Abstract 194: Angiopoietin-like 4 induces proliferation and migration of head and neck squamous cell carcinoma cells via p38 kinase and NRP1/ABL1/PXN pathway

Abstract Background: The molecular mechanisms in which angiopoietin-like 4 (ANGPTL4), a pluripotent protein implicated in cancer development, contribute to head and neck squamous cell carcinoma (HNSCC) growth and dissemination are unclear. Methods: We analyzed ANGPTL4 expression in human normal oral keratinocytes (NOKs), dysplastic oral keratinocytes (DOKs), oral leukoplakia cells (LEUK1), and HNSCC cell lines, HN13, HN6, HN4, HN12, and CAL27, as well as in tissue biopsies from patients with oral dysplasia, and primary and metastatic HNSCC. We further examined the contribution of ANGPTL4 cancer progression in an HNSCC orthotopic floor-of-mouth tumors model and upstream and downstream signaling pathways linking ANGPTL4 to cancer cell proliferation and migration. Results: ANGPTL4 expression was upregulated in premalignant DOKs and HNSCC cell lines compared to NOKs as well as in tissue biopsies from patients with oral dysplasia, and primary and metastatic HNSCC. Downregulation of ANGPTL4 expression inhibited primary and metastatic cancer growth in an HNSCC orthotopic tumor model. Interestingly, ANGPTL4 binding to the neuropilin 1 (NRP1) receptor led to phosphorylation of the focal adhesion protein, paxillin (PXN), and tumor cell migration; this was dependent on the tyrosine kinase ABL1. Further, we examined theextracellular signaling associated with ANGPTL4 expression in HNSCC. Intriguingly, amphiregulin (AREG), an epidermal growth factor receptor ligand, induced ANGPTL4 expression in NOKs and DOKs. AREG-induced activation of cell proliferation was dependent on ANGPTL4. We show that the proliferative potential of AREG in HNSCC is, in part, mediated by ANGPTL4. We also observed a role for p38 MAPK as an important downstream effector for the pro-tumorigenic effects ofANGPTL4 and an upregulation of a wide array of proliferative, proangiogenic, and proinflammatory factors upon treatment of NOKs with this adipokine. This suggests that ANGPTL4 may induce HNSCC tumorigenesis through both autocrine and paracrine pathways. Conclusion: Our findings identify novel opportunities for the development of therapies targeting the ANGPTL4-induced signaling pathways for the treatment of patients with HNSCC. Citation Format: Ajay Kumar. Angiopoietin-like 4 induces proliferation and migration of head and neck squamous cell carcinoma cells via p38 kinase and NRP1/ABL1/PXN pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 194.