TY - JOUR
T1 - Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer
AU - Genovese, Giannicola
AU - Carugo, Alessandro
AU - Tepper, James
AU - Robinson, Frederick Scott
AU - Li, Liren
AU - Svelto, Maria
AU - Nezi, Luigi
AU - Corti, Denise
AU - Minelli, Rosalba
AU - Pettazzoni, Piergiorgio
AU - Gutschner, Tony
AU - Wu, Chia Chin
AU - Seth, Sahil
AU - Akdemir, Kadir Caner
AU - Leo, Elisabetta
AU - Amin, Samirkumar
AU - Molin, Marco Dal
AU - Ying, Haoqiang
AU - Kwong, Lawrence N.
AU - Colla, Simona
AU - Takahashi, Koichi
AU - Ghosh, Papia
AU - Giuliani, Virginia
AU - Muller, Florian
AU - Dey, Prasenjit
AU - Jiang, Shan
AU - Garvey, Jill
AU - Liu, Chang Gong
AU - Zhang, Jianhua
AU - Heffernan, Timothy P.
AU - Toniatti, Carlo
AU - Fleming, Jason B.
AU - Goggins, Michael G.
AU - Wood, Laura D.
AU - Sgambato, Alessandro
AU - Agaimy, Abbas
AU - Maitra, Anirban
AU - Roberts, Charles W.M.
AU - Wang, Huamin
AU - Viale, Andrea
AU - DePinho, Ronald A.
AU - Draetta, Giulio F.
AU - Chin, Lynda
N1 - Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2017/2/16
Y1 - 2017/2/16
N2 - 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.
AB - 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.
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U2 - 10.1038/nature21064
DO - 10.1038/nature21064
M3 - Article
C2 - 28178232
AN - SCOPUS:85014650754
SN - 0028-0836
VL - 542
SP - 362
EP - 366
JO - Nature
JF - Nature
IS - 7641
ER -