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.