Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone

Hodgson, Kirsty; Orozco-Moreno, Margarita; Goode, Emily Archer; Fisher, Matthew; Garnham, Rebecca; Beatson, Richard; Turner, Helen; Livermore, Karen; Zhou, Yuhan; Wilson, Laura; Visser, Eline A.; Pijnenborg, Johan FA.; Eerden, Nienke; Moons, Sam J.; Rossing, Emiel; Hysenaj, Gerald; Krishna, Rashi; Peng, Ziqian; Nangkana, Kyla Putri; Schmidt, Edward N.; Duxfield, Adam; Dennis, Ella P.; Heer, Rakesh; Lawson, Michelle A.; Macauley, Matthew; Elliott, David J.; Büll, Christian; Scott, Emma; Boltje, Thomas J.; Drake, Richard R.; Wang, Ning; Munkley, Jennifer

doi:10.1016/j.ebiom.2024.105163

Cited by 10 publications

(1 citation statement)

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“…24 Recent research has focused on the development of strategies to inhibit aberrant sialylation as a potential route to control tumor growth and promote immune response while also enhancing the e ectiveness of conventional chemotherapeutics and contemporary immunotherapeutics. [25][26][27][28] As hypersialylation relies heavily on enhanced sialic acid biosynthesis from the oncogenic glycolytic upsurge in cancer cells, it stands to reason that nutrient (dietary) changes could impact the extent of sialylation of the glycocalyx. The link between diet and sialylation has been studied in the context of aging, and high fat diet or dietary restrictions have been shown to alter the acetylation pattern of cell surface sialic acids, based on the availability of acetyl CoA.…”

Section: Introductionmentioning

confidence: 99%

Ketomimetic Nutrients Trigger a Dual Metabolic Defense in Breast Cancer Cells

Kamra,

Chen,

Delgado

et al. 2024

Preprint

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Although metastasis accounts for the vast majority of cancer-related fatalities, the triggers for the metastatic transformation of breast cancer (BC) cells remain unknown. Recent evidence suggests that a common feature of invasive and resistant cells could be their metabolic state. However, attempts to control metabolic state via nutrient intake, e.g., ketogenic or low carbohydrate diets, have shown inconsistent results with respect to improving chemotherapy efficacy and curbing metastasis. Aiming to decode the molecular mechanisms that alter cell phenotype upon nutrient alteration, we study how a ketomimetic (ketone body-rich, low glucose) medium affects Doxorubicin (DOX) susceptibility and invasive disposition of BC cells. We quantified glycocalyx sialylation and found an inverse correlation with DOX-induced cytotoxicity and DOX internalization. These measurements were coupled with single-cell metabolic imaging, bulk migration studies, and transcriptomic and metabolomic analyses to map the mechanisms involved in ketone body-driven BC cell metabolic maneuvering. Our findings revealed that a ketomimetic medium enhances chemoresistance and invasive disposition of BC cells via two main oncogenic pathways: hypersialylation and lipid accumulation. We propose that the crosstalk between these pathways leads to synthesis of the glycan precursor UDP-GlcNAc, which leads to advancement of a metastatic phenotype in BC cells under ketomimetic conditions.

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