Targeting metastasis-initiating cells through the fatty acid receptor CD36. Expression levels of serine/glycine metabolism-related proteins in triple negative breast cancer tissues. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis addicted breast tumor growth. Limited environmental serine and glycine confer brain metastasis sensitivity to PHGDH inhibition. In vivo evidence for serine biosynthesis-defined sensitivity of lung metastasis, but not of primary breast tumors, to mTORC1 inhibition. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. EMT transition states during tumor progression and metastasis. Intra-tumor heterogeneity from a cancer stem cell perspective. The metabolism of cancer cells during metastasis. Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression. Intratumoral heterogeneity in cancer progression and response to immunotherapy.
#Cellprofiler analysing a set of images driver
Phenotypic plasticity: driver of cancer initiation, progression, and therapy resistance. B., Pastushenko, I., Skibinski, A., Blanpain, C. Thus, the presence of PHDGH heterogeneity in primary tumours could be considered a sign of tumour aggressiveness. In conclusion, although the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Inhibition of sialylation counteracts the metastatic ability of Phgdh low cancer cells. As a consequence, aberrant protein glycosylation occurs, including increased sialylation of integrin α vβ 3, which potentiates cell migration and invasion. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine–sialic acid pathway, which provides precursors for protein glycosylation. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdh low cancer cells, and silencing Phgdh in primary tumours increases metastasis formation. Specifically, we find that heterogeneous or low PHGDH expression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination.
Metabolic heterogeneity has also been observed 4, yet its role in cancer progression is less explored. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process 2, 3. Nature volume 605, pages 747–753 ( 2022) Cite this articleĬancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs 1. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis
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