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Transposon mutagenesis screen in mice identifies TM9SF2 as a novel colorectal cancer oncogene

Christopher R Clark1, Makayla Maile1, Patrick Blaney1

  • 1Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN, USA.

Scientific Reports
|October 19, 2018
PubMed

Insights

Transmembrane 9 Superfamily 2 (TM9SF2) is identified as a novel oncogene driving colorectal cancer (CRC) progression. Targeting TM9SF2 may offer new therapeutic strategies for advanced CRC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Advanced colorectal cancer (CRC) requires novel therapeutic targets.
  • The Transmembrane 9 Superfamily (TM9SF) protein family is conserved but understudied.
  • Insertional mutagenesis screens can identify novel cancer driver genes.

Purpose of the Study:

  • To identify and characterize novel therapeutic targets for advanced colorectal cancer.
  • To define the role of Transmembrane 9 Superfamily 2 (TM9SF2) as a potential oncogene in CRC.

Main Methods:

  • Conducted an insertional mutagenesis screen in mice to identify CRC driver genes.
  • Analyzed The Cancer Genome Atlas (TCGA) and independent CRC patient samples for TM9SF2 expression.
  • Utilized RNA interference (RNAi) and CRISPR/Cas9 gene editing to assess TM9SF2 function.
  • Performed transcriptome analysis to investigate TM9SF2's molecular pathways.

Main Results:

  • TM9SF2 was identified as a novel CRC oncogene and a candidate progression driver.
  • Elevated TM9SF2 mRNA levels were found in approximately 35% of CRC patients.
  • TM9SF2 silencing or knockout reduced CRC cell growth and tumor fitness in vitro and in vivo.
  • TM9SF2 influences cell cycle, oxidative phosphorylation, and ceramide signaling pathways.
  • Increased TM9SF2 expression correlates with advanced disease stage and poorer relapse-free survival.

Conclusions:

  • TM9SF2 is a novel oncogene that promotes colorectal cancer progression.
  • TM9SF2 represents a potential therapeutic target for advanced CRC.
  • Further investigation into TM9SF2's role in cancer biology is warranted.

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