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Summary: Salivary gland tumors are diverse neoplasms, likely reflecting differences in the tissue- and cell-of-origin. 80%–90% of tumors arising in the sublingual gland (SLG) are malignant, whereas the other major glands often form benign tumors. Owing to the lack of experimental models to explore the etiology of salivary gland tumors, the cellular and molecular bases of malignancy remain unknown. Here, we generated a murine model of HRASG12V-driven salivary gland tumors amenable to examine tumor onset and malignant progression. We found that HMGA2 marks the tumor onset, and transformed-SOX2+ stem/progenitor cells expand exclusively in SLG tumors. Lineage tracing experiments showed that SLG tumor cells undergo an extensive epithelial–mesenchymal transition (EMT) and TGF-β-responding tumor cells are a source of mesenchymal tumor cells invading the surrounding stroma. This study advances our understanding of the mechanistic basis of salivary gland malignancy and may help combat this highly heterogeneous cancer.

Kamphuis et al . argue that macrophages accumulated in the proximity of tumor-initiating cells do not express the high-affinity immunoglobulin E receptor FcεRIα. Although we cannot exclude the possibility of nonspecific binding of anti-FcεRIα antibody (clone MAR-1), we provide evidence that macrophages in squamous cell carcinomas express FcεRIα and that IL-33 induces FcεRIα expression in bone marrow cell–derived macrophages.

ADAP1, a GTPase-activating protein (GAP) for the small GTPase ARF6, is a strong predictor of poor survival in early-stage squamous cell carcinoma patients and a critical mediator of TGF-β-induced invasive cell migration by facilitating basement membrane breakdown., 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.