Open AccessKRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL
Author(s) -
Cody N. Rozeveld,
Katherine M. Johnson,
Lizhi Zhang,
Gina L. Razidlo
Publication year - 2020
Publication title -
cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.103
H-Index - 449
eISSN - 1538-7445
pISSN - 0008-5472
DOI - 10.1158/0008-5472.can-20-1255
Subject(s) - metastasis , lipid metabolism , kras , cancer research , lipid droplet , pancreatic cancer , oncogene , biology , cancer , cancer cell , cell , microbiology and biotechnology , endocrinology , medicine , cell cycle , biochemistry , colorectal cancer
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 .