biostudies-literatureRavichandran MNCINIDDK NIH HHSNCI NIH HHSNIH Director’s New Innovator AwardNIGMS NIH HHSNIH NCI2198-2219https://www.ebi.ac.uk/biostudies/studies/S-EPMC9444964biostudies-literatureUnknown12(9)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 seleCancer discoveryCoordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer.PMC9444964K08 CA21842002R37 CA230042R37CA230042K08 CA218420DP2CA216364R01 DK124384T32 GM136547R01CA240603R01 CA240603R01CA260249P50CA127003P50 CA127003R01 CA260249DP2 CA216364Kuljanin MHennessey CJStaes AALPerera RMYang ACakir ZVenida ADesousa BRJain IHMancias JDCai CYang YHu JDeNicola GMRavichandran MFoakes CRademaker GShen YAguirre AJWard NPfalseCoordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer.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 sele2022-01-01T00:00:00Z2022 Sep2026-05-29T00:04:10.756Z2025-04-07T05:08:24.111ZS-EPMC94449643577149410.1158/2159-8290.cd-22-004410.1158/2159-8290.CD-22-0044