Exploring the Role of DMBT1 Suppression in Invasion of Oral Cancer

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PROJECT SUMMARY/ABSTRACT Squamous cell carcinoma (SCC), the most common oral cancer, notoriously recurs, leading to poor survival. Invasion of cancer cells is essential for recurrence and progression, emphasizing the importance of investigating mechanisms of invasion in order to improve patient survival. We recently identified a mechanism in which SCC co-opts adjacent non-cancerous epithelium, referred to as cancer-associated keratinocytes (CAKs), to enhance lateral invasion, which was associated with recurrence. Deleted in malignant brain tumors 1 (DMBT1), a tumor suppressor, is downregulated in SCC to promote lateral invasion and formation of satellite lesions. In a feedback loop, SCC-secreted transforming growth factor-beta (TGF) suppresses DMBT1 in CAKs; this causes CAKs to release cytokines that enhance invasion of tumor cells away from the tumor bulk. The objective of the proposed study is to understand how TGF suppresses DMBT1 in CAKs and why it does so. Interestingly, DMBT1 is also an anti-microbial protein; preliminary data show that downregulation of DMBT1 in CAKs increases susceptibility to Porphyromonas gingivalis, a keystone pathogen in periodontal disease. There is a strong correlation between SCC and dysbiosis in the oral microbiome. Multiple studies have shown that P. gingivalis enhances SCC invasion, but none have examined the ability of P. gingivalis to enhance SCC invasion via CAKs. Normal keratinocytes infected with P. gingivalis secrete pro-inflammatory cytokines. The overall hypothesis is that SCC-mediated suppression of DMBT1 in CAKs via TGF facilitates bacterial entry into CAKs, thereby enhancing release of cytokines that promote invasion of SCC. To test this hypothesis, we propose two aims: Aim #1: Characterize the molecular mechanism by which TGF suppresses DMBT1 in CAKs; and Aim #2: Investigate the impact of DMBT1 suppression in CAKs on bacterial entry, release of pro-invasive cytokines, and SCC invasion. To understand the mechanism of DMBT1 suppression in CAKs, we will use in genetic and pharmacological approaches in cell lines. To understand the significance of DMBT1 suppression in CAKs on SCC invasion, we will use high-throughput proteomics to investigate the secretome of CAKs, and genetic and pharmacologic approaches to establish the role of these cytokines in invasion using in in vitro and in vivo models, including Dmbt1-/- mice. Overall, this project will investigate the mechanism by which SCC co-opts CAKs to promote the release of cytokines that enhance tumor invasion; this could provide therapeutic targets to prevent SCC recurrence and improve survival.