AXLerating the elimination of metastatic head and neck cancer cells

The survival rate for head and neck cancer (HNC) patients diagnosed with cervical lymph node (cLN) or distant metastasis is low. Invasion and migration of HNC cells is known to be enhanced by AXL expression, thus targeting AXL expression or eliminating AXL expressing tumor cells can serve as a potential therapy for metastatic disease. We investigated the molecular mechanism of AXL expression in HRAS mutated HNC, and we show how mutation in HRAS regulates AXL expression and effect cell invasion in vitro and in vivo using multiple HRASmut HNC models. We showed that mutation in HRAS in HNC cells was sufficient to drive metastasis, and demonstrated that HRASmut promotes AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity, which, in turn, contributes to induce AXL expression. Next we showed that AXL is required for HRASmut cells to invade in vitro and to form regional cLN and lung metastasis in vivo. In addition, we demonstrated that AXL-expressing HRASmut tumors were enriched with lymphatic and vascular angiogenesis in the primary tumor, and AXL expression determined VEGFA/C, thus regulating tumor-induced vascular-formation. For eliminating AXL-expressing tumor cells, we developed a novel bi-specific antibody that simultaneously binds AXL-expressing tumor cells and PD1 on T cells. Our bi-specific antibody showed a superior anti-tumor activity in vitro and in vivo when compared to the combination of anti-PD1 and anti-AXL antibodies. Altogether, our study indicate that AXL is crucial factor in metastasis of HRASmut HNC, and AXL-expressing cells can be eliminated using bi-specific Ab.