Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells

Abstract

The role of glutaminolysis in providing metabolites to support tumour growth is well-established, but the involvement of glutamine metabolism in invasive processes is yet to be elucidated. Here we show that normal mammary epithelial cells consume glutamine, but do not secrete glutamate. Indeed, low levels of extracellular glutamate are necessary to maintain epithelial homoeostasis, and provision of glutamate drives disruption of epithelial morphology and promotes key characteristics of the invasive phenotype such as lumen-filling and basement membrane disruption. By contrast, primary cultures of invasive breast cancer cells convert glutamine to glutamate which is released from the cell through the system Xc- antiporter to activate a metabotropic glutamate receptor. This contributes to the intrinsic aggressiveness of these cells by upregulating Rab27-dependent recycling of the transmembrane matrix metalloprotease, MT1-MMP to promote invasive behaviour leading to basement membrane disruption. These data indicate that acquisition of the ability to release glutamate is a key watershed in disease aggressiveness.

GPER‐regulated lncRNA‐Glu promotes glutamate secretion to enhance cellular invasion and metastasis in triple‐negative breast cancer

“…More importantly, this signaling contributes to the invasive ability and metastasis confirmed by Transwell assay and mice model. These results are in line with the discovery that glutamate secretion contributes to the aggressive behaviors of TNBC cells 40 and knockout of GPER significantly reduced lung metastases in transgenic mice model of mammary tumorigenesis. 44 The aggressiveness of TNBC cells causally leads to high incidence rates of metastasis and poor prognosis in patients with TNBC.…”

“…39 a abcd e revealed that normal mammary epithelial cells do not secrete glutamate, while invasive breast cancer cells release glutamate, which contributes to the intrinsic aggressiveness of these cells. 40 The secretion of glutamate induces HIF1α in TNBC cells that contributes to aggressive behaviors. 24 The antitumor activity of the glutaminase inhibitor, which decreases glutamate concentration, is dependent on extracellular glutamate in TNBC in vivo.…”

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

“…In 1978, Lawrence et al observed that glutamine is the major energy source in HeLa cell line (158). Additionally, evidence supports that glutaminolysis provides metabolites, such as glutamate to promote tumor growth, as observed by Dornier et al (159). The group investigated the participation of glutamine metabolism in invasive processes so that, they showed that mammary epithelial cells from normal tissue uptake glutamine, yet glutamate secretion was not observed.…”

Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells

“…Thus, glutamine can undergo glutaminolysis by glutamine synthetase to yield glutamate, which can be further deaminated into a-ketoglutarate and enter the TCA cycle. Glutamine and glutamate metabolism correlates with the expression of EMT-associated transcription factors (37) and glutaminolysis may serve as a driver of invasiveness of breast cancer cells (38). To analyze the contribution of glutamine to the aggressive behavior of 537S-ER-expressing cells, MCF-7 cells expressing either 537S-ER or WT-ER, were grown in the presence of E2 under glucose deprivation conditions (described under "Material and Methods").…”