The tumor suppressor SMAD4 acts through WNT signaling in progression from benign lesions to oral squamous cell carcinoma

SMAD4 is a tumor suppressor mutated or silenced in multiple cancers including oral squamous cell carcinoma (OSCC). Human clinical samples and cell lines, mouse models and organoid culture were used to investigate the role that SMAD4 plays in progression from benign disease to invasive OSCC. Human OSCC lost detectable SMAD4 protein within tumor epithelium in 24% of cases and this loss correlated with worse progression free survival independent of other major clinical and pathological features. In a mouse model, Kras mutation induced benign papillomas while additional loss of Smad4 expression resulted in rapid development of invasive carcinoma. Examining regulatory pathways in organoids from SMAD4+ and SMAD4- mouse tumors, we found that either loss of SMAD4 or inhibition of TGFb signaling upregulated the WNT pathway and altered the extracellular matrix. The gene signature of the mouse tumor organoids lacking SMAD4 was highly similar to the gene signature of human head and neck squamous cell carcinoma. In summary, this work has uncovered novel mechanisms by which SMAD4 acts as a tumor suppressor in OSCC.