Differentiating the Mechanistic Role and Chemotherapeutic Potential of SRC and Podoplanin in Oncogenic Transformation

There were an estimated 20 million new cancer cases worldwide in 2020, resulting in nearly 1000 deaths per hour [1]. Oral cancer exemplifies the difficulties of treating cancer patients. The first line for oral cancer treatment is surgery and radiation that can lead to patient disfigurement and decreased quality of life in cancer survivors [2-4]. Though there have been many developments in chemotherapy in the last 30 years, the 50% mortality rate associated with oral cancer has not changed [4, 5]. Longitudinal studies that track survival rates in oral cancer patients demonstrate a 3-fold reduction in patient deaths when patients are diagnosed with stage 1 through 3 tumors as opposed to stage 4 and beyond [5]. This indicates that we need to understand the stages of tumor development to find early-stage biomarkers that can be exploited as chemotherapeutic targets. The transmembrane receptor Podoplanin (Pdpn) has become a functionally relevant biomarker and chemotherapeutic target [6-8]. Pdpn is not typically expressed in oral epithelia; however, when Pdpn expression arises in oral cancer development, there is a 3-to-4-fold drop in 5-year patient survival [9]. Pdpn expression can be induced by oncogenes including the Src nonreceptor tyrosine kinase to promote cancer cell migration and metastasis [10-12]. In these studies, we demonstrate that Src and Pdpn promote cell anchorage independent cell growth and migration through independent mechanisms. We further elucidate the molecular pathways downstream that are altered when Pdpn is phosphorylated or targeted by extracellular agents. Recent work demonstrates that Maackia amurensis seed lectin (MASL) inhibits the cell migration and viability of Pdpn expressing melanoma cells [13]. We describe the chemotherapeutic potential and pleotropic effects of MASL in Pdpn expressing human oral squamous cell carcinoma (OSCC). Finally, we show that MASL has potential as an effective antiviral and anti-inflammatory agent that prevents the SARS-CoV-2 virus from binding host oral squamous cells. Together, these data suggest that Src and Pdpn induce discreet pathways to promote tumor development and these mechanisms can be targeted with MASL