Macropinocytosis confers resistance to therapies targeting cancer anabolism

Jayashankar, Vaishali; Edinger, Aimee L.

doi:10.1038/s41467-020-14928-3

Cited by 111 publications

(107 citation statements)

References 73 publications

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“…These results are consistent with our observations on utilization of the GlcNAc salvage pathway to fuel UDP-GlcNAc pools from HA-derived GlcNAc (Figure 4E). Our study also contributes to a growing body of data illuminating unexpected nutrient sources in the TME that support cancer metabolism (13,14,(16)(17)(18)(19)(20)(21)47), and this raises the possibility that other glycosaminoglycans may be similarly scavenged.…”

Section: Discussionmentioning

confidence: 64%

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: 64%

Hyaluronic Acid Fuels Pancreatic Cancer Growth

Kim

Halbrook

Kerk

et al. 2020

Preprint

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“…Therefore, CTP1 inhibitors can be used to both reduce lipid decomposition and reduce energy support for tumors. Moreover, another energy supply method called the giant cell drinking process has been found to be resistant to drug action [ 60 ]. Macrophages take up necessary biological materials from dead tumor cell fragments through endocytosis.…”

Section: Lipids and Drug Resistance In Cancersmentioning

confidence: 99%

“…PI3K regulates the actin cytoskeleton through Rac1 and promotes the closure of a large body through phosphoinositide signal [ 62 ]. The phagocytized necrotic cells are decomposed and metabolized to provide energy for tumor cell proliferation ( Figure 2 ) [ 38 , 58 , 59 , 60 , 61 , 62 ].…”

Section: Lipids and Drug Resistance In Cancersmentioning

confidence: 99%

The Function and Mechanism of Lipid Molecules and Their Roles in The Diagnosis and Prognosis of Breast Cancer

et al. 2020

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Lipids are essential components of cell structure and play important roles in signal transduction between cells and body metabolism. With the continuous development and innovation of lipidomics technology, many studies have shown that the relationship between lipids and cancer is steadily increasing, involving cancer occurrence, proliferation, migration, and apoptosis. Breast cancer has seriously affected the safety and quality of life of human beings worldwide and has become a significant public health problem in modern society, with an especially high incidence among women. Therefore, the issue has inspired scientific researchers to study the link between lipids and breast cancer. This article reviews the research progress of lipidomics, the biological characteristics of lipid molecules, and the relationship between some lipids and cancer drug resistance. Furthermore, this work summarizes the lipid molecules related to breast cancer diagnosis and prognosis, and then it clarifies their impact on the occurrence and development of breast cancer The discussion revolves around the current research hotspot long-chain non-coding RNAs (lncRNAs), summarizes and explains their impact on tumor lipid metabolism, and provides more scientific basis for future cancer research studies.

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“…There are a number of mouse cell lines that lead to tumor formation and metastasis such as 4T1, B16, Lewis lung carcinoma cells, Met-1, and RM1 [66]. It was recently reported using orthotopic injection of 4T1 mouse mammary tumor cells (generated from CARMIL1-WT or CARMIL1-AA cells) into BALB/c mice to study the role of macropinocytosis in mediating treatment resistance [68]. They found that macropinocytosis fuels tumor growth (possibly by generating intracellular cell nutrients such as amino acids, sugars, fatty acids, and nucleotides via necrocytosis) and increases resistance to 5-FU [68].…”

Section: Metastasismentioning

confidence: 99%

Current methods in translational cancer research

Lee

Miljanic

Triplett

et al. 2020

Cancer Metastasis Rev

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Recent developments in pre-clinical screening tools, that more reliably predict the clinical effects and adverse events of candidate therapeutic agents, has ushered in a new era of drug development and screening. However, given the rapid pace with which these models have emerged, the individual merits of these translational research tools warrant careful evaluation in order to furnish clinical researchers with appropriate information to conduct pre-clinical screening in an accelerated and rational manner. This review assesses the predictive utility of both well-established and emerging pre-clinical methods in terms of their suitability as a screening platform for treatment response, ability to represent pharmacodynamic and pharmacokinetic drug properties, and lastly debates the translational limitations and benefits of these models. To this end, we will describe the current literature on cell culture, organoids, in vivo mouse models, and in silico computational approaches. Particular focus will be devoted to discussing gaps and unmet needs in the literature as well as current advancements and innovations achieved in the field, such as co-clinical trials and future avenues for refinement.

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Macropinocytosis confers resistance to therapies targeting cancer anabolism

Cited by 111 publications

References 73 publications

Hyaluronic Acid Fuels Pancreatic Cancer Growth

Hyaluronic Acid Fuels Pancreatic Cancer Growth

The Function and Mechanism of Lipid Molecules and Their Roles in The Diagnosis and Prognosis of Breast Cancer

Current methods in translational cancer research

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