Proteogenomic insights into the biology and treatment of pancreatic ductal adenocarcinoma

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis. Proteogenomic characterization and integrative proteomic analysis provide a functional context to annotate genomic abnormalities with prognostic value. Methods We performed an integrated multi-omics analysis, including whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis of 217 PDAC tumors with paired non-tumor adjacent tissues. In vivo functional experiments were performed to further illustrate the biological events related to PDAC tumorigenesis and progression. Results A comprehensive proteogenomic landscape revealed that TP53 mutations upregulated the CDK4-mediated cell proliferation process and led to poor prognosis in younger patients. Integrative multi-omics analysis illustrated the proteomic and phosphoproteomic alteration led by genomic alterations such as KRAS mutations and ADAM9 amplification of PDAC tumorigenesis. Proteogenomic analysis combined with in vivo experiments revealed that the higher amplification frequency of ADAM9 (8p11.22) could drive PDAC metastasis, though downregulating adhesion junction and upregulating WNT signaling pathway. Proteome-based stratification of PDAC revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Immune clustering defined a metabolic tumor subset that harbored FH amplicons led to better prognosis. Functional experiments revealed the role of FH in altering tumor glycolysis and in impacting PDAC tumor microenvironments. Experiments utilizing both in vivo and in vitro assay proved that loss of HOGA1 promoted the tumor growth via activating LARP7-CDK1 pathway. Conclusions This proteogenomic dataset provided a valuable resource for researchers and clinicians seeking for better understanding and treatment of PDAC.

Activated NAD+ biosynthesis pathway induces olaparib resistance in BRCA1 knockout pancreatic cancer cells

“…High levels of NAMPT, a rate-limiting enzyme in the salvage pathway, have been reported to induce tumor progression in various cancers such as glioma, melanoma, breast and colon cancers [32][33][34]. Additionally, multi-omics analysis of PDAC tumors with paired non-cancerous adjacent tissues (NATs) in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) cohort revealed that protein and mRNA expression levels of NAMPT are significantly higher in PDAC tumors than in NATs [35]. In this study, analysis of TCGA database also showed that various tumors, including pancreatic cancers, have frequent gene amplification of NAMPT and NMNAT2.…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“…Abnormal kinase activity and expression are implicated in various types of cancers. In recent years, with the increasing development of mass spectrometry (MS) technology, the Clinical Proteomic Tumor Analysis Consortium and many other teams have conducted phosphoproteomics investigations in various cancers, such as lung cancer, 139 , 140 , 141 , 142 colorectal cancer (CRC), 143 , 144 , 145 , 146 liver cancer, 147 breast cancer, 148 prostate cancer, 149 gastric cancer, 150 , 151 head and neck cancer, 152 esophageal cancer, 153 pancreatic cancer (PC), 154 , 155 kidney cancer, 156 , 157 melanoma, 158 skin cancer, 159 leukemia, 160 pancreatic ductal adenocarcinoma (PDAC), 161 pituitary neuroendocrine tumors, 162 cholangiocarcinoma, 163 and urothelial carcinoma of the bladder. 164 …”

“…In addition, preliminary progress has also been made in the acetylome, ubiquitinome and glycosylome in clinical samples. 140 , 141 , 148 , 161 , 1486 , 1487 , 1488 , 1489 However, studies of the relationship between many other types of protein modifications and diseases in large clinical cohorts remain lacking. The establishment of a multiomics molecular network based on the genome, proteome, PTMome, and metabolome will provide new breakthroughs for the discovery of new biomarkers and drug targets.…”

“…Some phosphosites are closely related to the occurrence and development of these diseases. In addition, preliminary progress has also been made in the acetylome, ubiquitinome and glycosylome in clinical samples 140,141,148,1486–1489,161 . However, studies of the relationship between many other types of protein modifications and diseases in large clinical cohorts remain lacking.…”

Translating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies

“…Based on recent studies, protein modifications and diseases can be closely associated with each other [143]. For instance, the relationship between the occurrence and development of cancer and phosphorylation sites has been described [144][145][146]. The Kelleher Research Group at Northwestern University has reported 29,620 unique proteoforms which are expressed from human blood and bone marrow, accessible in the Blood Proteoform Atlas (BPA) (https://blood-proteoform-atlas.org (accessed on 24 August 2023)).…”