Metabolic shifts in residual breast cancer drive tumor recurrence

The Journal of Clinical Investigation
Kristina M HavasMartin Jechlinger

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...Continue Reading

References

Apr 1, 1994·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·J BorgerH Bartelink
Jan 1, 1993·Epidemiologic Reviews·J L KelseyE M John
Apr 23, 2003·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·C VrielingUNKNOWN EORTC Radiotherapy, Breast Cancer Groups
Jun 26, 2003·JAMA : the Journal of the American Medical Association·Rowan T ChlebowskiUNKNOWN WHI Investigators
Feb 14, 2004·Lancet·L HolmbergUNKNOWN HABITS steering and data monitoring committees
Feb 16, 2005·Proceedings of the National Academy of Sciences of the United States of America·Kiran Raosaheb Patil, Jens Nielsen
Jan 6, 2006·Nature·John StinglConnie J Eaves
Jan 7, 2006·Nature·Mark ShackletonJane E Visvader
Oct 6, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bas KreikeMarc J van de Vijver
Dec 2, 2006·Science·Aleksandra Jovanovic PooleEva Y-H P Lee
Sep 21, 2007·Nature Reviews. Cancer·Javier A Menendez, Ruth Lupu
Oct 25, 2007·Nature Reviews. Cancer·Julio A Aguirre-Ghiso
Mar 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·Katrina PodsypaninaHarold E Varmus
Apr 7, 2010·PLoS Computational Biology·Aleksej ZelezniakKiran Raosaheb Patil
May 7, 2010·Nature·Purna A JoshiRama Khokha
Sep 16, 2010·Free Radical Biology & Medicine·Simone ReuterBharat B Aggarwal
Dec 15, 2010·Current Opinion in Genetics & Development·Christoph A Klein
Dec 24, 2010·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Sarah NechutaXiao Ou Shu
Jan 25, 2011·Nature Reviews. Cancer·Rob A CairnsTak W Mak
Jan 26, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Katerina Politi, William Pao
Jan 12, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ana M Gonzalez-AnguloLajos Pusztai
Jun 14, 2012·The Biochemical Journal·Guohui WangKezhong Zhang
Aug 16, 2012·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Mia FahlénEva von Schoultz
Mar 5, 2013·Nature Biotechnology·Ines ThieleBernhard Ø Palsson
Sep 13, 2013·Journal of Oncology·Simon P GampenriederRichard Greil
Nov 10, 2013·Disease Models & Mechanisms·Franziska BaenkeAlmut Schulze
Nov 14, 2013·Nature Reviews. Molecular Cell Biology·Abdou Rachid ThiamTobias C Walther

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Citations

Feb 16, 2018·Journal of Mammary Gland Biology and Neoplasia·Martin JechlingerMaria dM Vivanco
Aug 17, 2018·Bioscience Reports·Peter ShyuGuillaume Thibault
Apr 16, 2019·Advanced Healthcare Materials·Fei GaoHai Ming Fan
Dec 9, 2017·Cell Research·Paolo Ettore PorporatoLorenzo Galluzzi
Nov 30, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Caijun WuChuanlin Ding
Feb 18, 2020·International Journal of Cancer. Journal International Du Cancer·Bernhard EnglingerWalter Berger
Jul 3, 2018·Oncotarget·Elizabeth A BrettDominik Duscher
May 1, 2018·Current Medicinal Chemistry·Camille AttanéCatherine Muller
Jan 4, 2019·Journal of Biological Engineering·Shantanu PradhanJohn H Slater
Mar 27, 2020·Frontiers in Oncology·Maria Andrea DesbatsMonica Montopoli
Jul 18, 2018·International Journal of Oncology·Silvia Jiménez-MoralesAlfredo Hidalgo-Miranda
Jan 8, 2020·Journal of Clinical Medicine·Benjamin J HersheyKristina M Havas
Apr 5, 2018·Frontiers in Oncology·Amit S YadavDhiraj Kumar
Sep 6, 2018·Breast Cancer Research : BCR·Zuzana KoledovaEva Gonzalez-Suarez
Mar 19, 2020·Frontiers in Oncology·Luigi IppolitoMatteo Parri
Apr 18, 2020·Frontiers in Oncology·Matthias LäscheCarsten Gründker
Jun 24, 2017·Nature Reviews. Cancer·Anna Dart
Dec 15, 2019·Journal of Clinical Medicine·Eugeni Lopez-BonetJavier A Menendez
Feb 17, 2019·Archives of Pharmacal Research·Min-Kyue Shin, Jae-Ho Cheong
Aug 23, 2019·Cancers·Rana Jahanban-EsfahlanPeyman Zare
Oct 8, 2020·Nature Reviews. Cancer·Christoph A Klein
Jan 24, 2018·Cancer Immunology Research·Neidy V RodriguesSérgio Dias
Dec 29, 2020·Free Radical Biology & Medicine·Ali GhanemStefan Wölfl
Nov 19, 2019·Trends in Cancer·Barrie Peck, Almut Schulze
Dec 8, 2020·Trends in Cancer·Marina BacciAndrea Morandi
Nov 20, 2020·Journal of Mammary Gland Biology and Neoplasia·Jakub SumbalZuzana Koledova
Apr 27, 2021·Pharmacology & Therapeutics·Xiao-Yuan MaoWei-Lin Jin
Jul 11, 2021·Cellular Oncology (Dordrecht)·Michelle van der MerweAnna-Mart Engelbrecht
Jul 17, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Yefei YuDu Cheng
Aug 19, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yuting MaMinxin Shi
Jul 11, 2020·Cancer Cell·John D HayesKenneth D Tew
Aug 20, 2021·Pathology Oncology Research : POR·Yu HuaXiaobo Li

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Datasets Mentioned

BETA
E-MTAB-4632

Methods Mentioned

BETA
biopsies
FACS
RNA-seq
hormone replacement therapy

Clinical Trials Mentioned

NCT01898312

Software Mentioned

Bioconducter
ArrayExpress
Graph Pad Prism
GraphPad
Oligo
Gene Set Enrichment Analysis ( GSEA )

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