Comprehensive Analysis of Bulk and Single-Cell Transcriptomic Data Reveals a Novel Signature Associated With Endoplasmic Reticulum Stress, Lipid Metabolism, and Liver Metastasis in Pancreatic Cancer

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy. METHODS: Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored. RESULTS: A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8 CONCLUSIONS: We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell-cell communication in the tumor microenvironment

Epigenetic Regulation in Cancer

Epigenetic modifications are defined as heritable changes in gene activity that do not involve changes in the underlying DNA sequence. The oncogenic process is driven by the accumulation of alterations that impact genome\u27s structure and function. Genetic mutations, which directly disrupt the DNA sequence, are complemented by epigenetic modifications that modulate gene expression, thereby facilitating the acquisition of malignant characteristics. Principals among these epigenetic changes are shifts in DNA methylation and histone mark patterns, which promote tumor development and metastasis. Notably, the reversible nature of epigenetic alterations, as opposed to the permanence of genetic changes, positions the epigenetic machinery as a prime target in the discovery of novel therapeutics. Our review delves into the complexities of epigenetic regulation, exploring its profound effects on tumor initiation, metastatic behavior, metabolic pathways, and the tumor microenvironment. We place a particular emphasis on the dysregulation at each level of epigenetic modulation, including but not limited to, the aberrations in enzymes responsible for DNA methylation and histone modification, subunit loss or fusions in chromatin remodeling complexes, and the disturbances in higher-order chromatin structure. Finally, we also evaluate therapeutic approaches that leverage the growing understanding of chromatin dysregulation, offering new avenues for cancer treatment

The effect of bridging locoregional therapies on survival in hepatocellular carcinoma patients undergoing orthotopic liver transplantation: UNOS population study.

346 Background: The effect of bridging locoregional therapies (LRT) on overall survival (OS) in pts with hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT) has not been investigated in large-scale population studies. Methods: TheUnited Network for Organ Sharing (UNOS) database was used to identify pts with HCC who received OLT between 2002 and 2010. Pts within Milan Criteria for whom an HCC Model for End-Stage Liver Disease (MELD) exception was approved were included. OS was compared between pts who received bridging LRT (including transarterial chemoembolization (TACE)) and those who did not. Kaplan-Meier estimation and Cox proportional hazard models were used for OS analysis. Results: Of 11,287 pts with HCC who received OLT, 9,876 pts had LRT data, mean age 56.6 yrs, 77% male; 5,103 received bridging LRT, including 3,676 who received TACE. Comparison groups were similar for age at OLT, waitlist duration, sex, race, BMI and MELD score (p&gt;.05 for all). Significantly prolonged OS with bridging LRT vs. none was observed from both OLT (111.6 vs 106.4 mo, p&lt;.001) and from Listing (176.1 vs 169.4 mo, p=.001). Similarly, significantly prolonged OS with bridging TACE vs. none was observed from both OLT (112.0 vs 107.2 mo, p&lt;.001) and from Listing (177.7 vs 169.9 mo, p=.001). Conclusions: In HCC pts undergoing OLT, both bridging LRT and TACE correlated with prolonged survival from OLT and from Listing in a UNOS population-based study. [Table: see text] </jats:p

Independent prognostic factors for posttransplant survival in hepatocellular carcinoma patients undergoing liver transplantation

The aim of this study was to investigate longitudinal trends in locoregional therapy (LRT) use in hepatocellular carcinoma (HCC) patients listed for transplant, and evaluate independent prognostic factors for overall survival (OS) in HCC patients undergoing orthotopic liver transplantation (OLT). The United Network for Organ Sharing (UNOS) database was used to identify HCC patients listed for liver transplantation from 1988 to 2014, and longitudinal rates of bridging LRT were calculated. OLT recipients listed from 2002 to 2013 and transplanted up to 2014, with ≥1 year of follow‐up were further analyzed. OS was compared between patients receiving bridging LRT versus none, high versus low wait times (HWT vs. LWT), and by geographic region. Bridging LRT use in the US has increased dramatically over 25 years, with more than 50% of listed patients receiving at least 1 LRT in 2014. Of 17,291 HCC patients listed for LT from 2002 to 2013, 14,511 received OLT, mean age 57.4 years, 76.8% male; 3889 received bridging LRT. Comparison groups were similar for gender, race, body mass index (BMI), HCC etiology, and biological MELD scores (P > 0.05). Significant differences in mean OS in regions with HWT/high LRT (122.4 months), HWT/low LRT (104.5 months), LWT/high LRT (104.2 months), and LWT/low LRT (102.3 months) were observed, P = 0.0006. Recipient age, donor age, bridging LRT, and longer wait times were independent prognostic factors of survival from OLT. Increasing longitudinal trends in bridging LRT for HCC patients were observed. Younger age, younger donor age, high wait times, and bridging LRT were significant independent prognostic factors for prolonged survival from transplant