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Macropinocytosis in Cancer-Associated Fibroblasts Is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness
Open accessPublished version of a preprint
Abstract
Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is also operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer–associated fibroblasts (CAF). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca2+ and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has a dual function in CAFs—it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging. Significance: Glutamine deprivation drives stromal macropinocytosis to support CAF cell fitness and provide amino acids that sustain PDAC cell survival. Selective disruption of macropinocytosis in CAFs suppresses PDAC tumor growth. This article is highlighted in the In This Issue feature, p. 1601
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“Examination of metabolic exchange between pancreatic CAFs and cancer cells revealed that alanine is selectively released by fibroblasts and consumed by PDAC cells248.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [248]
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“The exchange of alanine and other non-essential amino acids from fibroblasts to promote PDAC metabolism is linked to both autophagy and macropinocytosis in the fibroblasts248,249”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [248]
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Metadata
- Authors
- Zhang, Y., Recouvreux, M. V., Jung, M., Galenkamp, K. M. O., Li, Y., Zagnitko, O., Scott, D. A., Lowy, A. M., & Commisso, C.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of California San Diego (US)
- Corresponding author
- Commisso, Cosimo
- Venue
- Cancer Discovery
- Published
- 2021-03-02
- Volume
- 11
- Issue
- 7
- Pages
- 1808-1825
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8292164
- OpenAlex
- W3134011831
- Cited by
- 116
- References
- 51
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 16 · 2023: 23 · 2022: 22 · 2021: 7
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01CA207189)
- NIH NCI (CA211036)
- NCI Cancer Center Support (P30CA030199)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- 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
- Keywords
- macropinocytosis, cancer-associated fibroblasts, pancreatic ductal adenocarcinoma, ARHGEF2, CAMKK2, AMPK signaling, glutamine deprivation, tumor microenvironment, nutrient scavenging, amino acid secretion, intracellular calcium, tumor stroma, tumor growth
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Humans, Mice, Inbred C57BL, Pancreatic Neoplasms, Pinocytosis, Signal Transduction, Stromal Cells, Carcinoma, Pancreatic Ductal, Mice, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Tumor Microenvironment, Rho Guanine Nucleotide Exchange Factors
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