Common and mutation specific phenotypes of KRAS and BRAF mutations in colorectal cancer cells revealed by integrative -omics analysis

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Kundu, SnehangshuUppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab (author)

Common and mutation specific phenotypes of KRAS and BRAF mutations in colorectal cancer cells revealed by integrative -omics analysis

Article/chapterEnglish2021

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2021-07-07
BioMed Central (BMC),2021
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LIBRIS-ID:oai:DiVA.org:uu-452448
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-452448URI
https://doi.org/10.1186/s13046-021-02025-2DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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Background: Genes in the Ras pathway have somatic mutations in at least 60 % of colorectal cancers. Despite activating the same pathway, the BRAF V600E mutation and the prevalent mutations in codon 12 and 13 of KRAS have all been linked to different clinical outcomes, but the molecular mechanisms behind these differences largely remain to be clarified.Methods: To characterize the similarities and differences between common activating KRAS mutations and between KRAS and BRAF mutations, we used genome editing to engineer KRAS G12C/D/V and G13D mutations in colorectal cancer cells that had their mutant BRAF V600E allele removed and subjected them to transcriptome sequencing, global proteomics and metabolomics analyses.Results: By intersecting differentially expressed genes, proteins and metabolites, we uncovered (i) two-fold more regulated genes and proteins when comparing KRAS to BRAF mutant cells to those lacking Ras pathway mutation, (ii) five differentially expressed proteins in KRAS mutants compared to cells lacking Ras pathway mutation (IFI16, S100A10, CD44, GLRX and AHNAK2) and 6 (CRABP2, FLNA, NXN, LCP1, S100A10 and S100A2) compared to BRAF mutant cells, (iii) 19 proteins expressed differentially in a KRAS mutation specific manner versus BRAF V600E cells, (iv) regulation of the Integrin Linked Kinase pathway by KRAS but not BRAF mutation, (v) regulation of amino acid metabolism, particularly of the tyrosine, histidine, arginine and proline pathways, the urea cycle and purine metabolism by Ras pathway mutations, (vi) increased free carnitine in KRAS and BRAF mutant RKO cells.Conclusions: This comprehensive integrative -omics analysis confirms known and adds novel genes, proteins and metabolic pathways regulated by mutant KRAS and BRAF signaling in colorectal cancer. The results from the new model systems presented here can inform future development of diagnostic and therapeutic approaches targeting tumors with KRAS and BRAF mutations.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Medicinsk genetik hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medical Genetics hsv//eng
Ras pathway
KRAS
BRAF
Colorectal cancer
Isogenic cell models
Integrative -omics analysis

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Ali, Muhammad AkhtarUppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi,Univ Punjab, Sch Biol Sci, Lahore, Pakistan.(Swepub:uu)muhal319 (author)
Handin, NiklasUppsala universitet,Institutionen för farmaci(Swepub:uu)nikha230 (author)
Conway, Louis P.Uppsala universitet,Institutionen för kemi - BMC(Swepub:uu)louco786 (author)
Rendo, VerónicaUppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)verre103 (author)
Artursson, PerUppsala universitet,Institutionen för farmaci(Swepub:uu)perartur (author)
He, LiqunUppsala universitet,Vaskulärbiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)liqhe592 (author)
Globisch, DanielUppsala universitet,Analytisk kemi(Swepub:uu)dangl308 (author)
Sjöblom, TobiasUppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi(Swepub:uu)tobisjob (author)
Uppsala universitetExperimentell och klinisk onkologi (creator_code:org_t)

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In:Journal of Experimental & Clinical Cancer Research: BioMed Central (BMC)401756-9966

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