Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition

Michalopoulou, Evdokia; Auciello, Francesca R.; Bulusu, Vinay; Strachan, David; Campbell, Andrew D.; Tait-Mulder, Jacqueline; Karim, Saadia A.; Morton, Jennifer P.; Sansom, Owen J.; Kamphorst, Jurre J.

doi:10.1016/j.celrep.2020.01.080

Cited by 29 publications

(15 citation statements)

References 64 publications

(92 reference statements)

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“…Macropinocytos is a kind of pathway for internalization involving vesicles 50-300 nm in diameter. In the analysis of micropinocytosis, the concept of micropinocytosis index was de ned by Lee SW et al [9], which is widely applied, especially in the eld of cancer research [10][11][12]. Generally, macropinocytosis assay mainly includes two discontinuous stages: (1) images capture using uorescent microscope; (2) image quanti cation by means of ImageJ software.…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that intratumoral inhibition of macropinocytosis decreases amino acid levels [2]. Furthermore, macropinocytosis promotes both tumor growth and chemotherapy resistance in vivo by uptake necrotic cell debris [3,4]. The level of micropinocytosis can increase in the context of oncogenic transformation (e.g., oncogenic RAS or PI3K) or tumor suppressor mutations (e.g., loss of PTEN) [5][6].…”

Section: Introductionmentioning

confidence: 99%

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Quantitation of Macropinocytosis in Glioblastoma Based on High-Content Analysis

Wang

Yao

Dong

et al. 2021

Preprint

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Background: Macropinocytosis serves as an internalization pathway for extracellular fluid, albumin and dissolved molecules. Assessing macropinocytosis has been challenging in the past because manual acquisition in combination with visual evaluation of images is laborious, making it difficult for high-throughput applications. So, there is a need to develop sensitive and specific methods. Methods: This paper proposed a quantitative and time-saving method for macropinocytosis detection based on high-content analysis (HCA). Meanwhile, cell proliferation was tested by means of CCK8. Results: The term “macropinosome index” was defined to estimate macropinocytosis and allow comparison between different cell lines and treatments. Furthermore, we demonstrated that macropinocytosis can promote Glioblastoma (GBM) cells survival in glutamine deficient conditions which resemble tumor microenvironment. Conclusions: HCA represents a novel, non-subjective and high-throughput assay for macropinocytosis assessment. Besides, Gln deprivation increased the macropinosome index in GBM cells, which points to the possible exploitation of this process in the design of GBM therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitation of Macropinocytosis in Glioblastoma Based on High-Content Analysis

Wang

Yao

Dong

et al. 2021

Preprint

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“…In PANC-1 cells, inhibition of macropinocytosis led to an enhanced ROS level and induced mitochondrial apoptosis by increased Bax, decreased Bcl-2 expression, and activation of caspase-3, 7, 9, and PARP cleaved. In other studies, it was found that macropinocytosis rendered a subset of pancreatic tumor cells resistant to mTOR inhibition, and concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach [ 43 ]. Another interesting discovery was the SDC1 (syndecan-1) protein activated by KRAS on the cell surface that regulates macropinocytosis in pancreatic cancer cells.…”

Section: Changes Of the Adaptive Metabolic Pathwaysmentioning

confidence: 99%

Pancreatic cancer and adaptive metabolism in a nutrient-deficient environment

Słotwiński¹,

Słotwińska²

2021

cejoi

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Despite tremendous progress in the treatment of many cancer types, leading to a significant increase in survival, pancreatic ductal adenocarcinoma (PDAC) is still burdened with high mortality rates (5-year survival rate < 9%) due to late diagnosis, aggressiveness, and a lack of more effective treatment methods. Early diagnosis and new therapeutic approaches based on the adaptive metabolism of the tumor in a nutrient-deficient environment are expected to improve the future treatment of PDAC patients. It was found that blocking selected metabolic pathways related to the local adaptive metabolic activity of pancreatic cancer cells, improving nutrient acquisition and metabolic crosstalk within the microenvironment to sustain proliferation, may inhibit cancer development, increase cancer cell death, and increase sensitivity to other forms of treatment (e.g., chemotherapy). The present review highlights selected metabolic signaling pathways and their regulators aimed at inhibiting the neoplastic process. Particular attention is paid to the adaptive metabolism of pancreatic cancer, including fatty acids, autophagy, macropinocytosis, and deregulated cell-surface glycoproteins, which promotes cancer cell development in an oxygen-deficient and nutrient-poor environment.

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“…Approximately 10% of pancreatic cancers display PTEN deficiency. In KRAS-driven pancreatic cancer, PTEN deficiency appears to increase macropinocytosis via mTORC2 [20]. The WNT pathway is another driver of macropinocytosis [21].…”

Section: Editorialmentioning

confidence: 99%