Dr Rushika Perera
Associate Professor, School of Medicine, Department of Anatomy
Member, Helen Diller Family Comprehensive Cancer Center University of California, San Francisco
Rushika Perera is an Associate Professor in the Dept. of Anatomy, with appointments in the Dept. of Pathology and the Helen Diller Family Comprehensive Cancer Center.
She received her PhD from the University of Melbourne in Australia and conducted a part of her graduate training at Yale university before completing postdoctoral training at Massachusetts General hospital and Harvard Medical School in Boston.
Dr. Perera’s laboratory focuses on understanding how trafficking pathways such as autophagy co-operate with the lysosome – a degradative organelle – to enable metabolic and cellular adaptation to stress and contributes to the pathogenesis of pancreatic ductal adenocarcinoma.
She is the recipient of the NIH Director’s New Innovator Award, the Damon Runyon-Rachleff Innovation Award, an AACR-Pancreatic cancer action network career development award and most recently was selected as the 2021 Gunter Blobel Early Career Award winner of the American Society for Cell Biology.
Unravelling autophagy-lysosome dependent adaptations to stress in pancreatic cancer
The metabolic adaptations that enable pancreatic ductal adenocarcinoma (PDA) cells to overcome pharmacological inhibition of KRAS-MAPK signalling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor, Trametinib (MEKi), 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 co-occupy 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 gene expression and biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered MiT/TFE-driven reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi treated cells. MiT/TFE-dependent ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enables metabolic reprogramming, including 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.