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Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
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2018 (English)In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 10, article id 2Article in journal (Refereed) Published
Abstract [en]

Background:

The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in similar to 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway.

Methods:

To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted.

Results:

Of the 163 recurrently targeted genes in the two different genetic backgrounds, one-third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, nine genes also mutated in human colorectal cancers were identified. Among these, stable knockdown of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knockdown of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells.

Conclusions:

This work establishes a proof-of-concept that human cell-based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer.

Place, publisher, year, edition, pages
2018. Vol. 10, article id 2
Keywords [en]
Forward genetics, piggyBac transposon, Colorectal cancer, Ras pathway
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-341500DOI: 10.1186/s13073-017-0511-4ISI: 000419613600002PubMedID: 29301589OAI: oai:DiVA.org:uu-341500DiVA, id: diva2:1182675
Available from: 2018-02-14 Created: 2018-02-14 Last updated: 2018-02-14Bibliographically approved

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Kundu, SnehangshuAli, Muhammad AkhtarHandin, NiklasPadhan, NarendraLarsson, JimmyArtursson, PerHe, LiqunHellström, MatsSjöblom, Tobias

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Kundu, SnehangshuAli, Muhammad AkhtarHandin, NiklasPadhan, NarendraLarsson, JimmyArtursson, PerHe, LiqunHellström, MatsSjöblom, Tobias
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Experimental and Clinical OncologyScience for Life Laboratory, SciLifeLabDepartment of PharmacyVascular BiologyDepartment of Immunology, Genetics and Pathology
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