[en] [en] UNLABELLED: The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS-MAPK inhibition.
SIGNIFICANCE: Reduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy-lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS-MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007.
Disciplines :
Oncology
Author, co-author :
Ravichandran, Mirunalini ; Department of Anatomy, University of California, San Francisco, San Francisco, California ; Department of Pathology, University of California, San Francisco, San Francisco, California
Hu, Jingjie ; Department of Anatomy, University of California, San Francisco, San Francisco, California ; Department of Pathology, University of California, San Francisco, San Francisco, California
Cai, Charles ; Department of Neurology, Institute for Human Genetics, University of California, San Francisco, San Francisco, California
Ward, Nathan P ; Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida
Venida, Anthony ; Department of Anatomy, University of California, San Francisco, San Francisco, California ; Department of Pathology, University of California, San Francisco, San Francisco, California
Foakes, Callum ; Department of Anatomy, University of California, San Francisco, San Francisco, California ; Department of Pathology, University of California, San Francisco, San Francisco, California
Kuljanin, Miljan ; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Yang, Annan ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Hennessey, Connor J ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Yang, Yang ; Department of Anatomy, University of California, San Francisco, San Francisco, California ; Department of Pathology, University of California, San Francisco, San Francisco, California
Desousa, Brandon R ; Department of Biochemistry, University of California, San Francisco, San Francisco, California ; Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, California
Rademaker, Gilles ; Department of Anatomy, University of California, San Francisco, San Francisco, California ; Department of Pathology, University of California, San Francisco, San Francisco, California
Staes, Annelot A L ; Department of Anatomy, University of California, San Francisco, San Francisco, California ; Department of Pathology, University of California, San Francisco, San Francisco, California
Cakir, Zeynep ; Department of Anatomy, University of California, San Francisco, San Francisco, California ; Department of Pathology, University of California, San Francisco, San Francisco, California
Jain, Isha H ; Department of Biochemistry, University of California, San Francisco, San Francisco, California ; Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, California
Aguirre, Andrew J ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Mancias, Joseph D ; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Shen, Yin ; Department of Neurology, Institute for Human Genetics, University of California, San Francisco, San Francisco, California
DeNicola, Gina M ; Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida
Perera, Rushika M ; Department of Anatomy, University of California, San Francisco, San Francisco, California ; Department of Pathology, University of California, San Francisco, San Francisco, California ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer.
Publication date :
02 September 2022
Journal title :
Cancer Discovery
ISSN :
2159-8274
eISSN :
2159-8290
Publisher :
American Association for Cancer Research Inc., United States
Volume :
12
Issue :
9
Pages :
2198 - 2219
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
NIH. NCI - National Institutes of Health. National Cancer Institute
Funding text :
This work was supported by NCI grants R01CA240603 and R01CA260249, a Damon Runyon-Rachleff Innovation Award, NIH Director\u2019s New Innovator Award (DP2CA216364), the Shorenstein Fund, the Helen Diller Family Comprehensive Cancer Center, and the Ed Marra Passion to Win Fund (to R.M. Perera); NCI grant R37CA230042 (to G.M. DeNicola); and the Lustgarten Foundation, Dana-Farber Cancer Institute Hale Family Center for Pancreatic Cancer Research, the Doris Duke Charitable Foundation, the Pancreatic Cancer Action Network, and NIH/NCI K08 CA21842002 and P50CA127003 (to A.J. Aguirre). We thank Hani Goodarzi and Sohit Miglani for advice on ChIP-seq analysis as well as Suprit Gupta and Grace Hernandez for technical assistance. We thank Lenka Maliskova and Walter L. Eckalbar from the UCSF Genomics CoLab for assistance with RNA-seq and ChIP-seq library preparations.
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