Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.

Abstract:

:Nodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, while cancer stem cells and stroma-derived pancreatic stellate cells markedly overexpressed Nodal and Activin, but not TGF-β. Knockdown or pharmacological inhibition of the Nodal/Activin receptor Alk4/7 in cancer stem cells virtually abrogated their self-renewal capacity and in vivo tumorigenicity, and reversed the resistance of orthotopically engrafted cancer stem cells to gemcitabine. However, engrafted primary human pancreatic cancer tissue with a substantial stroma showed no response due to limited drug delivery. The addition of a stroma-targeting hedgehog pathway inhibitor enhanced delivery of the Nodal/Activin inhibitor and translated into long-term, progression-free survival. Therefore, inhibition of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a therapeutic strategy for targeting cancer stem cells.

journal_name

Cell Stem Cell

journal_title

Cell stem cell

authors

Lonardo E,Hermann PC,Mueller MT,Huber S,Balic A,Miranda-Lorenzo I,Zagorac S,Alcala S,Rodriguez-Arabaolaza I,Ramirez JC,Torres-Ruíz R,Garcia E,Hidalgo M,Cebrián DÁ,Heuchel R,Löhr M,Berger F,Bartenstein P,Aicher A,Hee

doi

10.1016/j.stem.2011.10.001

subject

Has Abstract

pub_date

2011-11-04 00:00:00

pages

433-46

issue

5

eissn

1934-5909

issn

1875-9777

pii

S1934-5909(11)00481-4

journal_volume

9

pub_type

杂志文章
  • An epigenomic road map for endoderm development.

    abstract::While studies of organ development have traditionally relied on model organisms, recent advances in embryonic stem cell (ESC) culture allow investigation of organogenesis in human cells. Wang et al. (2015) employ this system to map the dynamic enhancer landscape during ESC differentiation to the endoderm derivatives p...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2015.03.006

    authors: Kaestner KH

    更新日期:2015-04-02 00:00:00

  • TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia.

    abstract::Fanconi anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in huma...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2016.03.002

    authors: Zhang H,Kozono DE,O'Connor KW,Vidal-Cardenas S,Rousseau A,Hamilton A,Moreau L,Gaudiano EF,Greenberger J,Bagby G,Soulier J,Grompe M,Parmar K,D'Andrea AD

    更新日期:2016-05-05 00:00:00

  • Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro.

    abstract::The study of gastric epithelial homeostasis and cancer has been hampered by the lack of stem cell markers and in vitro culture methods. The Wnt target gene Lgr5 marks stem cells in the small intestine, colon, and hair follicle. Here, we investigated Lgr5 expression in the stomach and assessed the stem cell potential o...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2009.11.013

    authors: Barker N,Huch M,Kujala P,van de Wetering M,Snippert HJ,van Es JH,Sato T,Stange DE,Begthel H,van den Born M,Danenberg E,van den Brink S,Korving J,Abo A,Peters PJ,Wright N,Poulsom R,Clevers H

    更新日期:2010-01-08 00:00:00

  • Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma.

    abstract::Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integ...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2017.04.009

    authors: Haas TL,Sciuto MR,Brunetto L,Valvo C,Signore M,Fiori ME,di Martino S,Giannetti S,Morgante L,Boe A,Patrizii M,Warnken U,Schnölzer M,Ciolfi A,Di Stefano C,Biffoni M,Ricci-Vitiani L,Pallini R,De Maria R

    更新日期:2017-07-06 00:00:00

  • Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression.

    abstract::Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progre...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2016.12.001

    authors: Alvarado AG,Thiagarajan PS,Mulkearns-Hubert EE,Silver DJ,Hale JS,Alban TJ,Turaga SM,Jarrar A,Reizes O,Longworth MS,Vogelbaum MA,Lathia JD

    更新日期:2017-04-06 00:00:00

  • Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation.

    abstract::Naive human embryonic stem cells (hESCs) can be derived from primed hESCs or directly from blastocysts, but their X chromosome state has remained unresolved. Here, we show that the inactive X chromosome (Xi) of primed hESCs was reactivated in naive culture conditions. Like cells of the blastocyst, the resulting naive ...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2016.10.006

    authors: Sahakyan A,Kim R,Chronis C,Sabri S,Bonora G,Theunissen TW,Kuoy E,Langerman J,Clark AT,Jaenisch R,Plath K

    更新日期:2017-01-05 00:00:00

  • Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation.

    abstract::Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hemato...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2015.09.017

    authors: Mazumdar C,Shen Y,Xavy S,Zhao F,Reinisch A,Li R,Corces MR,Flynn RA,Buenrostro JD,Chan SM,Thomas D,Koenig JL,Hong WJ,Chang HY,Majeti R

    更新日期:2015-12-03 00:00:00

  • A high-efficiency system for the generation and study of human induced pluripotent stem cells.

    abstract::Direct reprogramming of human fibroblasts to a pluripotent state has been achieved through ectopic expression of the transcription factors OCT4, SOX2, and either cMYC and KLF4 or NANOG and LIN28. Little is known, however, about the mechanisms by which reprogramming occurs, which is in part limited by the low efficienc...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2008.08.003

    authors: Maherali N,Ahfeldt T,Rigamonti A,Utikal J,Cowan C,Hochedlinger K

    更新日期:2008-09-11 00:00:00

  • Importing human pluripotent stem cell lines derived at another institution: tailoring review to ethical concerns.

    abstract::Stem cell researchers commonly use human pluripotent stem cell lines derived by other investigators. Researchers may use lines derived elsewhere, provided that their derivation met consensus core standards. Some types of derivation raise heightened levels of ethical concern and require greater scrutiny. To maintain pu...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2009.01.013

    authors: Lo B,Parham L,Broom C,Cedars M,Gates E,Giudice L,Halme DG,Hershon W,Kriegstein A,Kwok PY,Oberman M,Roberts C,Wagner R

    更新日期:2009-02-06 00:00:00

  • EPO and super-EPO: erythropoietins direct neoangiogenesis by cardiac progenitor cells.

    abstract::Erythropoietin, the red blood cell-making cytokine, is also a potential cytoprotective agent in heart disease. In this issue of Cell Stem Cell, Hoch et al. (2011) use two heart failure models, including chemotherapeutic cardiotoxicity, to reveal a mechanistic connection between reduced cardiomyocyte production of eryt...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2011.07.008

    authors: Schneider MD

    更新日期:2011-08-05 00:00:00

  • CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs.

    abstract::Developing technologies for efficient and scalable disruption of gene expression will provide powerful tools for studying gene function, developmental pathways, and disease mechanisms. Here, we develop clustered regularly interspaced short palindromic repeat interference (CRISPRi) to repress gene expression in human i...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2016.01.022

    authors: Mandegar MA,Huebsch N,Frolov EB,Shin E,Truong A,Olvera MP,Chan AH,Miyaoka Y,Holmes K,Spencer CI,Judge LM,Gordon DE,Eskildsen TV,Villalta JE,Horlbeck MA,Gilbert LA,Krogan NJ,Sheikh SP,Weissman JS,Qi LS,So PL,Conk

    更新日期:2016-04-07 00:00:00

  • Genome Editing in hPSCs Reveals GATA6 Haploinsufficiency and a Genetic Interaction with GATA4 in Human Pancreatic Development.

    abstract::Human disease phenotypes associated with haploinsufficient gene requirements are often not recapitulated well in animal models. Here, we have investigated the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes using CRISPR (clustere...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2017.01.001

    authors: Shi ZD,Lee K,Yang D,Amin S,Verma N,Li QV,Zhu Z,Soh CL,Kumar R,Evans T,Chen S,Huangfu D

    更新日期:2017-05-04 00:00:00

  • Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons.

    abstract::We have recently demonstrated that reactive glial cells can be directly reprogrammed into functional neurons by a single neural transcription factor, NeuroD1. Here we report that a combination of small molecules can also reprogram human astrocytes in culture into fully functional neurons. We demonstrate that sequentia...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2015.09.012

    authors: Zhang L,Yin JC,Yeh H,Ma NX,Lee G,Chen XA,Wang Y,Lin L,Chen L,Jin P,Wu GY,Chen G

    更新日期:2015-12-03 00:00:00

  • Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells.

    abstract::Human induced pluripotent stem cells (HiPSCs) appear to be highly similar to human embryonic stem cells (HESCs). Using two genetic lineage-tracing systems, we demonstrate the generation of iPSC lines from human pancreatic islet beta cells. These reprogrammed cells acquired markers of pluripotent cells and differentiat...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2011.06.007

    authors: Bar-Nur O,Russ HA,Efrat S,Benvenisty N

    更新日期:2011-07-08 00:00:00

  • Capturing Totipotent Stem Cells.

    abstract::Minority subpopulations within embryonic stem cell cultures display an expanded developmental potential similar to that of early embryo blastomeres or the early inner cell mass. The ability to isolate and culture totipotent cells capable of giving rise to the entire conceptus would enhance our capacity to study early ...

    journal_title:Cell stem cell

    pub_type: 杂志文章,评审

    doi:10.1016/j.stem.2017.12.011

    authors: Baker CL,Pera MF

    更新日期:2018-01-04 00:00:00

  • Ground State Conditions Induce Rapid Reorganization of Core Pluripotency Factor Binding before Global Epigenetic Reprogramming.

    abstract::Mouse embryonic stem cells (mESCs) cultured under serum/LIF conditions exhibit heterogeneous expression of pluripotency-associated factors that can be overcome by two inhibitors (2i) of the MEK and GSK3 pathways. Several studies have shown that the "ground state" induced by 2i is characterized by global hypomethylatio...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2015.07.005

    authors: Galonska C,Ziller MJ,Karnik R,Meissner A

    更新日期:2015-10-01 00:00:00

  • CDK6 levels regulate quiescence exit in human hematopoietic stem cells.

    abstract::Regulated blood production is achieved through the hierarchical organization of dormant hematopoietic stem cell (HSC) subsets that differ in self-renewal potential and division frequency, with long-term (LT)-HSCs dividing the least. The molecular mechanisms underlying this variability in HSC division kinetics are unkn...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2015.01.017

    authors: Laurenti E,Frelin C,Xie S,Ferrari R,Dunant CF,Zandi S,Neumann A,Plumb I,Doulatov S,Chen J,April C,Fan JB,Iscove N,Dick JE

    更新日期:2015-03-05 00:00:00

  • Differentiation-defective stem cells outcompete normal stem cells for niche occupancy in the Drosophila ovary.

    abstract::Rapid progress has recently been made regarding how the niche controls stem cell function, but little is yet known about how stem cells in the same niche interact with one another. In this study, we show that differentiation-defective Drosophila ovarian germline stem cells (GSCs) can outcompete normal ones for niche o...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2007.10.021

    authors: Jin Z,Kirilly D,Weng C,Kawase E,Song X,Smith S,Schwartz J,Xie T

    更新日期:2008-01-10 00:00:00

  • Gut with the Program: Direct Reprogramming toward Intestinal Epithelium Realized.

    abstract::Intestinal organoids offer great promise for modeling intestinal diseases; however, harvesting intestinal tissue is invasive and directed hPSC differentiation protocols are laborious and costly. In this issue of Cell Stem Cell, Miura and Suzuki (2017) describe the direct conversion of somatic cells from both mice and ...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2017.09.011

    authors: Nakauka-Ddamba A,Lengner CJ

    更新日期:2017-10-05 00:00:00

  • Age-related changes in niche cells influence hematopoietic stem cell function.

    abstract::In a recent issue of Nature, Mayack et al. (2010) use young and old parabiotic mice to show that systemic signals from the young parabiont rejuvenate hematopoietic stem cell function via the microenvironmental niche. ...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2010.01.008

    authors: Oakley EJ,Van Zant G

    更新日期:2010-02-05 00:00:00

  • Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming.

    abstract::Cellular reprogramming converts differentiated cells into induced pluripotent stem cells (iPSCs). However, this process is typically very inefficient, complicating mechanistic studies. We identified and molecularly characterized rare, early intermediates poised to reprogram with up to 95% efficiency, without perturbin...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2018.06.013

    authors: Schwarz BA,Cetinbas M,Clement K,Walsh RM,Cheloufi S,Gu H,Langkabel J,Kamiya A,Schorle H,Meissner A,Sadreyev RI,Hochedlinger K

    更新日期:2018-08-02 00:00:00

  • Skinny Fat Cells Stimulate Wound Healing.

    abstract::In this issue of Cell Stem Cell, Shook et al. (2020) reveal that dermal adipocytes regulate skin wound repair via release of fatty acids that promote macrophage recruitment and accelerated revascularization. Furthermore, mature dermal adipocytes dedifferentiate into migratory extracellularmatrix-producing myofibroblas...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2020.04.021

    authors: Merrick D,Seale P

    更新日期:2020-06-04 00:00:00

  • Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy.

    abstract::The current widespread outbreak of Zika virus (ZIKV) infection has been linked to severe clinical birth defects, particularly microcephaly, warranting urgent study of the molecular mechanisms underlying ZIKV pathogenesis. Akt-mTOR signaling is one of the key cellular pathways essential for brain development and autoph...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2016.07.019

    authors: Liang Q,Luo Z,Zeng J,Chen W,Foo SS,Lee SA,Ge J,Wang S,Goldman SA,Zlokovic BV,Zhao Z,Jung JU

    更新日期:2016-11-03 00:00:00

  • Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer.

    abstract::Aging is characterized by a decrease in genome integrity, impaired organ maintenance, and an increased risk of cancer, which coincide with clonal dominance of expanded mutant stem and progenitor cell populations in aging tissues, such as the intestinal epithelium, the hematopoietic system, and the male germline. Here ...

    journal_title:Cell stem cell

    pub_type: 杂志文章,评审

    doi:10.1016/j.stem.2015.05.002

    authors: Adams PD,Jasper H,Rudolph KL

    更新日期:2015-06-04 00:00:00

  • Eliminating Cancer Stem Cells in CML with Combination Transcriptional Therapy.

    abstract::Leukemia stem cells (LSCs) are resistant to current therapies used to treat chronic myeloid leukemia (CML). Abraham et al. (2016) have identified a molecular network critical for CML LSC survival and propose that simultaneously targeting two of their major transcriptional regulators, p53 and c-Myc, may facilitate thei...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2016.06.005

    authors: Carvajal LA,Steidl U

    更新日期:2016-07-07 00:00:00

  • Establishment of endoderm progenitors by SOX transcription factor expression in human embryonic stem cells.

    abstract::In this study, we explore endoderm cell fate regulation through the expression of lineage-determining transcription factors. We demonstrate that stable endoderm progenitors can be established from human ES cells by constitutive expression of SOX7 or SOX17, producing extraembryonic endoderm and definitive endoderm prog...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2008.06.018

    authors: Séguin CA,Draper JS,Nagy A,Rossant J

    更新日期:2008-08-07 00:00:00

  • Self-Organizing 3D Human Trunk Neuromuscular Organoids.

    abstract::Neuromuscular networks assemble during early human embryonic development and are essential for the control of body movement. Previous neuromuscular junction modeling efforts using human pluripotent stem cells (hPSCs) generated either spinal cord neurons or skeletal muscles in monolayer culture. Here, we use hPSC-deriv...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2019.12.007

    authors: Faustino Martins JM,Fischer C,Urzi A,Vidal R,Kunz S,Ruffault PL,Kabuss L,Hube I,Gazzerro E,Birchmeier C,Spuler S,Sauer S,Gouti M

    更新日期:2020-02-06 00:00:00

  • Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development.

    abstract::Inducing immune tolerance to prevent rejection is a key step toward successful engraftment of stem-cell-derived tissue in a clinical setting. Using human pluripotent stem cells to generate thymic epithelial cells (TECs) capable of supporting T cell development represents a promising approach to reach this goal; howeve...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2013.04.004

    authors: Parent AV,Russ HA,Khan IS,LaFlam TN,Metzger TC,Anderson MS,Hebrok M

    更新日期:2013-08-01 00:00:00

  • Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming.

    abstract::Ectopic expression of combinations of transcription factors (TFs) can drive direct lineage conversion, thereby reprogramming a somatic cell's identity. To determine the molecular mechanisms by which Gata4, Mef2c, and Tbx5 (GMT) induce conversion from a cardiac fibroblast toward an induced cardiomyocyte, we performed c...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2019.06.012

    authors: Stone NR,Gifford CA,Thomas R,Pratt KJB,Samse-Knapp K,Mohamed TMA,Radzinsky EM,Schricker A,Ye L,Yu P,van Bemmel JG,Ivey KN,Pollard KS,Srivastava D

    更新日期:2019-07-03 00:00:00

  • Blood cells need glia, too: a new role for the nervous system in the bone marrow niche.

    abstract::Regulation of hematopoietic stem cell (HSC) dormancy by specific cell types in the hematopoietic niche remains poorly understood. Yamazaki et al. (2011) now report that nerve-associated nonmyelinating Schwann cells activate TGF-β to maintain dormant HSCs, suggesting that glia are novel players in the bone marrow niche...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2011.11.016

    authors: Brückner K

    更新日期:2011-12-02 00:00:00