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Metabolic shifts in residual breast cancer drive tumor recurrence
Kristina M. Havas, … , Rocio Sotillo, Martin Jechlinger
Kristina M. Havas, … , Rocio Sotillo, Martin Jechlinger
Published May 15, 2017
Citation Information: J Clin Invest. 2017;127(6):2091-2105. https://doi.org/10.1172/JCI89914.
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Research Article Metabolism Oncology

Metabolic shifts in residual breast cancer drive tumor recurrence

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Abstract

Tumor recurrence is the leading cause of breast cancer–related death. Recurrences are largely driven by cancer cells that survive therapeutic intervention. This poorly understood population is referred to as minimal residual disease. Here, using mouse models that faithfully recapitulate human disease together with organoid cultures, we have demonstrated that residual cells acquire a transcriptionally distinct state from normal epithelium and primary tumors. Gene expression changes and functional characterization revealed altered lipid metabolism and elevated ROS as hallmarks of the cells that survive tumor regression. These residual cells exhibited increased oxidative DNA damage, potentiating the acquisition of somatic mutations during hormonal-induced expansion of the mammary cell population. Inhibition of either cellular fatty acid synthesis or fatty acid transport into mitochondria reduced cellular ROS levels and DNA damage, linking these features to lipid metabolism. Direct perturbation of these hallmarks in vivo, either by scavenging ROS or by halting the cyclic mammary cell population expansion, attenuated tumor recurrence. Finally, these observations were mirrored in transcriptomic and histological signatures of residual cancer cells from neoadjuvant-treated breast cancer patients. These results highlight the potential of lipid metabolism and ROS as therapeutic targets for reducing tumor recurrence in breast cancer patients.

Authors

Kristina M. Havas, Vladislava Milchevskaya, Ksenija Radic, Ashna Alladin, Eleni Kafkia, Marta Garcia, Jens Stolte, Bernd Klaus, Nicole Rotmensz, Toby J. Gibson, Barbara Burwinkel, Andreas Schneeweiss, Giancarlo Pruneri, Kiran R. Patil, Rocio Sotillo, Martin Jechlinger

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Figure 3

Increased lipid metabolism as underlining hallmark of the regressed population.

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Increased lipid metabolism as underlining hallmark of the regressed popu...
(A) Schematic illustrating major deregulated lipid metabolism pathways and overexpressed genes (red) in the regressed populations versus the never-induced population. (B) Western blots of replicate samples run on multiple gels for several lipid metabolic genes: FASN, SREBP1, and 5 members of the mitochondrial respiratory chain complex (CI-V). Lysates of mammary glands isolated from control, MYC/KRAS, and MYC/NEU regressed mice; replicate samples were run on parallel gels; loading control, α-tubulin. (C) IHC of control and regressed mammary glands for FASN. Scale bar: 50 μm. (D) Nile red staining of lipid droplets in in vitro–cultured regressed structures from MYC/KRAS and MYC/NEU and never-induced structures. Scale bar: 14 μm. Quantification of lipid droplets was performed for n = 3 MYC/KRAS and MYC/NEU regressed, and n = 4 never-induced structures. Ex., excitation; Em., emission. MYC/KRAS vs. MYC/NEU (P = 0.75), never-induced vs. MYC/KRAS (P = 0.0017), and never-induced vs. MYC/NEU (P = 0.0025); 2 tailed t tests. (E) IHC for lipid droplet associated protein adipophilin in regressed mammary glands vs. controls. Scale bar: 50 μm. (F) Schematic illustrating assay for mitochondrial palmitate oxidative flux using 1-14C Palmitate (left). 1-14C-Palmitate provides a tractable carbon source for β-oxidative processing, with the read-out being the acid soluble metabolite (ASM) 14C-Acetyl-CoA and 14C-labeled CO2 produced by the TCA cycle. (G) Measurements of ASM and CO2 produced in mitochondria isolated from age-matched control, MYC/KRAS, and MYC/NEU regressed mice; values are normalized against total protein concentration (right). CO2 measurements: MYC/KRAS vs. control (P = 0.0235) and MYC/NEU vs. control (P = 0.0489), for ASM measurements: MYC/KRAS vs. control (P < 0.0001) and MYC/NEU vs. control (P < 0.0001). Represented for n = 3 control, n = 4 MYC/KRAS and MYC/NEU biological replicates; one-way ANOVA with Dunnett’s multiple comparison test. Data represented as mean ± SEM; *P < 0.05, ****P < 0.0001

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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