Squamous cell carcinoma subverts adjacent histologically normal epithelium to promote lateral invasion

Recurrent and new tumors, attributed in part to lateral invasion, are frequent in squamous cell carcinomas and lead to poor survival. We identified a mechanism by which cancer subverts adjacent histologically normal epithelium to enable small clusters of cancer cells to burrow undetected under adjacent histologically normal epithelium. We show that suppression of DMBT1 within cancer promotes aggressive invasion and metastasis in vivo and is associated with metastasis in patients. Cancer cells via TGF beta 1 and TNF alpha also suppress DMBT1 in adjacent histologically normal epithelium, thereby subverting it to promote invasion of a small population of tumor cells. The sufficiency of DMBT1 in this process is demonstrated by significantly higher satellite tumor nests in Dmbt1-/- compared with wild-type mice. Moreover, in patients, invasion of small tumor nests under adjacent histologically normal epithelium is associated with increased risk for recurrence and shorter disease-free survival. This study demonstrates a crucial role of adjacent histologically normal epithelium in invasion and its important role in the tumor microenvironment and opens new possibilities for therapeutic strategies that reduce tumor recurrence. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, with similar to 600,000 new cases per year (Leemans et al., 2018). Tumor recurrence and new tumors occur in up to 50% of patients with HNSCC (Leeman et al., 2017; Leemans et al., 2018). Identification of this clinical problem led to the concept of field cancerization. Slaughter et al. (1953) pioneered this concept and attributed it to discrete tumor

Automated summary

This study reveals a mechanism by which cancer cells subvert adjacent histologically normal epithelium to promote aggressive invasion and metastasis. It highlights the role of DMBT1 in this process and suggests new therapeutic strategies to reduce tumor recurrence.