Thursday, November 21, 2024
11/21/2024
Oral cancer is the 6th most common cancer, mostly tongue oral squamous cell carcinoma (OSCC). Surgery and radiation treatments result in severe quality of life issues, tissue stiffness and metastasis. Lysyl oxidase (LOX) is one of five paralogues. All catalyze the final extracellular enzymatic reaction required for collagen biosynthesis. Only LOX undergoes biosynthetic processing to release the active enzyme and the unique 18 kDa lysyl oxidase propeptide (LOX-PP) that inhibits tumor growth. Preliminary data show that a polymorphic point mutation in the LOX-PP region of LOX gene leading to R to Q amino acid change in LOX-PP is linked to increased OSCC. We further show that wildtype LOX-PP cross-talks with macrophages to shift phenotype to inflammatory tumor suppressive cells. In lesion microenvironments in 4NQO induced oral cancer WT mice exhibit tumor suppressive- T cell markers, while knockin Q LOX-PP (KI) mice show tumor cells. We published that LOX-PP, but not polymorphic Q LOX-PP, inhibits FGFR signaling, and that LOX-PP can bind directly to FGFR1. In non-oral cancers immunosuppressive macrophages overexpress FGF-2 and FGFR1 and FGF-2 regulates conversion to tumor suppressive cells in vitro and in vivo. Interestingly, LOX enzymes from all 5 paralogues can be up- regulated, including in OSCC, to promote fibrosis. Integrating these findings, we propose that in OSCC microenvironments, the polymorphic Q LOX-PP has lost its tumor suppressor function via its inability to block FGFR-dependent macrophage phenotype swich to pro-inflammatory tumor suppressive with consequences on T cell activation and OSCC outcomes. To investigate the hypothesis that LOX-PP regulation of macrophage phenotype contributes to OSCC tumor suppression that is lost in Q LOX-PP we propose 3 Aims. In Aim 1a we will investigate in tumor microenvironments vs adjacent regions macrophage phenotypes and local modulations of T cell and mesenchymal cell type and gene expression changes utilizing state of the art spatial transcriptomics technologies in WT compared to KI mice in the 4NQO model of cancer. The 4NQO model mimics human OSCC development. Pathways will be validated in vitro and in vivo. In Aim 1b we will determine the relative ability of recombinant WT R LOX-PP vs Q LOX-PP to block oral cancer development in mice. In Aim 1c we will investigate human cancer tissues for the same pathway differences in clinical samples from oral cancer subjects with WT and variant LOX genotype. Aim 2a will determine differential effects and regulatory mechanisms of WT vs variant LOX-PP on macrophages in vitro. In Aim 2b we will perform a loss of function study of secreted FGF-2 KO mice that may have rescued OSCC response to 4NQO in LOX-PP KI mice. In Aim 2c we investigate the ability of local wildtype AAV LOX-PP injection in KI mice with or without a LOX enzyme inhibitor (PXS-5505) to determine additive or synergistic benefits in 4NQO induced OSCC. In Aim 3 we will determine affinity of LOX-PP and Q LOX-PP to FGFR1 in vitro, and perform structure-function studies, and identify functional direct LOX-PP binding partners. Data will provide functional targets of LOX-PP in oral cancer tumor suppression.
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