PO-252 The circuit of oncofetal O-glycosylation, galectin-4, RTK, and MYC drives metastatic castration-resistant prostate cancer

Introduction Thomsen-Friedenreich (TF or T)-related antigens are short O-glycans highly expressed in over 90% of all human cancers including prostate, breast, ovary, bladder, colon, liver and gastric cancers. Especially in prostatic cancer (PCa), a higher level of T antigen was found correlated with the histological grade and bone metastasis; however, its functional impact in PCa and the underlying mechanism remain perplexing. We showed that spontaneous metastasis of human PCa xenografts expresses high levels of galectin-4, along with gene signatures for ERRB receptors signalling and sialylated core 1 O-glycosylation. Galectin-4 expression in clinical PCa is positively correlated with tumour grade, PSA recurrent rate, and poor survival. Galectin-4 binding to multiple receptor tyrosine kinases (RTKs) in PCa cells stimulates their autophosphorylation and downstream signalling pathways, therefore promoting epithelial-mesenchymal transition and invasive tumour growth. Material and methods Orthotopic xenografts of LNCaP PCa cell line were implanted in athymic nude mice to derive a series of castration-resistant prostate cancer (CRPC) cell populations. Gene expression was detected using qRT-PCR, western blotting, and IHC. Manipulation of gene expression was conducted by overexpression and shRNA knockdown approaches with lentivectors in relevance cell populations. Permission for all animal works has been obtained from the Institutional Animal Care and Use Committee, Academia Sinica. Results and discussions Galectin-4 was upregulated during the development of castration resistance and metastasis. High expression of galectin-4 in PCa cells exhibited castration resistance, tumor-regenerating stem-like cells, expressed SOX9 and ALDH1A1, and ability to colonise distant metastases. We identify a feed-forward signalling pathway by which galectin-4 signalling through RTK-Myc axis upregulated gene transcription of enzymes in a specific O-glycosylation pathway and the biosynthesis of their substrates, thus altered the cellular modification of O-glycosylation, and bolstered castration resistance and metastasis. These coordinated effects conferred more and more binding sites for galectin-4 and amplified the RTKs signalling, implicating crosstalk mechanisms to activate androgen receptor signalling and drive the PCa progression. Conclusion MYC regulates oncofetal O-glycosylation in RTKs thus primes the cells for binding to galectin-4 and downstream signalling, which promotes PCa castration resistance, metastasis, and clinically poor survival.