Characterization of anoikis-based molecular heterogeneity in pancreatic cancer and pancreatic neuroendocrine tumor and its association with tumor immune microenvironment and metabolic remodeling

Abstract

BackgroundAccumulating evidence suggests that anoikis plays a crucial role in the onset and progression of pancreatic cancer (PC) and pancreatic neuroendocrine tumors (PNETs); nevertheless, the prognostic value and molecular characteristics of anoikis in cancers are yet to be determined.Materials and methodsWe gathered and collated the multi-omics data of several human malignancies using the TCGA pan-cancer cohorts. We thoroughly investigated the genomics and transcriptomics features of anoikis in pan-cancer. We then categorized a total of 930 patients with PC and 226 patients with PNETs into distinct clusters based on the anoikis scores computed through single-sample gene set enrichment analysis. We then delved deeper into the variations in drug sensitivity and immunological microenvironment between the various clusters. We constructed and validated a prognostic model founded on anoikis-related genes (ARGs). Finally, we conducted PCR experiments to explore and verify the expression levels of the model genes.ResultsInitially, we identified 40 differentially expressed anoikis-related genes (DE-ARGs) between pancreatic cancer (PC) and adjacent normal tissues based on the TCGA, GSE28735, and GSE62452 datasets. We systematically explored the pan-cancer landscape of DE-ARGs. Most DE-ARGs also displayed differential expression trends in various tumors, which were strongly linked to favorable or unfavorable prognoses of patients with cancer, especially PC. Cluster analysis successfully identified three anoikis-associated subtypes for PC patients and two anoikis-associated subtypes for PNETs patients. The C1 subtype of PC patients showed a higher anoikis score, poorer prognosis, elevated expression of oncogenes, and lower level of immune cell infiltration, whereas the C2 subtype of PC patients had the exact opposite characteristics. We developed and validated a novel and accurate prognostic model for PC patients based on the expression traits of 13 DE-ARGs. In both training and test cohorts, the low-risk subpopulations had significantly longer overall survival than the high-risk subpopulations. Dysregulation of the tumor immune microenvironment could be responsible for the differences in clinical outcomes between low- and high-risk groups.ConclusionsThese findings provide fresh insights into the significance of anoikis in PC and PNETs. The identification of subtypes and construction of models have accelerated the progress of precision oncology.

Identification and Validation of a Novel Anoikis-Related Gene Signature for Predicting Survival in Patients With Serous Ovarian Cancer

“…In addition, anoikis is closely related to the TIME. Li et al [ 31 ] observed a positive correlation between anoikis scores and macrophage levels, as well as para-inflammation, in pancreatic cancer. Conversely, they found a negative correlation between anoikis scores and tumor-infiltrating lymphocytes (TIL) and Th1 levels [ 31 ].…”

“…Li et al [ 31 ] observed a positive correlation between anoikis scores and macrophage levels, as well as para-inflammation, in pancreatic cancer. Conversely, they found a negative correlation between anoikis scores and tumor-infiltrating lymphocytes (TIL) and Th1 levels [ 31 ]. According to the report by Xiao et al [ 32 ], in cases of colorectal cancer, there was a positive relationship observed between the risk score and regulatory T cells.…”

Combination of bulk RNA sequencing and scRNA sequencing uncover the molecular characteristics of MAPK signaling in kidney renal clear cell carcinoma

“…Then the violin plots of MAPK scores were constructed and the survival curves were plotted to explore the survival discrepancies among these three clusters. Following a methodology similar to previous studies [ 17 , 18 ], we curated a selection of classical immune pathways, metabolic pathways, and cell death pathways. Initially, we computed pathway scores using the “gsva” package, providing a measure of each pathway’s activity.…”

Focus on Therapeutic Options for Surgically Resectable Pancreatic Adenocarcinoma Based on Novel Biomarkers

“…In this regard, the modulation of DNA methylation, histone acetylation, and histone methylation has shown potential in enhancing the efficacy of immune checkpoint inhibitors. Additionally, it can induce a transformation of tumor cell clusters from those associated with a poorer prognosis, a heightened expression of oncogenes, and limited immune cell infiltration to clusters that exhibit an increased sensitivity to standard chemotherapy regimens and a more robust immunological microenvironment [32][33][34][35][36][37][38].…”