Multidimensional analyses identify genes of high priority for pancreatic cancer research

Date:	January 7, 2025
PMID:	https://pmc.ncbi.nlm.nih.gov/articles/PMC11949049/
Category:	N/A
Authors:	Zeribe C Nwosu, Heather M Giza, Maya Nassif, Verodia Charlestin, Rosa E Menjivar, Daeho Kim, Samantha B Kemp, Peter Sajjakulnukit, Anthony Andren, Li Zhang, William Km Lai, Ian Loveless, Nina Steele, Jiantao Hu, Biao Hu, Shaomeng Wang, Marina Pasca di Magliano, Costas A Lyssiotis
Abstract:

Pancreatic ductal adenocarcinoma (PDAC) is a drug-resistant and lethal cancer. Identification of the genes that consistently show altered expression across patient cohorts can expose effective therapeutic targets and strategies. To identify such genes, we separately analyzed 5 human PDAC microarray datasets. We defined genes as "consistent" if upregulated or downregulated in 4 or more datasets (adjusted P < 0.05). The genes were subsequently queried in additional datasets, including single-cell RNA-sequencing data, and we analyzed their pathway enrichment, tissue specificity, essentiality for cell viability, and association with cancer features, e.g., tumor subtype, proliferation, metastasis, and poor survival outcome. We identified 2,010 consistently upregulated and 1,928 downregulated genes, of which more than 50% to our knowledge were uncharacterized in PDAC. These genes spanned multiple processes, including cell cycle, immunity, transport, metabolism, signaling, and transcriptional/epigenetic regulation - cell cycle and glycolysis being the most altered. Several upregulated genes correlated with cancer features, and their suppression impaired PDAC cell viability in prior CRISPR/Cas9 and RNA interference screens. Furthermore, the upregulated genes predicted sensitivity to bromodomain and extraterminal (epigenetic) protein inhibition, which, in combination with gemcitabine, disrupted amino acid metabolism and in vivo tumor growth. Our results highlight genes for further studies in the quest for PDAC mechanisms, therapeutic targets, and biomarkers.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center