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Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.

ABSTRACT: MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor microenvironment, and metastasis in cooperation with Kras^G12D and Trp53^R172H mutations remains unknown. Deletion of Muc16 with activating mutations Kras^G12D/+ and Trp53^R172H/+ in mice significantly decreased progression and prolonged overall survival in Kras^G12D/+; Trp53^R172H/+; Pdx-1-Cre; Muc16^-/- (KPCM) and Kras^G12D/+; Pdx-1-Cre; Muc16^-/- (KCM), as compared to Kras^G12D/+; Trp53^R172H/+; Pdx-1-Cre (KPC) and Kras^G12D/+; Pdx-1-Cre (KC) mice, respectively. Muc16 knockout pancreatic tumor (KPCM) displays decreased tumor microenvironment factors and significantly reduced incidence of liver and lung metastasis compared to KPC. Furthermore, in silico data analysis showed a positive correlation of MUC16 with activated stroma and metastasis-associated genes. KPCM mouse syngeneic cells had significantly lower metastatic and endothelial cell binding abilities than KPC cells. Similarly, KPCM organoids significantly decreased the growth rate compared to KPC organoids. Interestingly, RNA-seq data revealed that the cytoskeletal proteins Actg2, Myh11, and Pdlim3 were downregulated in KPCM tumors. Further knockdown of these genes showed reduced metastatic potential. Overall, our results demonstrate that Muc16 alters the tumor microenvironment factors during pancreatic cancer progression and metastasis by changing the expression of Actg2, Myh11, and Pdlim3 genes.

SUBMITTER: Lakshmanan I

PROVIDER: S-EPMC9841597 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.

Lakshmanan Imayavaramban I Marimuthu Saravanakumar S Chaudhary Sanjib S Seshacharyulu Parthasarathy P Rachagani Satyanarayana S Muniyan Sakthivel S Chirravuri-Venkata Ramakanth R Atri Pranita P Rauth Sanchita S Nimmakayala Rama Krishna RK Siddiqui Jawed Akhtar JA Gautam Shailendra K SK Shah Ashu A Natarajan Gopalakrishnan G Parte Seema S Bhyravbhatla Namita N Mallya Kavita K Haridas Dhanya D Talmon Geoffrey A GA Smith Lynette M LM Kumar Sushil S Ganti Apar Kishor AK Jain Maneesh M Ponnusamy Moorthy P MP Batra Surinder K SK

Oncogene 20221021 48

MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor microenvironment, and metastasis in cooperation with KrasG12D and Trp53R172H mutations remains unknown. Deletion of Muc16 with activating mutations KrasG12D/+ and Trp53R172H/+ in mice significantly decreased progression and prolonged overall survival in KrasG12D/+; Trp53R ...[more]

PMID: 36271032

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Project description:IntroductionPancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among all solid tumors. Tumorigenesis is promoted by the oncogene KRAS, and KRAS mutations are prevalent in patients with PDAC. Therefore, a comprehensive understanding of the interactions between KRAS mutations and PDAC may expediate the development of therapeutic strategies for reversing the progression of malignant tumors. Our study aims at establishing and validating a prediction model of KRAS mutations in patients with PDAC based on survival analysis and mRNA expression.MethodsA total of 184 and 412 patients with PDAC from The Cancer Genome Atlas (TCGA) database and the International Cancer Genome Consortium (ICGC), respectively, were included in the study.ResultsAfter tumor mutation profile and copy number variation (CNV) analyses, we established and validated a prediction model of KRAS mutations, based on survival analysis and mRNA expression, that contained seven genes: CSTF2, FAF2, KIF20B, AKR1A1, APOM, KRT6C, and CD70. We confirmed that the model has a good predictive ability for the prognosis of overall survival (OS) in patients with KRAS-mutated PDAC. Then, we analyzed differential biological pathways, especially the ferroptosis pathway, through principal component analysis, pathway enrichment analysis, Gene Ontology (GO) enrichment analysis, and gene set enrichment analysis (GSEA), with which patients were classified into low- or high-risk groups. Pathway enrichment results revealed enrichment in the cytokine-cytokine receptor interaction, metabolism of xenobiotics by cytochrome P450, and viral protein interaction with cytokine and cytokine receptor pathways. Most of the enriched pathways are metabolic pathways predominantly enriched by downregulated genes, suggesting numerous downregulated metabolic pathways in the high-risk group. Subsequent tumor immune infiltration analysis indicated that neutrophil infiltration, resting CD4 memory T cells, and resting natural killer (NK) cells correlated with the risk score. After verifying that the seven gene expression levels in different KRAS-mutated pancreatic cancer cell lines were similar to that in the model, we screened potential drugs related to the risk score.DiscussionThis study established, analyzed, and validated a model for predicting the prognosis of PDAC based on risk stratification according to KRAS mutations, and identified differential pathways and highly effective drugs.

Dataset Information

Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.

Publications

Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.

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