Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

Sharma, Nikita; Gupta, Vineet; Garrido, Vanessa T.; Hadad, Roey; Durden, Brittany; Kesh, Kousik; Giri, Bhuwan; Ferrantella, Anthony; Dudeja, Vikas; Saluja, Ashok K.; Banerjee, Sulagna

doi:10.1172/jci127515

Cited by 155 publications

(144 citation statements)

References 71 publications

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“…Indeed, several pan glutamine-deamidase inhibitors (e.g. azaserine and 6diazo-5-oxo-L-norleucine), which potently suppress GFAT activity, have demonstrated antitumor activity in vitro and in vivo in PDA and other cancers (42,43). However, because these drugs are not specific to the HBP, it has not been clear what impact GFAT-specific inhibition had on these phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…This could occur through growth factor signaling-dependent (38) as well as signaling-independent pathways, like the GlcNAc salvage pathway described herein. In contrast, reduction in the HA content of tumors also facilitates T cell invasion (43), which may complement immunotherapy approaches, a concept that would be hindered by immunosuppressive chemotherapies. Given the conflicting roles of HA in tumor restraint and tumor growth, considerable work remains to be done to determine the most effective way to exploit this feature of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

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Hyaluronic Acid Fuels Pancreatic Cancer Growth

Kim

Halbrook

Kerk

et al. 2020

Preprint

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Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not impair tumor growth, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. Here, we show that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Furthermore, HA facilitates proliferation in nutrient-starved wild-type PDA. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hyaluronic Acid Fuels Pancreatic Cancer Growth

Kim

Halbrook

Kerk

et al. 2020

Preprint

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“…Remarkably, inhibiting IL6 had a striking effect on collagen in the stroma (Figure 7A). A recently published study from our laboratory show that inhibiting of hexosamine biosynthesis pathway decreased collagen in the pancreatic tumors and increased CD8+ infiltration 29 . Whether inhibition of IL6 signaling functions similarly is unclear and beyond the scope of the current manuscript.…”

Section: Discussionmentioning

confidence: 82%

“…However, whether this metabolic reprogramming drives immune suppression in pancreatic cancer is not known. Our recently published studies have shown that tumor intrinsic metabolic pathways like hexosamine biosynthesis pathway can be targeted to modulate the microenvironment and thus sensitize pancreatic cancer cells to checkpoint inhibitor therapy 29 . Thus, metabolic inhibitors are being evaluated to sensitize normally immune evasive pancreatic tumors to checkpoint inhibitor therapy…”

Section: Introductionmentioning

confidence: 99%

Stroma secreted IL6 selects for “stem-like” population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways

Kesh

Garrido

Doesch

et al. 2020

Preprint

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Pancreatic adenocarcinoma is a devastating disease with an abysmal survival rate of 9%. A robust fibro-inflammatory and desmoplastic stroma, characteristic of pancreatic cancer, contributes to the challenges in developing viable therapeutic strategies in this disease. Apart from constricting blood vessels and preventing efficient drug delivery to the tumor, the stroma also contributes to aggressive biology of the cancer along with its immune-evasive microenvironment. In this study, we show that in pancreatic tumors, the developing stroma increases tumor initiation frequency in pancreatic cancer cells in vivo by enriching for CD133+ aggressive “stem-like” cells. Additionally, the stromal fibroblasts secrete IL6 as the major cytokine, increases glycolytic flux in the pancreatic tumor cells and increases lactate efflux in the microenvironment via activation of the STAT signaling pathway. We also show that the secreted lactate favors activation of M2 macrophages in the tumor microenvironment, which excludes CD8+ T-cells in the tumor. Our data additionally confirms that treatment of pancreatic tumors with anti-IL6 antibody results in tumor regression as well as decreased CD133+ population within the tumor. Furthermore, inhibiting the lactate efflux in the microenvironment reduces M2 macrophages, and makes pancreatic tumors more responsive to anti-PD1 therapy. This suggests that stromal IL6 driven metabolic reprogramming plays a significant role in the development of an immune evasive microenvironment. In conclusion, our study shows that targeting the metabolic pathways affected by stromal IL6 can make pancreatic tumors amenable to checkpoint inhibitor therapy.

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“…Advances in mass spectrometry (MS)-based methods will facilitate the discovery of novel O-GlcNAc-modified proteins in cancer cells. Therefore, modulating the HBP or O-GlcNAcylation (which regulate oncogenic activation in human cancers) represents a promising anti-cancer strategy that can potentially be used in combination with other treatments 22,23 .…”

Section: Introductionmentioning

confidence: 99%

Gluconeogenic Enzyme PCK1 Deficiency Is Critical for CHK2 O-GlcNAcylation and Hepatocellular Carcinoma Growth upon Glucose Deprivation

Jin

Chang

et al. 2020

Preprint

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Elevated hexosamine-biosynthesis pathway (HBP) activity and O-GlcNAcylation are emerging hallmarks of hepatocellular carcinoma (HCC). Inhibiting O-GlcNAcylation could be a promising anti-cancer strategy. Here, we investigate this possibility and demonstrate that deficiency of phosphoenolpyruvate carboxykinase 1 (PCK1), a rate-limiting enzyme in gluconeogenesis, promotes O-GlcNAcylation and hepatoma cell proliferation under low-glucose conditions. PCK1 loss results in oxaloacetate accumulation and AMPK inactivation, promoting uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) synthesis and CHK2 threonine 378 O-GlcNAcylation and counteracting its ubiquitination and degradation. O-GlcNAcylation also promotes CHK2-dependent Rb phosphorylation and HCC cell proliferation. Therefore, blocking HBP-mediated O-GlcNAcylation suppresses tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation.

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Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

Cited by 155 publications

References 71 publications

Hyaluronic Acid Fuels Pancreatic Cancer Growth

Hyaluronic Acid Fuels Pancreatic Cancer Growth

Stroma secreted IL6 selects for “stem-like” population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways

Gluconeogenic Enzyme PCK1 Deficiency Is Critical for CHK2 O-GlcNAcylation and Hepatocellular Carcinoma Growth upon Glucose Deprivation

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