Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes.

Abstract:

:Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC. SIGNIFICANCE: Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.See related commentary by Pickering and Morton, p. 1448.This article is highlighted in the In This Issue feature, p. 1426.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Miyabayashi K,Baker LA,Deschênes A,Traub B,Caligiuri G,Plenker D,Alagesan B,Belleau P,Li S,Kendall J,Jang GH,Kawaguchi RK,Somerville TDD,Tiriac H,Hwang CI,Burkhart RA,Roberts NJ,Wood LD,Hruban RH,Gillis J,Krasnitz

doi

10.1158/2159-8290.CD-20-0133

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

1566-1589

issue

10

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-20-0133

journal_volume

10

pub_type

杂志文章
  • Palmitoylation Alters STAT3 Activity and Tumor Response to High-Fat Diet.

    abstract::STAT3 palmitoylation increases dimerization, nuclear localization, and activation of target genes. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2019-139

    authors:

    更新日期:2019-09-06 00:00:00

  • Not expecting the unexpected: diacylglycerol kinase alpha as a cancer target.

    abstract::In this issue of Cancer Discovery, Dominguez and colleagues identify diacylglycerol kinase alpha (DGKα), an enzyme that converts the membrane lipid diacylglycerol to phosphatidic acid, as a central node upstream of mTOR and other oncogenic pathways. Importantly, targeting DGKα causes apoptosis in cancer cells and tumo...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-13-0244

    authors: Bhat KP,Aldape K

    更新日期:2013-07-01 00:00:00

  • A FATal Combination: Fibroblast-Derived Lipids and Cancer-Derived Autotaxin Promote Pancreatic Cancer Growth.

    abstract::In this issue of Cancer Discovery, Auciello and colleagues find that in the pancreatic cancer microenvironment activated fibroblasts secrete specific lipids that provide a source of biomass production and signaling molecules for cancer cells, fueling their proliferation and migration. Targeting of this stromal-tumor m...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-19-0273

    authors: Biffi G,Tuveson DA

    更新日期:2019-05-01 00:00:00

  • Genomic Screens Identify Genes That Regulate MHC-I Expression in DLBCL.

    abstract::MHC-I and MHC-II regulators in lymphomas, some of which had subtype or tumor specificity, were identified. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2020-178

    authors:

    更新日期:2020-12-11 00:00:00

  • Desmoid Tumors Respond to Sorafenib.

    abstract::A recent clinical trial shows that sorafenib is effective against desmoid tumors. The study found that 33% of tumors shrank in patients who received the drug. The estimated 1-year progression-free survival for the sorafenib-treated patients was 89%, and the 2-year rate was 81%. ...

    journal_title:Cancer discovery

    pub_type: 评论,新闻

    doi:10.1158/2159-8290.CD-NB2019-004

    authors:

    更新日期:2019-03-01 00:00:00

  • Evolutionary pathways in BRCA1-associated breast tumors.

    abstract::BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of t...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-11-0325

    authors: Martins FC,De S,Almendro V,Gönen M,Park SY,Blum JL,Herlihy W,Ethington G,Schnitt SJ,Tung N,Garber JE,Fetten K,Michor F,Polyak K

    更新日期:2012-06-01 00:00:00

  • ARID1A mutations in cancer: another epigenetic tumor suppressor?

    abstract:UNLABELLED:Although disordered chromatin organization has long been recognized as a feature of cancer, the molecular underpinnings of chromatin structure, epigenetic regulation, and their relationships to transcription are only beginning to be understood. Cancer genome sequencing studies have revealed a novel theme: fr...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-12-0361

    authors: Wu JN,Roberts CW

    更新日期:2013-01-01 00:00:00

  • Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival.

    abstract:UNLABELLED:Alterations in metabolic activity contribute to the proliferation and survival of cancer cells. We investigated the effect of siRNA-mediated gene silencing of 222 metabolic enzymes, transporters, and regulators on the survival of 3 metastatic prostate cancer cell lines and a nonmalignant prostate epithelial ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-11-0234

    authors: Ros S,Santos CR,Moco S,Baenke F,Kelly G,Howell M,Zamboni N,Schulze A

    更新日期:2012-04-01 00:00:00

  • Q&A: Mitchell Zeller on the FDA and tobacco.

    abstract::By law, the U.S. Food and Drug Administration has the authority, through its Center for Tobacco Products, to regulate the manufacture, marketing, and distribution of tobacco products. Its director, Mitchell Zeller, JD, talks about how the center, though its research, public education, and enforcement activities, aims ...

    journal_title:Cancer discovery

    pub_type: 面试

    doi:10.1158/2159-8290.CD-ND2013-028

    authors: Zeller M,Rose S

    更新日期:2014-01-01 00:00:00

  • Antibody-Drug Conjugate Kills Neuroblastoma Cells.

    abstract::Researchers have developed an antibody-drug conjugate with the potential to treat neuroblastoma. The agent targets ALK, which is found on neuroblastoma cells but not healthy cells, delivering a drug that causes DNA cross-links. Researchers have found that the antibody-drug conjugate kills ALK-expressing cells in vitro...

    journal_title:Cancer discovery

    pub_type: 评论,新闻

    doi:10.1158/2159-8290.CD-NB2019-052

    authors:

    更新日期:2019-06-01 00:00:00

  • Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine.

    abstract:UNLABELLED:The relationships between telomerase and telomeres represent attractive targets for new anticancer agents. Here, we report that the nucleoside analogue 6-thio-2'-deoxyguanosine (6-thio-dG) is recognized by telomerase and is incorporated into de novo-synthesized telomeres. This results in modified telomeres, ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-14-0609

    authors: Mender I,Gryaznov S,Dikmen ZG,Wright WE,Shay JW

    更新日期:2015-01-01 00:00:00

  • Novel Mitochondrial Mechanisms of Cytarabine Resistance in Primary AML Cells.

    abstract:: Farge and colleagues describe a novel in vivo approach to identify and study primary acute myeloid leukemia (AML) cells that persist in the marrow after chemotherapy. They discovered that AML cells that persist in the mouse marrow after treatment with cytarabine have increased oxidative phosphorylation and that i...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-17-0476

    authors: Schimmer AD

    更新日期:2017-07-01 00:00:00

  • Capecitabine Extends Survival for Biliary Tract Cancer.

    abstract::Based on results of the phase III BILCAP study, adjuvant capecitabine should become standard treatment for patients with biliary tract cancer. Among 430 patients who were treated according to the study protocol, capecitabine was associated with a 25% lower risk of death than observation. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-079

    authors:

    更新日期:2017-07-01 00:00:00

  • RAS Mutations Are Not Created Equal.

    abstract::In this issue of Cancer Discovery, Poulin and colleagues apply structural, biochemical, and biological profiling of two mutants of KRAS, one found most frequently in all cancers (G12D) and one found nearly exclusively in colorectal cancer (A146T). They provide compelling evidence that specific mutations will impart di...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-19-0406

    authors: Hobbs GA,Der CJ

    更新日期:2019-06-01 00:00:00

  • Global Cost of Smoking Passes $1 Trillion.

    abstract::A new report from the World Health Organization and the NCI estimates that the worldwide cost of smoking-due to health problems and lost productivity-exceeds $1 trillion annually, with the biggest economic burden falling on low- and middle- income countries. That's because proven interventions, such as tax and price i...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-014

    authors:

    更新日期:2017-03-01 00:00:00

  • Forty years of translational cancer research.

    abstract::Forty years after the signing of the National Cancer Act, we have produced a stunning repository of scientific information that is being translated into better therapies for patients. Although challenges remain, many solutions have been adopted, leading to early signs of progress against some of humankind's most dread...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-11-0196

    authors: Hait WN

    更新日期:2011-10-01 00:00:00

  • Recurrent Fusions in MYB and MYBL1 Define a Common, Transcription Factor-Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma.

    abstract:UNLABELLED:Adenoid cystic carcinoma (ACC), the second most common malignancy of salivary glands, is a rare tumor with a bleak prognosis for which therapeutic targets are unavailable. We used RNA sequencing (RNA-seq) to analyze low-quality RNA from archival, formaldehyde-fixed, paraffin-embedded samples. In addition to ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-15-0859

    authors: Brayer KJ,Frerich CA,Kang H,Ness SA

    更新日期:2016-02-01 00:00:00

  • Combo Therapy for Lung Cancer Extends Survival.

    abstract::The PD-1 inhibitor pembrolizumab in combination with chemotherapy may be an effective therapy for patients with newly diagnosed advanced non-squamous non-small cell lung cancer. In a clinical trial, patients who received the combination had an estimated 12-month overall survival rate of 69.2%, compared with 49.4% in p...

    journal_title:Cancer discovery

    pub_type: 评论,新闻

    doi:10.1158/2159-8290.CD-NB2018-051

    authors:

    更新日期:2018-06-01 00:00:00

  • Engineering Multidimensional Evolutionary Forces to Combat Cancer.

    abstract::With advances in technology and bioinformatics, we are now positioned to view and manage cancer through an evolutionary lens. This perspective is critical as our appreciation for the role of tumor heterogeneity, tumor immune compartment, and tumor microenvironment on cancer pathogenesis and evolution grows. Here, we e...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-18-1196

    authors: McCoach CE,Bivona TG

    更新日期:2019-05-01 00:00:00

  • Cancer "Clock" Opens New Therapeutic Avenues.

    abstract::Long ignored, the importance of circadian rhythms-the focus of this year's Nobel Prize in Physiology or Medicine-is beginning to gain attention from researchers interested in cancer prevention, drug discovery, and therapeutic optimization. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-149

    authors:

    更新日期:2017-12-01 00:00:00

  • Targeting HDAC And PI3K Inhibits MYC-Driven Medulloblastoma Growth.

    abstract::HDAC inhibitors synergize with PI3K inhibitors to reduce MYC-driven medulloblastoma (MB) growth. ...

    journal_title:Cancer discovery

    pub_type: 评论,信件

    doi:10.1158/2159-8290.CD-RW2016-052

    authors:

    更新日期:2016-05-01 00:00:00

  • Proteomics Sharpens Brain Tumor Genomic Analysis.

    abstract::A recent study integrating proteomic and genomic analyses uncovered unexpected similarities in some types of pediatric brain tumors, such as certain craniopharyngiomas and low-grade gliomas, suggesting potential treatments and more refined prognoses. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2020-119

    authors:

    更新日期:2021-01-07 00:00:00

  • Measuring oncogenic signaling pathways in cancer with PET: an emerging paradigm from studies in castration-resistant prostate cancer.

    abstract:UNLABELLED:As parallel advances in cancer biology and drug development continue to elevate the role of targeted therapies in oncology, the need for imaging biomarkers that systematically measure the biology associated with therapeutic intervention has become more urgent. Although the molecular imaging community has a c...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-12-0178

    authors: Evans MJ

    更新日期:2012-11-01 00:00:00

  • Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis.

    abstract::Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abunda...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-18-0567

    authors: Carrer A,Trefely S,Zhao S,Campbell SL,Norgard RJ,Schultz KC,Sidoli S,Parris JLD,Affronti HC,Sivanand S,Egolf S,Sela Y,Trizzino M,Gardini A,Garcia BA,Snyder NW,Stanger BZ,Wellen KE

    更新日期:2019-03-01 00:00:00

  • Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma.

    abstract::MYC is implicated in the development and progression of pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumor development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arisin...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-19-0620

    authors: Muthalagu N,Monteverde T,Raffo-Iraolagoitia X,Wiesheu R,Whyte D,Hedley A,Laing S,Kruspig B,Upstill-Goddard R,Shaw R,Neidler S,Rink C,Karim SA,Gyuraszova K,Nixon C,Clark W,Biankin AV,Carlin LM,Coffelt SB,Sansom OJ,

    更新日期:2020-06-01 00:00:00

  • Patient-derived xenograft models: an emerging platform for translational cancer research.

    abstract:UNLABELLED:Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have ...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-14-0001

    authors: Hidalgo M,Amant F,Biankin AV,Budinská E,Byrne AT,Caldas C,Clarke RB,de Jong S,Jonkers J,Mælandsmo GM,Roman-Roman S,Seoane J,Trusolino L,Villanueva A

    更新日期:2014-09-01 00:00:00

  • Clonal evolution: multiregion sequencing of esophageal adenocarcinoma before and after chemotherapy.

    abstract::It is possible to decipher the clonal architecture of a tumor and the sequence in which cancer clones acquire genomic alterations through multiregion sequencing (M-seq). Serial evaluation of tumor specimens through M-seq can provide valuable information on the molecular basis of resistance to therapy. ...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-15-0739

    authors: Devarakonda S,Govindan R

    更新日期:2015-08-01 00:00:00

  • Pan-Cancer Analysis Pinpoints Targets in PI3K Pathway.

    abstract::A new study of all 32 cancer types in The Cancer Genome Atlas identifies genomic alterations that increase the activity of the PI3K/AKT/mTOR pathway. The study, which combines mutation data with measures of protein levels and phosphorylation status, suggests that mutations in IDH1, VHL, and STK11 promote activation of...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-092

    authors:

    更新日期:2017-08-01 00:00:00

  • Molecular dissection of microsatellite instable colorectal cancer.

    abstract:UNLABELLED:Colorectal cancer was one of the first solid tumors to be classified on the basis of molecular profiling. Microsatellite instability has allowed researchers to distinguish a specific subtype of colorectal cancer that has a clearly identified molecular origin (mismatch repair deficiency), arises on a heredita...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-12-0471

    authors: Vilar E,Tabernero J

    更新日期:2013-05-01 00:00:00

  • Combined Analysis of Antigen Presentation and T-cell Recognition Reveals Restricted Immune Responses in Melanoma.

    abstract::The quest for tumor-associated antigens (TAA) and neoantigens is a major focus of cancer immunotherapy. Here, we combine a neoantigen prediction pipeline and human leukocyte antigen (HLA) peptidomics to identify TAAs and neoantigens in 16 tumors derived from seven patients with melanoma and characterize their interact...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-17-1418

    authors: Kalaora S,Wolf Y,Feferman T,Barnea E,Greenstein E,Reshef D,Tirosh I,Reuben A,Patkar S,Levy R,Quinkhardt J,Omokoko T,Qutob N,Golani O,Zhang J,Mao X,Song X,Bernatchez C,Haymaker C,Forget MA,Creasy C,Greenberg P,

    更新日期:2018-11-01 00:00:00