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.
Highlights
Invasive squamous cell carcinomas (SCCs) arising from skin, lung, oral, esophagus, and cervical epithelial tissues are significant contributors to cancer mortality worldwide (Dotto & Rustgi, 2016)
We first narrowed down a list of genes that were significantly up-regulated in TGF-β-responding tumor cells (Oshimori et al, 2015) by the following criteria: (1) genes showed >2-fold up-regulation in TGF-β-responding cells compared with nonresponding cells were included; (2) genes had fragments per kilobase million > 5 in TGF-β-responding cells were included; and (3) the genes expressed less in primary tumors than normal tissue according to The Cancer Genome Atlas (TCGA) head and neck SCC (HNSCC) data were excluded
Because Adap1 had the greatest fold up-regulation in TGF-β-responding tumor cells compared with nonresponding counterparts in our murine model (Fig S1D), we focused on ADAP1 in this study
Summary
Invasive squamous cell carcinomas (SCCs) arising from skin, lung, oral, esophagus, and cervical epithelial tissues are significant contributors to cancer mortality worldwide (Dotto & Rustgi, 2016). 5–20% of cutaneous SCC cases progress to regional metastasis (Alam & Ratner, 2001; Moore et al, 2005; Kang & Toland, 2016), but of these cases, the 5-yr survival rate is only 25–35% (Rowe et al, 1992; Kraus et al, 1998) It is, essential to find molecular targets unique to metastatic cases to diagnose and treat high-risk SCCs effectively. To study the role of TGF-β in tumor development, we previously developed a mouse model of SCC that harbors an in vivo fluorescent reporter and lineage tracing system for the TGF-β–SMAD2/3 signaling pathway (Oshimori et al, 2015) Using this system, we showed that TGF-β-responding tumor cells are drug-resistant, stem-like tumor-initiating cells (TICs) that promote invasive tumor growth. The mechanisms by which TGF-β-responding TICs acquire invasive properties may be a potential target for novel cancer diagnostics and treatment
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