Evidence map›Paper›PMID 28178232›Full record

ArticleNature2017

Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer.

Giannicola Genovese, Alessandro Carugo, James Tepper, Frederick Scott Robinson, Liren Li, Maria Svelto, Luigi Nezi, Denise Corti, Rosalba Minelli, Piergiorgio Pettazzoni and 33 more

Erratum issuedOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 91 papers.

0numbers the graph read from it
0cells of the map it votes in
91citing papers in PubMed
7.2field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

91 citing papers in PubMed, 128 citations in OpenAlex.

  1. Trial
  2. Overcoming Adaptive Resistance to KRASG12D Blockade in Pancreatic Cancer through Vertical Pathway Inhibition.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
    Article
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  18. Acquired resistance to molecularly targeted therapies for cancer.Cancer drug resistance (Alhambra, Calif.) · 2025
    Review
  19. Article
  20. Article

31 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

43 authors at 6 institutions in 4 countries.

Giannicola GenoveseDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Alessandro CarugoDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
James TepperDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Frederick Scott RobinsonDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Liren LiDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Maria SveltoDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Luigi NeziDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Denise CortiDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Rosalba MinelliDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Piergiorgio PettazzoniDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Tony GutschnerDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Chia-Chin WuDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Sahil SethDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Kadir Caner AkdemirDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Elisabetta LeoInstitute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Samirkumar AminDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Marco Dal MolinDepartment of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Haoqiang YingDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Lawrence N KwongDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Simona CollaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Koichi TakahashiDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Papia GhoshOffice of Technology Commercialization, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Virginia GiulianiInstitute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Florian MullerDepartment of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Prasenjit DeyDepartment of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Shan JiangDepartment of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jill GarveyInstitute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Chang-Gong LiuDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jianhua ZhangInstitute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Timothy P HeffernanInstitute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Carlo ToniattiORBIT Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jason B FlemingDepartment of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Michael G GogginsDepartment of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Laura D WoodDepartment of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Alessandro SgambatoIstituto di Patologia Generale, Universitá Cattolica del Sacro Cuore, Rome 00168, Italy.
Abbas AgaimyDepartment of Pathology, Friedrich Alexander University Erlangen-Nuremberg, University Hospital, Erlangen 91054, Germany.
Anirban MaitraDepartment of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Charles W M RobertsComprehensive Cancer Center and Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 77027, USA.
Huamin WangDepartment of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Andrea VialeDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ronald A DePinhoDepartment of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Giulio F DraettaDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Lynda ChinDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
The University of Texas MD Anderson Cancer Center · USJohns Hopkins University · USCancer Research Center · USFriedrich-Alexander-Universität Erlangen-Nürnberg · DESt. Jude Children's Research Hospital · USUniversità Cattolica del Sacro Cuore · IT

Funding

Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Fabien Delerue · 1985 to 2026
$290.8M
Tumor Antigens for Individual Signatures and TherapyP50CA062924 · NCI · JOHNS HOPKINS UNIVERSITY · PI JAFFEE, ELIZABETH M. · 1993 to 2022
$54.6M
Uses of GEM models for Translational Cancer ResearchU01CA141508 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI CHIN, LYNDA · 2009 to 2013
$3.9M
Targeting Malic Enzyme 3 as a Synthetic Lethality Target in Pancreatic CancerR00CA218891 · NCI · ROSWELL PARK CANCER INSTITUTE CORP · PI DEY, PRASENJIT · 2019 to 2021
$747k
Targeting malic enzyme 3 as a synthetic lethality target in pancreatic cancerK99CA218891 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DEY, PRASENJIT · 2018 to 2019
$171k
National Institute of Health 5 U01 CA141508NCI NIH HHS K99 CA218891NCI NIH HHS P30 CA016672NCI NIH HHS P50 CA062924NCI NIH HHS R00 CA218891NCI NIH HHS U01 CA141508
6 · The paper itself

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.

Indexed as

AnimalsCarcinoma, Pancreatic DuctalDeoxycytidineEndoplasmic Reticulum StressFemaleGemcitabineGenes, mycGenes, rasHumansMaleMAP Kinase Kinase 4MAP Kinase Signaling SystemMesodermMiceMosaicismOncogene Protein p55(v-myc)DeoxycytidineGemcitabineMAP2K4 protein, humanMAP Kinase Kinase 4Oncogene Protein p55(v-myc)Proto-Oncogene Proteins p21(ras)SMARCB1 ProteinSmarcb1 protein, mouse

Identifiers

PMID28178232
PMCPMC7609022
OpenAlexW2586537166

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.