KRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL

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 drop...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2020-11, Vol.80 (22), p.4932-4945
Main Authors: Rozeveld, Cody N, Johnson, Katherine M, Zhang, Lizhi, Razidlo, Gina L
Format: Article
Language:English
Subjects:
Humans
Lipase - genetics
Lipid Metabolism - genetics
Lipids
Male
Pancreatic Neoplasms - genetics
Proto-Oncogene Proteins p21(ras) - genetics
Sterol Esterase - genetics
Sterol Esterase - metabolism
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Summary: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 and metastasis . 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. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-20-1255