The DOI matches its Crossref record; 18 of the 18 references it cites were found in a registry or an index.
KRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL
Open accessAbstract
Oncogene-induced metabolic reprogramming is a hallmark of pancreatic cancer (PDAC), yet the metabolic drivers of metastasis are unclear. In PDAC, obesity and excess fatty acids accelerate tumor growth and increase metastasis. Here, we report that excess lipids, stored in organelles called lipid droplets (LD), are a key resource to fuel the energy-intensive process of metastasis. The oncogene KRAS controlled the storage and utilization of LD through regulation of hormone-sensitive lipase (HSL), which was downregulated in human PDAC. Disruption of the KRAS–HSL axis reduced lipid storage, reprogrammed tumor cell metabolism, and inhibited invasive migration in vitro and metastasis in vivo. Finally, microscopy-based metabolic analysis revealed that migratory cells selectively utilize oxidative metabolism during the process of migration to metabolize stored lipids and fuel invasive migration. Taken together, these results reveal a mechanism that can be targeted to attenuate PDAC metastasis. Significance: KRAS-dependent regulation of HSL biases cells towards lipid storage for subsequent utilization during invasion of pancreatic cancer cells, representing a potential target for therapeutic intervention. See related commentary by Man et al., p. 4886
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Cites
Dynamics and functions of lipid droplets
Olzmann, J. A., & Carvalho, P. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0085-z · Cited by 2,740
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Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway
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Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
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Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
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Cited by
Lipid metabolism in cancer: New perspectives and emerging mechanisms
Broadfield, L. A., Pane, A. A., Talebi, A., Swinnen, J. V., & Fendt, S.-M. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.04.013 · Cited by 758
Lipid droplet biogenesis and functions in health and disease
Zadoorian, A., Du, X., & Yang, H. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00845-0 · Cited by 617
Wang, S., Zheng, Y., Yang, F., Zhu, L., Zhu, X.-Q., Wang, Z.-F., Wu, X.-L., Zhou, C.-H., Yan, J.-Y., Hu, B.-Y., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00659-4 · Cited by 369
Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer
Stefanoudakis, D., Frountzas, M., Schizas, D., Michalopoulos, N. V., Drakaki, A., & Toutouzas, K. G. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46040177 · Cited by 110
Ma, Y., Nenkov, M., Chen, Y., & Gaßler, N. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25158352 · Cited by 28
Metadata
- Authors
- Rozeveld, C. N., Johnson, K. M., Zhang, L., & Razidlo, G. L.
- Venue
- Cancer Research
- Published
- 2020-11-13
- Volume
- 80
- Issue
- 22
- Pages
- 4932-4945
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W3051499127
- Cited by
- 165
- References
- 18
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- green
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