Alteration of Lipid\nMetabolism in Hypoxic Cancer Cells

Due to uncontrolled cell proliferation and disrupted\nvascularization,\nmany cancer cells in solid tumors have limited oxygen supply. The\nhypoxic microenvironments of tumors lead to metabolic reprogramming\nof cancer cells, contributing to therapy resistance and metastasis.\nTo identify better targets for the effective removal of hypoxia-adaptive\ncancer cells, it is crucial to understand how cancer cells alter their\nmetabolism in hypoxic conditions. Here, we studied lipid metabolic\nchanges in cancer cells under hypoxia using coherent Raman scattering\n(CRS) microscopy. We discovered the accumulation of lipid droplets\n(LDs) in the endoplasmic reticulum (ER) in hypoxia. Time-lapse CRS\nmicroscopy revealed the release of old LDs and the reaccumulated LDs\nin the ER during hypoxia exposure. Additionally, we explored the impact\nof carbon sources on LD formation and found that MIA PaCa2 cells preferred\nfatty acid uptake for LD formation, while glucose was essential to\nalleviate lipotoxicity. Hyperspectral-stimulated Raman scattering\n(SRS) microscopy revealed a reduction in cholesteryl ester content\nand a decrease in lipid saturation levels of LDs in hypoxic MIA PaCa2\ncancer cells. This alteration in LD content is linked to reduced efficacy\nof treatments targeting cholesteryl ester formation. This study unveils\nimportant lipid metabolic changes in hypoxic cancer cells, providing\ninsights that could lead to better treatment strategies for hypoxia-resistant\ncancer cells.