Pilot: The Role Of Collagen Glycosylation In Prometastatic Signaling And Metabolic Reprogramming

Abstract: Lung cancer is the primary cause of cancer death in the western countries including united states. Kentucky leads the nation both in lung cancer incidence and mortality. Lung cancer-related mortality is largely due to metastasis. During metastasis, malignant tumors accumulate crosslinked collagen fibrils with increased levels of glycosylation. While numerous studies showed that increased levels of collagen crosslinks drive cancer metastasis, to what extent and how collagen glycosylation contributes to pro- metastatic signaling and metabolic reprogramming is still not clear. We identified two new collagen glycosyltransfereases and found that collagen glycosyltransfereases are highly expressed in metastatic lung cells and promote cell-collagen interaction and cancer metastasis. Based on these findings, we hypothesize that collagen glycosylation increases collagen receptor binding and activation to initiate pro-metastatic signaling. Moreover, given that collagen is the most abundant protein in tumor stroma and collagen glycosylation requires large amount of metabolism intermediates, we speculate that cancer cells hyperactivate their glycosylation pathway in the tumor microenvironment to deplete metabolism intermediates and drive metabolic reprogramming. We will test our hypotheses via two aims: (1) Define whether and how collagen hyl-O-linked glycosylation initiates prometastatic signaling. (2) Determine whether collagen hyl-O-linked glycosylation reprograms tumor metabolism. We seek to use the structural insights and small molecule inhibitors we have produced to elucidate how collagen hyl-O-linked glycosylation promotes cancer pro-metastatic signaling and metabolic reprogramming. Our findings from this work will significantly advance our understanding of the role collagen glycosylation in lung cancer metastasis. This work will also provide new strategies to target hyl-O-linked glycosylation pathway for cancer treatment. We are confident that data collected from this project will be used for the submission of a competitive NCI R01 grant focusing on developing knowledge-based small molecule therapeutics against lung cancer.