Metabolic buffering suppresses phenotype switching in cancer

The impact of the microenvironment on epigenetically plastic cancer cells underpins phenotypic heterogeneity, a major cause of metastatic dissemination and therapy resistance that together represent the primary cause of cancer-related death. Nutrient limitation is a key microenvironmental stress that can cause a phenotypic transition from proliferation to invasion via activation of the integrated stress response. However, whether and how the capacity to store and mobilize nutrients impacts phenotype-switching through metabolic buffering remains unknown. Here, using melanoma as a model, we reveal that the ability to accumulate and mobilize glycogen, that buffers glucose availability, plays a key role in phenotypic transitions in melanoma. While proliferative phenotype cells exhibit high levels of glycogen, invasion is marked by low glycogen levels. Significantly, an inability to store and metabolize glycogen leads to phenotype instability and a switch to invasion. Accordingly, glycogen levels inversely correlate with Clark levels in primary melanomas, with low expression of the glycogen phosphorylases PYGB/L and phosphoglucomutase 1 (PGM1) being associated with worse overall survival. The importance of metabolic buffering in suppressing phenotypic transitions likely extrapolates to other cancer types. HighlightsO_LIMelanoma phenotypes are distinguished by their ability to store and mobilize glycogen. C_LIO_LIProliferative MITFHigh melanoma cells store glycogen to improve survival under stressful conditions. C_LIO_LIInhibition of glycogen degradation impairs proliferation in MITFHigh melanoma cells. C_LIO_LILack of PGM1 drives invasion and metastatic dissemination. C_LI