Cited by 116Pancreatic and Hepatic Oncology ResearchCellular transport and secretionCancer, Hypoxia, and Metabolism

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Macropinocytosis in Cancer-Associated Fibroblasts Is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness

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Zhang, Yijuan, Recouvreux, M. Victoria, Jung, Michael, Galenkamp, Koen M.O., Li, Yunbo, Zagnitko, Olga, Scott, David A., Lowy, Andrew M., Commisso, Cosimo·2021·Cancer Discovery

DOI 10.1158/2159-8290.cd-20-0119PMC PMC8292164

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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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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
ORCID: Zhang, Yijuan
Galenkamp, Koen M.O.
Li, Yunbo
Scott, David A.
Lowy, Andrew M.
Commisso, Cosimo
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2021-03-02
Volume: 11
Issue: 7
Pages: 1808-1825
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-20-0119
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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Macropinocytosis in Cancer-Associated Fibroblasts Is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness

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