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TSPAN6 is a suppressor of Ras-driven cancer

Patrick O Humbert1, Tamara Zoranovic Pryjda2,3, Blanka Pranjic2

  • 1Department of Biochemistry & Genetics, School of Molecular Sciences, La Trobe University, Bundoora, VIC, 3086, Australia. P.Humbert@latrobe.edu.au.

Oncogene
|February 20, 2022
PubMed

Insights

TSPAN6 acts as a tumor suppressor in RAS-driven cancers. This tetraspanin blocks EGFR signaling, inhibiting tumor growth and metastasis in pancreatic and lung cancers, with low expression predicting poor prognosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • RAS GTPase mutations drive approximately 30% of human cancers.
  • The tetraspanin Tsp29Fb was identified in a Drosophila screen affecting Ras-driven tumorigenesis.
  • The role of the mammalian orthologue, TSPAN6, in RAS-driven human epithelial tumors remained unknown.

Purpose of the Study:

  • To investigate the function of TSPAN6 in RAS-driven human epithelial cancers.
  • To determine if TSPAN6 acts as a tumor suppressor in pancreatic and lung cancer models.
  • To elucidate the molecular mechanisms by which TSPAN6 affects tumor progression.

Main Methods:

  • Utilized human RAS-activating mutant pancreatic cancer xenografts.
  • Generated whole-body and tumor-cell-specific Tspan6 knockout mouse models.
  • Investigated TSPAN6 binding to EGFR and its effect on EGFR-induced RAS activation.
  • Assessed epithelial-to-mesenchymal transition and cell migration in vitro and in vivo.
  • Correlated TSPAN6 expression with patient prognosis in lung and pancreatic cancers.

Main Results:

  • TSPAN6 suppressed tumor growth and metastasis in human pancreatic cancer xenografts.
  • Tspan6 inactivation in mice enhanced KrasG12D-driven lung tumor initiation and progression.
  • TSPAN6 binds to EGFR, inhibiting EGFR-induced RAS activation.
  • TSPAN6 inactivation promoted epithelial-to-mesenchymal transition and impaired cell migration.
  • Low TSPAN6 expression correlated with poor prognosis in lung and pancreatic cancers with mesenchymal features.

Conclusions:

  • TSPAN6 functions as a novel tumor suppressor receptor in RAS-driven epithelial cancers.
  • TSPAN6 regulates epithelial cell identity and restrains tumor progression.
  • TSPAN6 represents a potential therapeutic target for cancers with RAS mutations.

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