Systematic analysis of proteome turnover in an organoid model of pancreatic cancer by dSILO.
Alison B Ross, Darvesh Gorhe, Jenny Kim Kim, Stefanie Hodapp, Lela DeVine, Karina M Chan, Iok In Christine Chio, Marko Jovanovic, Marina Ayres Pereira
Author Information
Alison B Ross: Department of Biological Sciences, Columbia University, New York City, NY 10027, USA.
Darvesh Gorhe: Department of Biological Sciences, Columbia University, New York City, NY 10027, USA.
Jenny Kim Kim: Department of Biological Sciences, Columbia University, New York City, NY 10027, USA.
Stefanie Hodapp: Department of Biological Sciences, Columbia University, New York City, NY 10027, USA.
Lela DeVine: Department of Biology, Barnard College, New York, NY 10027, USA; Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
Karina M Chan: Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
Iok In Christine Chio: Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: ic2445@cumc.columbia.edu.
Marko Jovanovic: Department of Biological Sciences, Columbia University, New York City, NY 10027, USA. Electronic address: mj2794@columbia.edu.
Marina Ayres Pereira: Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: marinaayrespereira@gmail.com.
The role of protein turnover in pancreatic ductal adenocarcinoma (PDA) metastasis has not been previously investigated. We introduce dynamic stable-isotope labeling of organoids (dSILO): a dynamic SILAC derivative that combines a pulse of isotopically labeled amino acids with isobaric tandem mass-tag (TMT) labeling to measure proteome-wide protein turnover rates in organoids. We applied it to a PDA model and discovered that metastatic organoids exhibit an accelerated global proteome turnover compared to primary tumor organoids. Globally, most turnover changes are not reflected at the level of protein abundance. Interestingly, the group of proteins that show the highest turnover increase in metastatic PDA compared to tumor is involved in mitochondrial respiration. This indicates that metastatic PDA may adopt alternative respiratory chain functionality that is controlled by the rate at which proteins are turned over. Collectively, our analysis of proteome turnover in PDA organoids offers insights into the mechanisms underlying PDA metastasis.
