EGFR-Pak signaling selectively regulates glutamine deprivation-induced macropinocytosis
Open accessAbstract
Macropinocytosis has emerged as an important nutrient-scavenging pathway that supports tumor cell fitness. By internalizing extracellular protein and targeting it for lysosomal degradation, this endocytic pathway functions as an amino acid supply route, permitting tumor cell growth and survival despite the nutrient-poor conditions of the tumor microenvironment. Here, we provide evidence that a subset of pancreatic ductal adenocarcinoma (PDAC) tumors are wired to integrate contextual metabolic inputs to regulate macropinocytosis, dialing up or down this uptake pathway depending on nutrient availability. We find that regional depletion of amino acids coincides with increased levels of macropinocytosis and that the scarcity of glutamine uniquely drives this process. Mechanistically, this stimulation of macropinocytosis depends on the nutrient stress-induced potentiation of epidermal growth factor receptor signaling that, through the activation of Pak, controls the extent of macropinocytosis in these cells. These results provide a mechanistic understanding of how nutritional cues can control protein scavenging in PDAC tumors.
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Macropinocytosis utilizes necrotic cell debris as a fuel source, providing sugars, fatty acids, nucleotides, and amino acids to fuel cancer cell metabolism.
“Macropinocytosis has also been shown to utilize necrotic cell debris as a fuel source, which can provide sugars, fatty acids, nucleotides, and amino acids to fuel cancer cell metabolism233,234.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [234]
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- Authors
- Lee, S.-W., Zhang, Y., Jung, M., Cruz, N., Alas, B., & Commisso, C.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Commisso, Cosimo
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 50
- Issue
- 3
- Pages
- 381-392.e5
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC6684838
- OpenAlex
- W2955844551
- Cited by
- 172
- References
- 49
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 23 · 2023: 25 · 2022: 29 · 2021: 26 · 2020: 20 · 2019: 4
- FWCI
- 10.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01CA207189)
- National Cancer Institute (P30CA030199, US 2018/0335420 A1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- macropinocytosis, glutamine deprivation, EGFR signaling, pancreatic ductal adenocarcinoma, nutritional stress, tumor microenvironment, lysosomal degradation, cancer metabolism
- MeSH terms
- Animals, Female, Glutamine, Humans, Lysosomes, Mice, Nude, Pancreatic Neoplasms, Pinocytosis, Signal Transduction, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice, p21-Activated Kinases, ErbB Receptors
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