Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer.

Abstract:

:Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53-/- PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2+ macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGFβ to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME. SIGNIFICANCE: Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components.See related commentary by Carr and Fernandez-Zapico, p. 910.This article is highlighted in the In This Issue feature, p. 890.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Hou P,Kapoor A,Zhang Q,Li J,Wu CJ,Li J,Lan Z,Tang M,Ma X,Ackroyd JJ,Kalluri R,Zhang J,Jiang S,Spring DJ,Wang YA,DePinho RA

doi

10.1158/2159-8290.CD-19-0597

subject

Has Abstract

pub_date

2020-07-01 00:00:00

pages

1058-1077

issue

7

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-19-0597

journal_volume

10

pub_type

杂志文章
  • The Metabolic Basis of Kidney Cancer.

    abstract::Kidney cancer is not a single disease but represents several distinct types of cancer that have defining histologies and genetic alterations and that follow different clinical courses and have different responses to therapy. Mutation of genes associated with kidney cancer, such as VHL, FLCN, TFE3, FH, or SDHB, dysregu...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-18-1354

    authors: Linehan WM,Schmidt LS,Crooks DR,Wei D,Srinivasan R,Lang M,Ricketts CJ

    更新日期:2019-08-01 00:00:00

  • Cryo-Electron Microscopy Reveals Architecture of the BAF Complex.

    abstract::The structure of the chromatin-remodeling BAF complex provides molecular-scale mechanistic insight. ...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-RW2020-020

    authors:

    更新日期:2020-03-01 00:00:00

  • Advancing the Precision Medicine Initiative.

    abstract::The NIH has approved the framework to build a national research cohort of 1 million Americans, a key part of President Obama's Precision Medicine Initiative. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2015-146

    authors:

    更新日期:2015-12-01 00:00:00

  • Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors.

    abstract::HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant so...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-19-1014

    authors: Tsurutani J,Iwata H,Krop I,Jänne PA,Doi T,Takahashi S,Park H,Redfern C,Tamura K,Wise-Draper TM,Saito K,Sugihara M,Singh J,Jikoh T,Gallant G,Li BT

    更新日期:2020-05-01 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

  • Cancer Care Goes Virtual in Response to COVID-19.

    abstract::Amid concerns over the spread of COVID-19, oncology practices have "gone virtual," with video appointments scheduled for any service that does not require diagnostic testing or treatment. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2020-027

    authors:

    更新日期:2020-06-01 00:00:00

  • Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming.

    abstract::Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4-CD8-NK1.1- innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and human...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-19-0161

    authors: Hundeyin M,Kurz E,Mishra A,Rossi JAK,Liudahl SM,Leis KR,Mehrotra H,Kim M,Torres LE,Ogunsakin A,Link J,Sears RC,Sivagnanam S,Goecks J,Islam KMS,Dolgalev I,Savadkar S,Wang W,Aykut B,Leinwand J,Diskin B,Adam S,Is

    更新日期:2019-09-01 00:00:00

  • EZH2 Inhibitors: Take It EZy, It Is All About Context.

    abstract::Even in diffuse large B-cell lymphoma (DLBCL), a cancer of professional antigen-presenting cells, response rates to immune checkpoint blockade therapy have been limited. One reason for DLBCL immune evasion is epigenetic repression instead of activation of the antigen-presenting MHC-a dissection of mechanisms underlyin...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-19-0090

    authors: Velcheti V,Wong KK,Saunthararajah Y

    更新日期:2019-04-01 00:00:00

  • Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay.

    abstract::E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls the transcription of genes involved in cell fate. Overexpression of ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-11-0104

    authors: Herman AG,Hayano M,Poyurovsky MV,Shimada K,Skouta R,Prives C,Stockwell BR

    更新日期:2011-09-01 00:00:00

  • Sending CAR T Cells After Multiple Myeloma.

    abstract::Preliminary results from an ongoing phase I clinical trial in China suggest that chimeric antigen receptor T cells engineered to home in on a protein called BCMA may be a potent therapeutic option for multiple myeloma. The therapy was well tolerated and induced complete, durable responses in patients with relapsed/ref...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-088

    authors:

    更新日期:2017-08-01 00:00:00

  • Pegylated Engineered IL2 plus Anti-PD-1 Monoclonal Antibody: The Nectar Comes from the Combination.

    abstract::In this issue of Cancer Discovery, Diab and colleagues demonstrate in a phase I trial enrolling 38 patients diagnosed with advanced solid tumors that combining the pegylated IL2 bempegaldesleukin with an anti-PD-1 mAb is safe, with an overall response rate of 59.5%. This compelling clinical activity is supported by th...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-20-0786

    authors: Rouanne M,Zitvogel L,Marabelle A

    更新日期:2020-08-01 00:00:00

  • Anatomic Gene Expression Atlas Fuels Glioblastoma Discovery.

    abstract::The Ivy Glioblastoma Atlas provides detailed information about genes expressed in different anatomic regions of human brain tumors. Researchers are already drawing upon the resource to identify novel therapeutic targets for this deadly cancer. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2018-066

    authors:

    更新日期:2018-07-01 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

  • Advice Offered for Sharing Research Results.

    abstract::A report from the National Academies of Sciences, Engineering, and Medicine lays out 12 recommendations to help scientists decide whether to return research results to study participants and, if they do, how to improve the sharing of information. The most important change the report recommends is harmonizing contradic...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2018-102

    authors:

    更新日期:2018-09-01 00:00:00

  • Database Drives Biomarker Research.

    abstract::The Genomics of Drug Sensitivity in Cancer project recently added 4 years of additional data to a large-scale database designed to identify predictive biomarkers for cancer therapies. Freely available online, these data are driving research on the relationship between genomic features and drug responses to better tail...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2019-114

    authors:

    更新日期:2019-11-01 00:00:00

  • Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.

    abstract:UNLABELLED:Tyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKI) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase "gatekeeper" residues, which control access to an allosteric pocket adjacent to the ATP-binding site, has ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-15-0060

    authors: Smith CC,Zhang C,Lin KC,Lasater EA,Zhang Y,Massi E,Damon LE,Pendleton M,Bashir A,Sebra R,Perl A,Kasarskis A,Shellooe R,Tsang G,Carias H,Powell B,Burton EA,Matusow B,Zhang J,Spevak W,Ibrahim PN,Le MH,Hsu HH,H

    更新日期:2015-06-01 00:00:00

  • Intense Radiotherapy Slows Prostate Cancer Growth.

    abstract::Adding stereotactic ablative radiotherapy (SABR) to standard treatment slowed 6-month disease progression in men with hormone-sensitive metastatic prostate cancer, allowing them to delay androgen deprivation therapy, according to findings from the phase II ORIOLE trial. Larger studies are needed to determine if SABR, ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2020-034

    authors:

    更新日期:2020-06-01 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

  • Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.

    abstract::Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung canc...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-13-0741

    authors: de Bruin EC,Cowell C,Warne PH,Jiang M,Saunders RE,Melnick MA,Gettinger S,Walther Z,Wurtz A,Heynen GJ,Heideman DA,Gómez-Román J,García-Castaño A,Gong Y,Ladanyi M,Varmus H,Bernards R,Smit EF,Politi K,Downward J

    更新日期:2014-05-01 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

  • Olaparib shows promise in multiple tumor types.

    abstract::A phase II study of the PARP inhibitor olaparib (AstraZeneca) for cancer patients with inherited BRCA1 and BRCA2 gene mutations confirmed earlier results showing clinical benefit for advanced breast and ovarian cancers, and demonstrated evidence of effectiveness against pancreatic and prostate cancers. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2013-082

    authors:

    更新日期:2013-07-01 00:00:00

  • RNA Missplicing Triggers Antiviral Immune Response in Breast Cancer.

    abstract::Spliceosome inhibitors induced mRNA missplicing, retaining introns that formed double-stranded RNA. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2021-008

    authors:

    更新日期:2021-01-22 00:00:00

  • Biomarkers define distinct types of diffuse glioma.

    abstract::Three genetic markers performed far better than histologic criteria to classify diffuse low-grade gliomas, laying the foundation for molecular diagnosis of this heterogeneous group of brain tumors. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2015-092

    authors:

    更新日期:2015-08-01 00:00:00

  • Exosome Profiling Pinpoints Cancer Type.

    abstract::A study shows that analyzing the protein contents of exosomes and related extracellular vesicles can distinguish tumors from nearby noncancerous tissue, and profiling extracellular vesicle proteins obtained from plasma may also reveal cancer type. The results support using vesicle proteins for liquid biopsies. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2020-083

    authors:

    更新日期:2020-11-01 00:00:00

  • E-cigarettes Best Other Cessation Tools.

    abstract::Electronic cigarettes (e-cigarettes) may be an effective tool for smoking cessation. In a randomized trial, researchers found that 18% of those assigned to use e-cigarettes were smoke-free after a year, compared with 9.9% of those assigned to nicotine replacement therapies such as patches and gum. However, those in th...

    journal_title:Cancer discovery

    pub_type: 评论,新闻

    doi:10.1158/2159-8290.CD-NB2019-018

    authors:

    更新日期:2019-04-01 00:00:00

  • Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.

    abstract:UNLABELLED:Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp5...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-14-0362

    authors: Yang A,Rajeshkumar NV,Wang X,Yabuuchi S,Alexander BM,Chu GC,Von Hoff DD,Maitra A,Kimmelman AC

    更新日期:2014-08-01 00:00:00

  • Notch Shapes the Innate Immunophenotype in Breast Cancer.

    abstract::Notch activation, which is associated with basal-like breast cancer (BLBC), normally directs tissue patterning, suggesting that it may shape the tumor microenvironment. Here, we show that Notch in tumor cells regulates the expression of two powerful proinflammatory cytokines, IL1β and CCL2, and the recruitment of tumo...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-17-0037

    authors: Shen Q,Cohen B,Zheng W,Rahbar R,Martin B,Murakami K,Lamorte S,Thompson P,Berman H,Zúñiga-Pflücker JC,Ohashi PS,Reedijk M

    更新日期:2017-11-01 00:00:00

  • Cause of Early-Onset Colorectal Cancer Multifactorial.

    abstract::A report from the American Cancer Society reveals that colorectal cancer in people younger than 50 continues to increase, a trend that has spread to the 50-to-64 age group for the first time. Multiple lines of evidence indicate that obesity, often pinpointed as the cause, is not the only contributor. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2020-016

    authors:

    更新日期:2020-06-01 00:00:00

  • Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer.

    abstract::Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. Because of its heterogeneity and lack of hormone receptors or HER2 expression, targeted therapy is limited. Here, by performing a functional siRNA screening for 2-OG-dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-20-0288

    authors: Liao C,Zhang Y,Fan C,Herring LE,Liu J,Locasale JW,Takada M,Zhou J,Zurlo G,Hu L,Simon JM,Ptacek TS,Andrianov VG,Loza E,Peng Y,Yang H,Perou CM,Zhang Q

    更新日期:2020-11-01 00:00:00

  • Drugs, diagnostic tests approved quickly.

    abstract::Accelerated review and greater understanding of tumor biology speed targeted treatments to patients. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-ND11-09

    authors: Rose S

    更新日期:2011-10-01 00:00:00