Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer

Abstract

Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial–mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the up-regulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation–induced EMT, cell motility, and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

“…Due to the poor vascularization and hypoxic environment, PDAC tumors have been found to be commonly deprived of several nutrients, including glutamine (110). Pharmacologically, glutamine deprivation by glutamine analog DON leads to the induction of EMT through selectively up-regulating the EMT transcription factor Slug in both KPC mouse model and human PDAC cell lines, contributing to enhanced tumor migration and invasion capacities (111). Besides, under the hypoxic condition, Xiang et al found that GLS1 was implicated in hypoxia-induced cancer cell invasion and metastasis, where GLS1 knockdown significantly suppressed CRC cell migration and invasion in vitro, as well as tumor growth and metastatic colonization in vivo (64).…”

Pancreatic cancer SLUGged

“…In this report, Recouvreux et al (2020) demonstrate a link between nutrient stress and EMT activation in PDAC cells, showing that glutamine deprivation plays a major part. Specifically, they report that glutamine limitation up-regulates the expression of EMT transcription factor Slug via MAPK signaling and ATF4 activation, a wellknown stress response pathway that gets activated in response to nutrient starvation.…”

“…Not only could this decrease metastatic spread, but targeting Slug could also reduce the tumor's resistance to proapoptotic signals and cell death to engender improved responses to therapies. In closing, Recouvreux et al (2020)…”

“…With the recent development of animal and organoid models, PDAC also serves as a proto-typical malignancy in which general concepts of fundamental cancer biology can be readily explored. In this issue of JEM, Recouvreux et al (2020) explore glutamine dependency in PDAC, and thereby uncover a link to cell differentiation states and epithelial-mesenchymal transition (EMT), providing new mechanistic insights into the process of metastasis.…”

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

“…These results suggest that the proproliferation and anti-apoptotic functions of KLK8 may not be dependent on activation of Notch signaling pathway. Notably, our GSEA analysis data showed that KLK8 overexpression might also lead to the activation of EMT (epithelial-mesenchymal transition), glycolysis and KRAS signaling pathway, which have been implicated in the pathogenesis and progression of pancreatic cancers [17,[43][44][45]. Whether these processes and the related signaling pathways contribute to the KLK8-induced pro-proliferation and anti-apoptotic effects in pancreatic cancers merits further investigation.…”