Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer.
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.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Giannicola
G
Genovese
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|European Institute of Oncology, Milano 20141, Italy.
Alessandro
A
Carugo
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
James
J
Tepper
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Frederick Scott
FS
Robinson
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.
Liren
L
Li
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Istituto di Patologia Generale, Universitá Cattolica del Sacro Cuore, Rome 00168, Italy.
Maria
M
Svelto
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Luigi
L
Nezi
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Denise
D
Corti
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Rosalba
R
Minelli
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Piergiorgio
P
Pettazzoni
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Tony
T
Gutschner
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Chia-Chin
CC
Wu
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Sahil
S
Seth
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Kadir Caner
KC
Akdemir
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Elisabetta
E
Leo
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Graduate program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Samirkumar
S
Amin
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Marco Dal
MD
Molin
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Haoqiang
H
Ying
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Lawrence N
LN
Kwong
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Simona
S
Colla
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Koichi
K
Takahashi
Office of Technology Commercialization, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Papia
P
Ghosh
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Virginia
V
Giuliani
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Florian
F
Muller
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Prasenjit
P
Dey
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Shan
S
Jiang
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jill
J
Garvey
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Chang-Gong
CG
Liu
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jianhua
J
Zhang
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Timothy P
TP
Heffernan
ORBIT Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Carlo
C
Toniatti
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jason B
JB
Fleming
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Michael G
MG
Goggins
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Laura D
LD
Wood
Istituto di Patologia Generale, Universitá Cattolica del Sacro Cuore, Rome 00168, Italy.
Alessandro
A
Sgambato
Department of Pathology, Friedrich Alexander University Erlangen-Nuremberg, University Hospital, Erlangen 91054, Germany.
Abbas
A
Agaimy
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Anirban
A
Maitra
Comprehensive Cancer Center and Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 77027, USA.
Charles W M
CW
Roberts
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Huamin
H
Wang
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Andrea
A
Viale
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ronald A
RA
DePinho
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Giulio F
GF
Draetta
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Lynda
L
Chin
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D016259:Genes, myc; D011905:Genes, ras; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009030:Mosaicism; D016274:Oncogene Protein p55(v-myc) / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D059748:Proteolysis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D000071796:SMARCB1 Protein / Q000172:deficiency / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D000093542:Gemcitabine
D016274:Oncogene Protein p55(v-myc); D000071796:SMARCB1 Protein; C513265:Smarcb1 protein, mouse; D003841:Deoxycytidine; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine