Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer. Genovese, G., Carugo, A., Li, L., Robinson, F., Svelto, M., Pettazzoni, P., Nezi, L., Wu, C. C., Seth, S., Akdemir, K., Tepper, J., Leo, E., Amin, S. B., Gutschner, T., Marco Dal Molin, H. Y., Depinho, R., Goggins, M., Agaimy, A., & Chin, L. Nature, February, 2017. doi abstract bibtex Malignant neoplasms evolve in response to changes in oncogenic signalling. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α-MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.
@article{Genovese_synthetic_2016,
title = {Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer},
abstract = {Malignant neoplasms evolve in response to changes in oncogenic signalling. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α-MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.},
issn = {1538-7445},
volume = {Accepted},
language = {ENG},
journal = {Nature},
author = {Genovese, Giannicola and Carugo, Alessandro and Li, Liren and Robinson, Frederick and Svelto, Maria and Pettazzoni, Piergiorgio and Nezi, Luigi and Wu, Chia Chin and Seth, Sahil and Akdemir, Kadir and Tepper, James and Leo, Elisabetta and Amin, Samirkumar B. and Gutschner, Tony and Marco Dal Molin, Haoqiang Ying, Lawrence Kwong, Simona Colla, Koichi Takahashi, Denise Corti, Virginia Giuliani, Florian Muller, Shan Jiang, Jill Garvey, Chang-Gong Liu, John Zhang, Timothy Heffernan, Carlo Toniatti, Jason Fleming, Andrea Viale, Laura Wood, Alessandro Sgambato, Anirban Maitra, Charles Roberts, Huamin Wang, Giulio Draetta, Rosalba Minelli, Prasenjit Dey, Papia Ghosh and Depinho, Ronald and Goggins, Michael and Agaimy, Abbas and Chin, Lynda},
month = feb,
year = {2017},
doi = "10.1038/nature21064",
pmid = "28178232",
authorclass = {coauthor},
contribution = {data\_analysis, interpretation},
affiliation = {BCM, MDANDERSON}
}
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Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α-MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. 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