Integrative landscape of dysregulated signaling pathways of clinically distinct pancreatic cancer subtypes

Sinkala, Musalula; Mulder, Nicola; Martin, Darren P.

doi:10.18632/oncotarget.25632

Cited by 15 publications

(15 citation statements)

References 89 publications

(127 reference statements)

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“…Its incidence has continued to increase over the last few years predominantly because of life-style shifts in population and increase in life expectancy [3][4][5][6]. The molecular characterization of pancreatic cancer, including the transcriptomic, genomic, and epigenetic landscape has been studied by large-scale molecular profiling projects and many other studies [7][8][9][10]. Gene expression changes have led to the identification of molecular subtypes of the disease, which have the treatment and prognostic importance [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Proteogenomic Analysis of Pancreatic Cancer Subtypes

Kafita

Nkhoma

Zulu

et al. 2020

Preprint

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Pancreatic cancer remains a significant public health problem with an ever-rising incidence of disease. Cancers of the pancreas are characterised by various molecular aberrations, including changes in the proteomics and genomics landscape of the tumour cells. There is a need, therefore, to identify the proteomic landscape of pancreatic cancer and the specific genomic and molecular alterations associated with disease subtypes. Here, we carry out an integrative bioinformatics analysis of The Cancer Genome Atlas dataset that includes proteomics and whole-exome sequencing data collected from pancreatic cancer patients. We apply unsupervised clustering on the proteomics dataset to reveal the two distinct subtypes of pancreatic cancer. Using functional and pathway analysis, we demonstrate the different molecular processes and signalling aberrations of the pancreatic cancer subtypes.We explore the clinical characteristic of these subtypes to show differences in disease outcome. Using datasets of mutations and copy number alterations, we show that various signalling pathways are altered among pancreatic tumours, including the Wnt pathway, Notch pathway and PI3K-mTOR pathways. Altogether, we reveal the proteogenomic landscape of pancreatic cancer subtypes and the altered molecular processes which can be leveraged to devise more effective treatments.

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Section: Introductionmentioning

confidence: 99%

Proteogenomic Analysis of Pancreatic Cancer Subtypes

Kafita

Nkhoma

Zulu

et al. 2020

Preprint

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“…Several genetic aberrations, including mutations in, and copy number variations of, MAPK pathway genes have been identified in human cancers, and several of the proteins encoded by these genes are promising drug targets [14][15][16][17] . However, we still do not have a complete understanding of the extent to which MAPK pathways are altered across the entire spectrum of human cancers, and whether these alterations impact either disease outcomes or the responses of tumours to anti-MAPK pathway drugs.…”

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confidence: 99%

Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies

et al. 2021

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The mitogen-activated protein kinase (MAPK) pathways are crucial regulators of the cellular processes that fuel the malignant transformation of normal cells. The molecular aberrations which lead to cancer involve mutations in, and transcription variations of, various MAPK pathway genes. Here, we examine the genome sequences of 40,848 patient-derived tumours representing 101 distinct human cancers to identify cancer-associated mutations in MAPK signalling pathway genes. We show that patients with tumours that have mutations within genes of the ERK-1/2 pathway, the p38 pathways, or multiple MAPK pathway modules, tend to have worse disease outcomes than patients with tumours that have no mutations within the MAPK pathways genes. Furthermore, by integrating information extracted from various large-scale molecular datasets, we expose the relationship between the fitness of cancer cells after CRISPR mediated gene knockout of MAPK pathway genes, and their dose-responses to MAPK pathway inhibitors. Besides providing new insights into MAPK pathways, we unearth vulnerabilities in specific pathway genes that are reflected in the re sponses of cancer cells to MAPK targeting drugs: a revelation with great potential for guiding the development of innovative therapies.

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“…In the past multiple studies have performed the integrative analysis on transcriptome, SNPs, the proteome and non-coding RNAs 57–59 to identify PDAC prognostic and diagnostics markers based on molecules that are alerted across multiple genomic spaces. The identification of robust biomarkers achieved minimal success due to limited number of studies, lack of paired samples, and minimal correlation between transcriptome and proteome data.…”

Section: Discussionmentioning

confidence: 99%

Systems Biology Approach to Identify Novel Genomic Determinants for Pancreatic Cancer Pathogenesis

Khatri

Ganguly

Sharma

et al. 2019

Sci Rep

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a 5-year survival rate of <8%. Its dismal prognosis stems from inefficient therapeutic modalities owing to the lack of understanding about pancreatic cancer pathogenesis. Considering the molecular complexity and heterogeneity of PDAC, identification of novel molecular contributors involved in PDAC onset and progression using global “omics” analysis will pave the way to improved strategies for disease prevention and therapeutic targeting. Meta-analysis of multiple miRNA microarray datasets containing healthy controls (HC), chronic pancreatitis (CP) and PDAC cases, identified 13 miRNAs involved in the progression of PDAC. These miRNAs showed dysregulation in both tissue as well as blood samples, along with progressive decrease in expression from HC to CP to PDAC. Gene-miRNA interaction analysis further elucidated 5 miRNAs (29a/b, 27a, 130b and 148a) that are significantly downregulated in conjunction with concomitant upregulation of their target genes throughout PDAC progression. Among these, miRNA-29a/b targeted genes were found to be most significantly altered in comparative profiling of HC, CP and PDAC, indicating its involvement in malignant evolution. Further, pathway analysis suggested direct involvement of miRNA-29a/b in downregulating the key pathways associated with PDAC development and metastasis including focal adhesion signaling and extracellular matrix organization. Our systems biology data analysis, in combination with real-time PCR validation indicates direct functional involvement of miRNA-29a in PDAC progression and is a potential prognostic marker and therapeutic candidate for patients with progressive disease.

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Integrative landscape of dysregulated signaling pathways of clinically distinct pancreatic cancer subtypes

Cited by 15 publications

References 89 publications

Proteogenomic Analysis of Pancreatic Cancer Subtypes

Proteogenomic Analysis of Pancreatic Cancer Subtypes

Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies

Systems Biology Approach to Identify Novel Genomic Determinants for Pancreatic Cancer Pathogenesis

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