monitoring-breast-cancer-growth-metastatic-colony-formation-mice

Monitoring Breast Cancer Growth and Metastatic Colony Formation in Mice using Bioluminescence

Breast cancer is a frequent heterogeneous malignancy and the second leading cause of mortality in women, mainly due to distant organ metastasis. Several ...

The Hebrew University-Hadassah Medical School

Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.

A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate.

Cancer-dependent metabolic rewiring is often manifested by selective expression of enzymes essential for the transformed cells' viability. However, the metabolic variations between normal and transformed cells are not fully characterized, and therefore, a systematic analysis will result in the identification of unknown cellular mechanisms crucial for tumorigenesis. Here, we applied differential gene expression transcriptome analysis to examine the changes in metabolic gene profiles between a wide range of normal tissues and cancer samples. We found that, in contrast to normal tissues which exhibit a tissue-specific expression profile, cancer samples are more homogenous despite their diverse origins. This similarity is due to a "proliferation metabolic signature" (PMS), composed of 158 genes (87 upregulated and 71 downregulated gene sets), where 143 are common to all proliferative cells but 15 are cancer specific. Intriguingly, the PMS gene set is enriched for genes encoding rate-limiting enzymes, and its upregulated set with genes associated with poor patient outcome and essential genes. Among these essential genes is ribulose-5-phosphate-3-epimerase (), which encodes a pentose phosphate pathway enzyme and whose role in cancer is still unclear. Collectively, we identified a set of metabolic genes that can serve as novel cancer biomarkers and potential targets for drug development.

Large-Scale Differential Gene Expression Transcriptomic Analysis Identifies a Metabolic Signature Shared by All Cancer Cells.

One of the emerging hallmarks of cancer illustrates the importance of metabolic reprogramming, necessary to synthesize the building blocks required to fulfill the high demands of rapidly proliferating cells. However, the proliferation-independent instructive role of metabolic enzymes in tumor plasticity is still unclear. Here, we provide evidence that glutathione peroxidase 8 (GPX8), a poorly characterized enzyme that resides in the endoplasmic reticulum, is an essential regulator of tumor aggressiveness. We found that GPX8 expression was induced by the epithelial-mesenchymal transition (EMT) program. Moreover, in breast cancer patients, GPX8 expression significantly correlated with known mesenchymal markers and poor prognosis. Strikingly, GPX8 knockout in mesenchymal-like cells (MDA-MB-231) resulted in an epithelial-like morphology, down-regulation of EMT characteristics, and loss of cancer stemness features. In addition, GPX8 knockout significantly delayed tumor initiation and decreased its growth rate in mice. We found that these GPX8 loss-dependent phenotypes were accompanied by the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). In these cells, IL-6 bound to the soluble receptor (sIL6R), stimulating the JAK/STAT3 signaling pathway by IL-6 -signaling mechanisms, so promoting cancer aggressiveness. We observed that in GPX8 knockout cells, this signaling mechanism was impaired as sIL6R failed to activate the JAK/STAT3 signaling pathway. Altogether, we present the GPX8/IL-6/STAT3 axis as a metabolic-inflammatory pathway that acts as a robust regulator of cancer cell aggressiveness.

Article	Year
A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nature chemical biology\| PubMed ID: 27110680	2016
Large-Scale Differential Gene Expression Transcriptomic Analysis Identifies a Metabolic Signature Shared by All Cancer Cells. Biomolecules\| PubMed ID: 32365991	2020
The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 32817494	2020

Yoav D. Shaul

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