ADAP1 promotes invasive squamous cell carcinoma progression and predicts patient survival.
Avery Van DuzerSachiko TaniguchiAjit ElhanceTakahiro TsujikawaNaoki OshimoriPublished in: Life science alliance (2019)
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.
Keyphrases
- cell migration
- squamous cell carcinoma
- early stage
- papillary thyroid
- mouse model
- transforming growth factor
- end stage renal disease
- free survival
- lymph node metastasis
- squamous cell
- transcription factor
- induced apoptosis
- chronic kidney disease
- locally advanced
- cell proliferation
- case report
- cell death
- prognostic factors
- peritoneal dialysis
- poor prognosis
- oxidative stress
- endothelial cells
- cell cycle arrest
- diabetic rats
- small molecule
- rectal cancer
- long non coding rna
- endoplasmic reticulum stress
- smoking cessation
- combination therapy