Summary Oral cancer kills over 8,000 people in the USA and 120,000 people worldwide every year. In addition to this mortality, oral cancer survivors suffer from permanent sequelae and decreased quality of life. Over 90% of oral cancers are caused by oral squamous cell carcinoma (OSCC). This project is based on the premise that nontransformed cells can control the growth of neighboring transformed cells by contact normalization. Direct contact between transformed and nontransformed cells is required for this process. However, junctions responsible for contact normalization, and gene products that enable cancer cells to overcome this form of growth control, have not been defined. We found that contact normalization suppresses expression of the transmembrane mucin receptor podoplanin (PDPN) downstream of oncogenic Src tyrosine kinase activity. Many cancer cells, including OSCCs, express PDPN to promote cancer progression. Precancerous oral lesions (e.g. leukoplakia) that express high levels of PDPN are several times more likely to become cancers than lesions that do not express PDPN. In addition, PDPN has been identified as an immune cell checkpoint corepressor. Indeed, PDPN has emerged as a functionally relevant biomarker and chemotherapeutic target that can be used to detect and treat oral cancer. Our rationale is based on the fact that cadherin junctions are often disrupted between transformed cells, while PDPN expression is enhanced. PDPN antibodies and Maackia amurensis seed lectin (MASL) efficiently target PDPN to decrease OSCC cell motility and viability. Moreover, MASL is nontoxic and can be administered orally to inhibit tumor growth and vascularization without notable side effects in preclinical studies. We hypothesize that cadherins mediate contact normalization to suppress PDPN expression, and PDPN can be utilized as a functionally relevant chemotherapeutic target to synergistically inhibit tumor cell growth and augment anticancer immune response. We propose 3 Specific Aims to test this hypothesis. In Aim 1, we will determine if cadherins are needed for nontransformed cells to normalize morphology, growth, motility, Wnt signaling, and PDPN expression of adjacent Src transformed and OSCC cells. In Aim 2, we will determine if PDPN signaling enables Src transformed fibroblasts and OSCC cells to override growth control by neighboring nontransformed cells. In Aim 3, we will determine if MASL can target PDPN to augment host immune response in concert with its ability to inhibit OSCC cell growth in an FDA approved Phase 1 human clinical trial on oral cancer patients. This project will expose graduate and medical students to basic research in molecular and cell biology to elucidate fundamental mechanisms behind contact normalization. This work will enhance our abilities to detect, prevent, and treat oral cancer, as well as other cancers that are driven by PDPN signaling.

Narrative Conventional cytotoxic drugs are very toxic, and more targeted chemotherapies are limited to only a handful of reagents. Malignant oral cancers do not respond well to current chemotherapies. Elucidating how normal cells control OSCC progression in the microenvironment, and developing a strategy target PDPN on these cells, could open new avenues to prevent and treat cancer.