ADAP1 promotes invasive squamous cell carcinoma progression and predicts patient survival

Life Sci Alliance. 2019 Dec 2;2(6):e201900582. doi: 10.26508/lsa.201900582. Print 2019 Dec.

Abstract

Invasive squamous cell carcinoma (SCC) is aggressive cancer with a high risk of recurrence and metastasis, but the critical determinants of its progression remain elusive. Here, we identify ADAP1, a GTPase-activating protein (GAP) for ARF6 up-regulated in TGF-β-responding invasive tumor cells, as a strong predictor of poor survival in early-stage SCC patients. Using a mouse model of SCC, we show that ADAP1 overexpression promotes invasive tumor progression by facilitating cell migration and breakdown of the basement membrane. We found that ADAP1-rich, TGF-β-responding tumor cells exhibit cytoplasmic laminin localization, which correlated with the absence of laminin and type IV collagen from the pericellular basement membrane. Interestingly, although tumors overexpressing a GAP activity-deficient mutant of ADAP1 resulted in morphologically complex tumors, those tumor cells failed to breach the basement membrane. Moreover, Adap1 deletion in tumor cells ameliorated the basement membrane breakdown and had less invading cells in the stroma. Our study demonstrates that ADAP1 is a critical mediator of TGF-β-induced cancer invasion and might be exploited for the treatment of high-risk SCC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Basement Membrane / metabolism
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Movement / genetics
  • Collagen Type IV / metabolism
  • Databases, Genetic
  • Disease Models, Animal
  • Disease Progression
  • GTPase-Activating Proteins / metabolism
  • Humans
  • Laminin / metabolism
  • Mice
  • Mice, Transgenic
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Transforming Growth Factor beta / metabolism

Substances

  • ADAP1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Collagen Type IV
  • GTPase-Activating Proteins
  • Laminin
  • Nerve Tissue Proteins
  • Transforming Growth Factor beta