL-17A and IL-23 were significantly increased in PDAC patients as compared to CP and HC (P < 0.001). In addition, the higher level of IL-17A was significantly correlated with the poor overall survival of the PDAC patients. Furthermore, the frequencies of Th17 cells and IL-17A were significantly higher in stage III+IV PDAC patients versus stage I+II. A significant increase in IL-17A, STAT3 and RORγT mRNA was observed in patients with PDAC. Taken together, these findings suggest that the increased circulating Th17 cells and serum IL-17A may be involved in the development and metastasis of PDAC, and thus represent potential targets for the treatment of PDAC.

Prognostic value of cancer-associated fibroblasts-related genes in lung adenocarcinoma.

The incidence of lung adenocarcinoma is in the forefront of malignant tumors in the world. The purpose of this study was to investigate the role of cancer-associated fibroblast-related genes (CAFRGs) in the occurrence, diagnosis and development of lung adenocarcinoma. RNA data and corresponding clinical information of lung adenocarcinoma patients were acquired from The Cancer Genome Atlas (TCGA) database. Consensus clustering was performed to identify different molecular subgroups. The tumor immune states of different subgroups were determined by Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE; https://bioinformatics.mdanderson.org/estimate/index.html), microenvironment cell populations (MCP)-counter (which can reliably quantify the abundance of eight immune cell populations and two stromal cell populations), and single sample gene set enrichment analysis (ssGSEA) analyses. In order to elucidate the potential mechanism of CAFRGs, functional enrichment analysis including gene ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG), and GSEA analysis were performed on the differentially expressed genes (DEGs). Least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analysis were used to construct the prognostic risk model, which was verified by lung adenocarcinoma data from Gene Expression Omnibus (GEO) dataset GSE37745. This study identified two molecular subgroups with significant differences in survival. High immunoscore and immune cell infiltration were more common in the subgroup with better prognosis. GO and KEGG analysis showed that DEGs between the two different subgroups were mainly concentrated in the mitotic cell cycle, cell proliferation, vascular development, and humoral immune response, adaptive immune-related pathways. GSEA analysis indicated that RNA degradation and P53 signaling pathway might be related to the increased invasiveness of lung adenocarcinoma. Risk models based on CAFRGs have demonstrated potent potential for predicting lung adenocarcinoma survival and have been validated in validation cohorts. The nomogram combined with risk model and clinical characteristics can predict the prognosis of patients with lung adenocarcinoma. The expression of CAFRGs is related to tumor immune microenvironment (TIME) of lung adenocarcinoma patients, and can predict the prognosis of lung adenocarcinoma patients.

Targeting CD36 determines nicotine derivative NNK-induced lung adenocarcinoma carcinogenesis

Smoking carcinogen nicotine-derived nitrosamine ketone (NNK) is the most potent contributor to lung adenocarcinoma (LUAD) development, but the mechanism has not been fully elucidated. Here, we reported that fatty acid translocase CD36 was significantly overexpressed in both human LUAD tissues and NNK-induced A/J mice LUAD tumors. The overexpressed CD36 was positively correlated with Src kinase activation, smoking status, metastasis, and worse overall survival of patients with smoking history. Upon NNK binding with α7 nicotinic acetylcholine receptor (α7nAChR), sarcolemmal CD36 was increased and it interacted with surface α7nAChR and cytosol Src simultaneously, which in turn activated Src and downstream pro-carcinogenic kinase ERK1/2 and Akt, and finally caused LUAD cells to form subcutaneous and pulmonary metastatic tumors. This process could be blocked by CD36 knockdown and CD36 irreversible inhibitor SSO. Furthermore, the effect of NNK was inhibited obviously in CD36-/- A/J mice. Thus, targeting CD36 may provide a breakthrough therapy of LUAD.

USF1-mediated ALKBH5 stabilizes FLII mRNA in an m6A-YTHDF2-dependent manner to repress glycolytic activity in prostate adenocarcinoma.

Upstream-stimulating factor 1 (USF1) is a ubiquitously expressed transcription factor implicated in multiple cellular processes, including metabolism and proliferation. This study focused on the function of USF1 in glycolysis and the malignant development of prostate adenocarcinoma (PRAD). Bioinformatics predictions suggested that USF1 is poorly expressed in PRAD. The clinical PRAD samples revealed a low level of USF1, which was correlated with an unfavorable prognosis. Artificial upregulation of USF1 significantly repressed glycolytic activity in PRAD cells and reduced cell growth and metastasis in vitro and in vivo. Potential downstream genes of USF1 were probed by integrated bioinformatics analyses. The chromatin immunoprecipitation and luciferase assays indicated that USF1 bound to the α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) promoter for transcription activation. Flightless I (FLII) was identified as the gene showing the highest degree of correlation with ALKBH5. As an m6A demethylase, ALKBH5 enhanced FLII mRNA stability by inducing m6A demethylation in an m6A-YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2)-dependent manner. Either silencing of ALKBH5 or FLII blocked the role of USF1 in PARD cells and restored glycolysis, cell proliferation, and invasion. This study demonstrates that USF1 activates ALKBH5 to stabilize FLII mRNA in an m6A-YTHDF2-dependent manner, thereby repressing glycolysis processes and the progression of PRAD.

Improved prediction of prognosis and therapy response for lung adenocarcinoma after identification of DNA-directed RNA polymerase-associated lncRNAs.

DNA-directed RNA polymerase (DDRP) related genes and long non-coding RNAs (lncRNAs) play an important role in the development of lung adenocarcinoma (LUAD), the leading cause of cancer-related death worldwide. Therefore, we aimed to construct a DDRP-associated lncRNA model to predict the prognosis of LUAD and to evaluate its sensitivity to immunotherapy and chemotherapy. To construct a predictive signature, we used univariate and multivariate Cox regression analyses, as well as the least absolute shrinkage and selection operator regression analysis. The prognostic model was verified by applying the ROC curve analysis, Kaplan-Meier analysis, GO/KEGG analysis, and a predictive nomogram. Eventually, immunotherapy and drug susceptibility were examined and stemness indices were analyzed. 24 DDRP-associated lncRNAs were found as independent prognosis factors, which may be further developed as potential therapeutic vaccines for LUAD. The area under the ROC curve and the conformance index showed that the constructed model can predict the prognosis of LUAD patients. The predicted incidences of overall survival showed perfect conformance. And there were significant changes in immunological markers between the two risk subgroups in the model. Finally, an analysis of 50% maximum inhibitory concentration between the two risk subgroups showed that the high-risk subgroup was more sensitive to certain chemotherapy drugs. We constructed a model that accurately predicts the outcomes of LUAD based on 24 DDRP-related lncRNAs and provided promising treatment options for the future.

Decreased Risk of Esophageal Adenocarcinoma After Gastric Bypass Surgery in a Cohort Study From 3 Nordic Countries.

The objective of this study was to test the hypothesis that bariatric surgery decreases the risk of esophageal and cardia adenocarcinoma. Obesity is strongly associated with esophageal adenocarcinoma and moderately with cardia adenocarcinoma, but whether weight loss prevents these tumors is unknown. This population-based cohort study included patients with an obesity diagnosis in Sweden, Finland, or Denmark. Participants were divided into a bariatric surgery group and a nonoperated group. The incidence of esophageal and cardia adenocarcinoma (ECA) was first compared with the corresponding background population by calculating standardized incidence ratios (SIR) with 95% CIs. Second, the bariatric surgery group and the nonoperated group were compared using multivariable Cox regression, providing hazard ratios (HR) with 95% CI, adjusted for sex, age, comorbidity, calendar year, and country. Among 748,932 participants with an obesity diagnosis, 91,731 underwent bariatric surgery, predominantly gastric bypass (n=70,176; 76.5%). The SIRs of ECA decreased over time after gastric bypass, from SIR=2.2 (95% CI, 0.9-4.3) after 2 to 5 years to SIR=0.6 (95% CI, <0.1-3.6) after 10 to 40 years. Gastric bypass patients were also at a decreased risk of ECA compared with nonoperated patients with obesity [adjusted HR=0.6, 95% CI, 0.4-1.0 (0.98)], with decreasing point estimates over time. Gastric bypass was followed by a strongly decreased adjusted risk of esophageal adenocarcinoma (HR=0.3, 95% CI, 0.1-0.8) but not of cardia adenocarcinoma (HR=0.9, 95% CI, 0.5-1.6), when analyzed separately. There were no consistent associations between other bariatric procedures (mainly gastroplasty, gastric banding, sleeve gastrectomy, and biliopancreatic diversion) and ECA. Gastric bypass surgery may counteract the development of esophageal adenocarcinoma in morbidly obese individuals.

Exploring the key genetic association between chronic pancreatitis and pancreatic ductal adenocarcinoma through integrated bioinformatics.

Background: Pancreatic ductal adenocarcinoma (PDAC) develops rapidly and has a poor prognosis. It has been demonstrated that pancreatic ductal adenocarcinoma and chronic pancreatitis (CP) have a close connection. However, the underlying mechanisms for chronic pancreatitis transforming into pancreatic ductal adenocarcinoma are still unclear. The purpose of this study was to identify real hub genes in the development of chronic pancreatitis and pancreatic ductal adenocarcinoma. Methods: RNA-seq data of chronic pancreatitis and pancreatic ductal adenocarcinoma were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between chronic pancreatitis and pancreatic ductal adenocarcinoma. GEO2R and a Venn diagram were used to identify differentially expressed genes. Then visualized networks were constructed with ClueGO, and modules of PPI network were calculated by MCODE plugin. Further validation of the results was carried out in two additional cohorts. Analyses of CEL-coexpressed genes and regulators including miRNAs and transcription factors were performed by using the corresponding online web tool. Finally, the influence of CEL in the tumor immune microenvironment (TIME) was assessed by immune contextual analysis. Results: With the help of WGCNA and GEO2R, four co-expression modules and six hub genes were identified, respectively. ClueGO enrichment analysis and MCODE cluster analysis revealed that the dysfunctional transport of nutrients and trace elements might contribute to chronic pancreatitis and pancreatic ductal adenocarcinoma development. The real hub gene CEL was identified with a markedly low expression in pancreatic ductal adenocarcinoma in external validation sets. According to the miRNA-gene network construction, hsa-miR-198 may be the key miRNA. A strong correlation exists between CEL and TIME after an evaluation of the influence of CEL in TIME. Conclusion: Our study revealed the dysfunctional transport of nutrients and trace elements may be common pathogenesis of pancreatic ductal adenocarcinoma and chronic pancreatitis. Examination on these common pathways and real hub genes may shed light on the underlying mechanism.

Overexpression of MRPL19 in predicting poor prognosis and promoting the development of lung adenocarcinoma.

Mitochondrial ribosomal protein L19 (MRPL19) is a member of the mitochondrial ribosomal protein (MRP) family. MRPs have a role in the progression of many cancers. However, the role of MRPL19 in lung adenocarcinoma (LUAD) is yet unknown. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, real-time polymerase chain reaction, and immunohistochemistry (IHC) were used to assess MRPL19 expression and clinical relevance. Gene Expression Profiling Interactive Analysis (GEPIA) and the online Kaplan-Meier (KM) Plotter database were used to determine the prognostic significance. Through use of LinkedOmics, genes that were coexpressed with MRPL19 and its regulators were identified. The biological roles of MRPL19 were investigated through R-implemented packages and RNA interference. The Tumor Immune Estimation Resource (TIMER) was employed to assess the connection between MRPL19 expression and infiltrated immune cells in LUAD. MRPL19 expression in LUAD was upregulated and was correlated with lymph node metastasis, differentiation level, and tumor status. MRPL19 was prognostic and associated with poor prognosis. Functional network analysis revealed that MRPL19 may be associated with the cell cycle, cell adhesion molecules, spliceosome, and T-helper cell differentiation and was regulated by several microRNA and the E2F family. The gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network indicated that MRPL19 was correlated with cancer proliferation signaling pathways. The immune infiltration analysis revealed a correlation between MRPL19 expression and the extent of B cells, CD4+ T cells, and dendritic cells' infiltration in LUAD. Additionally, MRPL19 knockdown in LUAD cells substantially reduced cell growth, migration, and invasion of malignant cells. The poor prognosis and immunological infiltration in LUAD were significantly associated with MRPL19, which may have pro-oncogenic effects on the disease.

Retracted] Increased resistin suggests poor prognosis and promotes development of lung adenocarcinoma.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the colony formation assay data shown in Fig. 3A on p. 3399 were strikingly similar to data that were already under consideration for publication in another article written by different authors at different research institutes. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 40: 3392‑3404, 2018; DOI: 10.3892/or.2018.6736].

Multiple Omics Analysis of the Role of RBM10 Gene Instability in Immune Regulation and Drug Sensitivity in Patients with Lung Adenocarcinoma (LUAD).

The RNA-binding protein RBM10 can regulate apoptosis during the proliferation and migration of pancreatic cancer, endometrial cancer, and osteosarcoma cells; however, the molecular mechanism underlying lung adenocarcinoma is rarely reported. Recent studies have detected multiple truncated and missense mutations in RBM10 in lung adenocarcinoma, but the role of RBM10 in lung adenocarcinoma is unclear. This study mainly explored the immune regulation mechanism of RBM10 in the development of lung adenocarcinoma and its influence on sensitivity to targeted therapy drugs. The transcriptome data of CGAP were used to analyze the RNA-seq data of lung adenocarcinoma patients from different subgroups by using the CIBERSORT algorithm to infer the relative proportion of various immune infiltrating cells, and Spearman correlation analysis was performed to determine the gene expression and immune cell content. In addition, this study utilized drug trial data from the GDSC database. The IC50 estimates for each specific targeted therapy were obtained by using a regression method, and the regression and prediction accuracy were tested via ten cross-validations with the GDSC training set. An immunohistochemical test was performed on the samples of 20 patients with lung adenocarcinoma in the subcomponent analysis of immune cells, and the protein expression of RBM10 in lung adenocarcinoma tissues was verified by cellular immunofluorescence assays. Nucleic acids were extracted at low temperatures, and qRT-PCR was used to verify the expression levels of the mRNA of RBM10 in lung adenocarcinoma tissues and normal tissues (p < 0.05). After screening and inclusion using a machine language, the results showed that RBM10 was significantly highly expressed in the lung adenocarcinoma tissues. The related signaling pathways were mainly concentrated in ncRNA processing, rRNA metabolic processes, ribosome biogenesis, and the regulation of translation. The qRT-PCR for 20 lung adenocarcinoma tissues showed that the expression of RBM10 in these tissues was significantly different from that in normal tissues (p = 0.0255). Immunohistochemistry analysis and cell immunofluorescence staining also confirmed that RBM10 was involved in the immune regulation of lung adenocarcinoma tissues, and the number of immune cell aggregations was significantly higher than that of the control group. RBM10 regulates B cell memory-CIBERSORT (p = 0.042) and B cell memory-CIBERSOTRT-abs (p = 0.027), cancer-associated fibroblast-EPIC (p = 0.001), cancer-associated fibroblast- MCPCounter (p = 0.0037), etc. The risk score was significantly associated with the sensitivity of patients to lapatinib (p = 0.049), nilotinib (p = 0.015), pazopanib (p = 0.001), and sorafenib (p = 0.048). RBM10 can inhibit the proliferation and invasion of lung adenocarcinoma cells through negative regulation and promote the apoptosis of lung adenocarcinoma cells through immunomodulatory mechanisms. The expression level of RBM10 affects the efficacy of targeted drug therapy and the survival prognosis of lung adenocarcinoma patients, which has a certain guiding significance for the clinical treatment of these patients.

METTL3 regulates N6-methyladenosine modification of ANGPTL3 mRNA and potentiates malignant progression of stomach adenocarcinoma

BackgroundN6-methyladenosine (m6A) is associated with mammalian mRNA biogenesis, decay, translation and metabolism, and also contributes greatly to gastrointestinal tumor formation and development. Therefore, the specific mechanisms and signaling pathways mediated by methyltransferase-like 3 (METTL3), which catalyzes the formation of m6A chemical labeling in stomach adenocarcinoma (STAD), are still worth exploring.MethodsQuantitative real-time PCR (qRT-PCR) was constructed to detect the expression of METTL3 in gastric cancer cell lines and patient tissues. The biological function of METTL3 was investigated in vitro/in vivo by Cell Counting Kit-8, colony formation assay, Transwell assay and nude mouse tumorigenesis assay. Based on the LinkedOmics database, the genes co-expressed with METTL3 in the TCGA STAD cohort were analyzed to clarify the downstream targets of METTL3. Methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) and RNA stability analysis were employed to explore the mechanism of METTL3 in gastric cancer progression.ResultsWe analyzed TCGA data and found that METTL3 was frequently elevated in STAD, and demonstrated that METTL3 was present at high levels in clinical STAD tissues and cells. High METTL3 expression was more likely to have advanced TNM tumors and distant metastasis. On the other hand, METTL3 silencing effectively impeded the higher oncogenic capacity of AGS and HGC27 cells in vivo and in vitro, as reflected by slowed cell growth and diminished migration and invasion capacities. Continued mining of the TCGA dataset identified the co-expression of angiopoietin-like 3 (ANGPTL3) and METTL3 in STAD. Lower level of ANGPTL3 was related to increased level of METTL3 in STAD samples and shorter survival times in STAD patients. ANGPTL3 enrichment limited the growth and metastasis of STAD cells. Besides, ANGPTL3 mRNA levels could be decreased by METTL3-dominated m6A modifications, a result derived from a combination of MeRIP-qPCR and RNA half-life experiments. Importantly, the inhibitory effect of METTL3 silencing on cancer could be reversed to some extent by ANGPTL3 inhibition.ConclusionsOverall, our findings suggested that METTL3 functioned an oncogenic role in STAD by reducing ANGPTL3 expression in an m6A-dependent manner. The discovery of the METTL3-ANGPTL3 axis and its effect on STAD tumor growth will contribute to further studies on the mechanisms of gastric adenocarcinoma development.

Investigation and verification of GIMAP6 as a robust biomarker for prognosis and tumor immunity in lung adenocarcinoma.

According to previous reports, GTPase of immunity-associated protein 6 (GIMAP6) is essential for autophagy. However, it is unclear how GIMAP6 affects the development and tumor immunity of lung adenocarcinoma (LUAD). In the present study, the role of GIMAP6 in vivo and in vitro was examined using reverse transcription-quantitative PCR, western blotting, and Cell Counting Kit-8, colony formation and Transwell assays. Datasets from The Cancer Genome Atlas and Genotype-Tissue Expression databases were thoroughly analyzed using R software. A nomogram was created using GIMAP6 and prognostic characteristics. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis were applied to explore the potential mechanism of GIMAP6 in lung cancer. The link between GIMAP6 and the immunological landscape was studied using single-cell RNA sequencing datasets from Tumor Immune Estimation Resource (TIMER) 2.0 and Tumor Immune Single-cell Hub. Patients with high GIMAP6 expression had improved overall and disease-specific survival compared with those patients with low GIMAP6 expression. According to the receiver operating characteristic and calibration curve, the nomogram based on T stage, N stage and GIMAP6 had predictive value for prognosis. According to functional enrichment analysis, GIMAP6 was primarily involved in T-cell receptor signaling pathway, chemokine signaling pathway, cytokine and cytokine receptor interaction. GIMAP6 was shown to be favorably linked with the infiltration of immune cells and immune-related molecules, including cytotoxic T-lymphocyte associated protein 4, programmed death-ligand 1, and T cell immunoreceptor with Ig and ITIM domains, by single-cell sequencing and TIMER2.0 analysis. The role of GIMAP6 in lung cancer cell proliferation, invasion, migration and immunity was experimentally verified. These findings confirmed that GIMAP6 was an effective prognostic molecule that was involved in the regulation of the immune microenvironment of LUAD, and may become a predictor for the efficacy of immunotherapy.

The ufmylation modification of ribosomal protein L10 in the development of pancreatic adenocarcinoma

Pancreatic adenocarcinoma (PAAD) is the most malignant cancer with a high mortality rate. Despite the association of ribosomal protein L10 (RPL10) with PAAD and previous reports on RPL26 ufmylation, the relationship between RPL10 ufmylation and PAAD development remains unexplored. Here, we report the dissection of ufmylating process of RPL10 and potential roles of RPL10 ufmylation in PAAD development. The ufmylation of RPL10 was confirmed in both pancreatic patient tissues and cell lines, and specific modification sites were identified and verified. Phenotypically, RPL10 ufmylation significantly increased cell proliferation and stemness, which is principally resulted from higher expression of transcription factor KLF4. Moreover, the mutagenesis of ufmylation sites in RPL10 further demonstrated the connection of RPL10 ufmylation with cell proliferation and stemness. Collectively, this study reveals that PRL10 ufmylation plays an important role to enhance the stemness of pancreatic cancer cells for PAAD development.

Abstract A028: Dissecting the role of cellular senescence in prostate cancer initiation and immune suppression

Abstract Prostate cancer is the most common malignancy and the second leading cause of cancer-related death in American men. Although many disease cases remain latent for decades, others progress to malignant prostate cancer with high rates of mortality. The molecular underpinnings driving malignancy are still poorly understood, and there is an urgent need to identify mechanisms and informative biomarkers of disease progression. Using the Pb-Cre+; Ptenfl/fl (CP) mouse model, we and others found that Pten genomic loss, a common occurrence in human prostate cancer, leads to induction of cellular senescence, senescence-associated inflammation, and immune suppression during tumor onset. Similarly, senescence markers have also been identified in benign and early prostate cancer lesions in humans. This suggests that senescence may play a yet uncharacterized functional role in prostate tumorigenesis. Cellular senescence is a damage-induced pathway leading to durable growth arrest and has long been considered a potent tumor suppressive mechanism that limits the ability of pre-malignant cells to proliferate and develop into malignant tumors. However, recent findings suggest that the accumulation of senescent cells can paradoxically lead to chronic inflammation that fosters an environment for eventual tumor development and progression through the induction of growth and inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). Thus, it remains unclear whether senescence or specific senescent cell populations block or rather promote prostate tumor development. Leveraging the CP prostate cancer mouse model and genetic tools to track senescent cells, we observed that markers of senescence (SA-β-gal, p16, Bcl2) and the inflammatory SASP (NF-𝜅B, IL-1b, CXCL1, CSF-1) were not only present in early prostate intraepithelial neoplasia (PIN) lesions but remained elevated following adenocarcinoma development and progression, and could be found in both epithelial cells as well as other immune and stromal populations. Expression of the canonical senescence marker p16 also correlated with disease progression in human prostate cancer samples. Moreover, senescent cell accumulation was associated with a reduction in cytotoxic lymphocytes and an influx of suppressive myeloid populations that we and others have previously shown contribute to prostate cancer progression. Senolytic approaches to eliminate these senescent cell populations reduced progression to adenocarcinoma and remodeled the immune system to reverse myeloid-mediated immune suppression and activate cytotoxic lymphocyte immunity. Together, our preliminary results suggest that senescence might contribute to prostate cancer initiation and progression, and that removal of senescent cells could delay tumor onset and reverse prostate cancer immune suppression. Citation Format: Lin Zhou, Jarin Snyder, Katherine C. Murphy, Kelly D. DeMarco, Sachliv Chana, Karl Simin, Zhong Jiang, Marcus Ruscetti. Dissecting the role of cellular senescence in prostate cancer initiation and immune suppression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A028.

Diffuse pancreatic parenchymal atrophy, an imaging finding predictive of the development of pancreatic ductal adenocarcinoma: A case-control study.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer, partly because its early detection is difficult. This study aimed to identify computed tomography (CT) findings associated with PDAC prior to diagnosis. Past CT images were retrospectively collected from the PDAC group (n = 54) and the control group (n = 90). The following imaging findings were compared: pancreatic mass, main pancreatic duct (MPD) dilatation with or without cutoff, cyst, chronic pancreatitis with calcification, partial parenchymal atrophy (PPA), and diffuse parenchymal atrophy (DPA). In the PDAC group, CT findings were examined during the pre-diagnostic period and 6-36 months and 36-60 months before diagnosis. Multivariate analyses were performed using logistic regression. MPD dilatation with cutoff (P < 0.0001) and PPA (P = 0.023) were identified as significant imaging findings 6-36 months before diagnosis. DPA was identified as a novel imaging finding at 6-36 months (P = 0.003) and 36-60 months (P = 0.009) before diagnosis. DPA, MPD dilatation with cutoff, and PPA were identified as imaging findings associated with pre-diagnostic PDAC.

The prognostic effect of ADH1B and ALDH2in lung adenocarcinoma.

e15167 Background: Alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) are major enzymes involved in the metabolism of carcinogenic acetaldehyde, converting alcohol to acetaldehyde and detoxifying acetaldehyde to harmless acetic acid, respectively. To investigate the role of ADH isoenzymes and ALDH isoenzymes in the development of lung adenocarcinoma (LUAD), we performed a retrospective analysis of gene expression. Methods: RNA sequencing data derived from 497 tumour samples and 54 adjacent normal samples were obtained from the Cancer Genome Atlas (TCGA) database. The transcript levels of ADH and ALDH family genes were compared between tumour tissue and adjacent normal tissue through a Wilcoxon test. The results were validated in transcriptomic data from 111 lung cancer patients available as part of a prior study. The diagnostic and prognostic value of ADH and ALDH family genes was further investigated by survival analysis and nomogram through the TCGA database. Insights into the mechanism of action were gained through gene set enrichment analysis (GSEA). Results: Numerous ADH and ALDH family genes showed nominally significant differential expression between tumour and adjacent normal tissues. The expression levels of ADH1B and ALDH2 showed significant and replicable depression in tumour tissue. Low expression of ADH1B and ALDH2 was associated with worse overall survival, with the combination of these genes providing greater prognostic value than the additive effects of these genes individually in the TCGA database. ADH1B and ALDH2 transcript levels were linked with the regulation of metabolism, cell cycle, DNA repair and cancer-associated pathways. A risk score model for predicting LUAD prognosis was developed and showed good performance in predicting 1, 3 and 5-year overall survival (OS). Consistent with TCGA results, our 111-patient replication dataset showed that the tumour-specific depression was most pronounced for ADH1B, and the lower expression was associated with vascular, pleural and lymphatic invasions. Moreover, smoking status and/or cumulative smoking history do not provide a direct, clinically accessible proxy for tumour ADH1B or ALDH2 expression. Conclusions: The combination of ADH1B and ALDH2 are potential prognostic markers in LUAD and may have utility as an independent clinical factor for evaluating the prognosis of LUAD.

POT1 germline pathogenic variants and evolving understanding of tumor spectrum: Evidence for lung cancer predisposition.

10511 Background: As a critical component of the shelterin complex, the protection of telomeres 1 protein (POT1) plays important roles in telomere length regulation and tumorigenesis. POT1 germline pathogenic/likely pathogenic variants (PVs) have been primarily linked to the development of melanoma, chronic lymphocytic leukemia, and glioma. Recent studies report POT1 PVs also predispose to other tumors such as certain sarcomas and thyroid cancer. Methods: To better understand the role of POT1 in the development of solid tumors, we explored the spectrum of POT1 germline variants in 6644 patients with POT1 sequencing performed utilizing the MSK-IMPACT assay. Results: In total, 91 POT1 germline rare variants (population frequency &lt; 0.01%) were identified in our cohort in 90 patients across 47 cancer types. We found 16 POT1 PVs including frameshift variants (p.Ile49fs, p.Gln358fs, p.Asp617fs), a nonsense variant (p.Arg363Ter), a missense variant (p.Asp224Asn), and splice site variants (c.10-2A &gt; C, c.1369+1G &gt; T). One cutaneous melanoma patient, one uveal melanoma patient, and one glioma patient were identified to have POT1 PVs. Interestingly, 8 patients with germline POT1 PVs were diagnosed with lung cancer (7 with lung adenocarcinoma and one with small cell lung cancer). Three of these 7 patients with lung adenocarcinoma had biallelic inactivation of POT1 in their tumor. The proportions of POT1 PVs in MSK lung adenocarcinoma compared to the gnomAD non-cancer control cohort were statistically significantly different (odds ratio = 16.28, 95%CI = 6.52-33.54, P = 2.87e-06). Moreover, of the 90 patients with rare germline POT1 variants, 22 had POT1 biallelic inactivation, and 9 of these 22 were diagnosed with lung adenocarcinoma. Conclusions: Taken together, our study refines the role of POT1 germline variants in solid tumors and highlights an apparent association of POT1 PVs with lung adenocarcinoma development.

Establishment and Validation of Prognostic Model of Lung Adenocarcinoma Based on Apoptosis-Related Genes

Objective: Apoptosis is an autonomous cell death process controlled by genes that can keep the internal environment of cells relatively stable. Lately, many studies have shown that apoptosis plays an important role in the construction of tumor microenvironment, mainly through the release of a series of regulatory factors to control cell growth. Therefore, it is very valuable to find and explore the possible role of apoptosis in the pathogenesis of lung cancer and its impact on the prognosis of patients. Materials and Methods: We selected 10 apoptosis-related genes and used different statistical methods to construct a model to predict the survival and prognosis of patients with lung adenocarcinoma. Univariate and multivariate Cox analysis were used to evaluate the predictive power and value of prognostic models, as well as receiver operating characteristic (ROC) curve analysis. Results: We defined two subgroups (cluster1 and cluster2). Compared with cluster1, cluster2 was named "apoptosis inhibition subgroup". The survival prognosis of cluster1 was significantly better than that of cluster2, and the infiltration of immune cells in cluster2 suggested that its immune system was inhibited. Then, we established a new prognostic model of apoptosis-related genes to identify high-risk patients with lung adenocarcinoma. Two types of Cox proportional hazards analysis and ROC curve showed that our model can be used as a new independent factor for the prognosis of lung adenocarcinoma patients, and had strong predictive ability. Conclusion: Apoptosis is involved in the formation and development of lung adenocarcinoma and plays an important role. Our survival model can better predict the survival and prognosis of lung adenocarcinoma, and our study may be helpful for further research on new therapeutic targets and precise individualized treatment in the future.

S100A10 promotes proliferation and invasion of lung adenocarcinoma cells by activating the Akt-mTOR signaling pathway

To investigate the effects of expression levels of S100 calcium-binding protein A10 (S100A10) in lung adenocarcinoma (LUAD) on patient prognosis and the regulatory role of S100A10 in lung cancer cell proliferation and metastasis. Immunohistochemistry was used to detect the expression levels of S100A10 in LUAD and adjacent tissues, and the relationship between S100A10 expression and clinicopathological parameters and prognosis of the patients was statistically analyzed. The lung adenocarcinoma expression dataset in TCGA database was analyzed using gene enrichment analysis (GSEA) to predict the possible regulatory pathways of S100A10 in the development of lung adenocarcinoma. Lactate production and glucose consumption of lung cancer cells with S100A10 knockdown or overexpression were analyzed to assess the level of glycolysis. Western blotting, CCK-8 assay, EdU-594 assay, and Transwell assays were performed to determine the expression level of S100A10 protein, proliferation and invasion ability of lung cancer cells. A549 cells with S100A10 knockdown and H1299 cells with S100A10 overexpression were injected subcutaneously in nude mice, and tumor growth was observed. The expression level of S100A10 was significantly upregulated in LUAD tissues as compared with the adjacent tissues, and an elevated S100A10 expression level was associated with lymph node metastasis, advanced tumor stage and distant organ metastasis (P < 0.05), but not with tumor differentiation or the patients' age or gender (P > 0.05). Survival analysis showed that elevated S100A10 expressions in the tumor tissue was associated with a poor outcome of the patients (P < 0.001). In the lung cancer cells, S100A10 overexpression significantly promoted cell proliferation and invasion in vitro (P < 0.001). GSEA showed that the gene sets of glucose metabolism, glycolysis and mTOR signaling pathway were significantly enriched in high expressions of S100A10. In the tumor-bearing nude mice, S100A10 overexpression significantly promoted tumor growth, while S100A10 knockdown obviously suppressed tumor cell proliferation (P < 0.001). S100A10 overexpression promotes glycolysis by activating the Akt-mTOR signaling pathway to promote proliferation and invasion of lung adenocarcinoma cells.