title: CRIPTO/GRP78 signaling maintains fetal and adult mammary stem cells ex vivo.
abstract: Little is known about the extracellular signaling factors that govern mammary stem cell behavior. Here, we identify CRIPTO and its cell-surface receptor GRP78 as regulators of stem cell behavior in isolated fetal and adult mammary epithelial cells. We develop a CRIPTO antagonist that promotes differentiation and reduces self-renewal of mammary stem cell-enriched populations cultured ex vivo. By contrast, CRIPTO treatment maintains the stem cell phenotype in these cultures and yields colonies with enhanced mammary gland reconstitution capacity. Surface expression of GRP78 marks CRIPTO-responsive, stem cell-enriched fetal and adult mammary epithelial cells, and deletion of GRP78 from adult mammary epithelial cells blocks their mammary gland reconstitution potential. Together, these findings identify the CRIPTO/GRP78 pathway as a developmentally conserved regulator of fetal and adult mammary stem cell behavior ex vivo, with implications for the stem-like cells found in many cancers.
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Spike
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92037, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kelber
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Booker
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Kalathur
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Rose
authors.initials: R
authors.lastname: Rodewald
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Lipianskaya
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: La
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Marielle
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92037, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Wright
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92037, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Klemke
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Wahl
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gray
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D015415:Biomarkers; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology* / Q000502:physiology; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012038:Regeneration; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; D058851:GPI-Linked Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I
references.citation: Oncogene. 2009 Jun 18;28(24):2324-36
references.pmid: 19421146
references.citation: Cell Rep. 2013 Apr 25;3(4):1128-39
references.pmid: 23545496
references.citation: Mol Reprod Dev. 1995 Jul;41(3):277-86
references.pmid: 8588926
references.citation: Nature. 2001 Nov 1;414(6859):98-104
references.pmid: 11689954
references.citation: Cell Stem Cell. 2012 Feb 3;10(2):183-97
references.pmid: 22305568
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5193-8
references.pmid: 12682303
references.citation: Nature. 2006 Feb 23;439(7079):993-7
references.pmid: 16395311
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22745-50
references.pmid: 21149740
references.citation: Nature. 2011 Oct 09;479(7372):189-93
references.pmid: 21983963
references.citation: Am J Pathol. 2012 Jun;180(6):2188-200
references.pmid: 22542493
references.citation: J Exp Med. 2011 Mar 14;208(3):421-8
references.pmid: 21402747
references.citation: Mol Cell Biol. 2002 Apr;22(8):2586-97
references.pmid: 11909953
references.citation: Mol Cell Biol. 2008 Jan;28(2):666-77
references.pmid: 17991893
references.citation: Genes Cancer. 2011 Apr;2(4):404-19
references.pmid: 21779509
references.citation: Proc Natl Acad Sci U S A. 2008 May 20;105(20):7252-6
references.pmid: 18480259
references.citation: Methods. 2003 Jul;30(3):256-68
references.pmid: 12798140
references.citation: Am J Pathol. 2008 Feb;172(2):345-57
references.pmid: 18202186
references.citation: Cancer Res. 2007 Apr 15;67(8):3496-9
references.pmid: 17440054
references.citation: Cell Stem Cell. 2010 Jun 4;6(6):568-77
references.pmid: 20569694
references.citation: PLoS One. 2012;7(6):e39047
references.pmid: 22723926
references.citation: PLoS One. 2009 Nov 05;4(11):e7708
references.pmid: 19890402
references.citation: Cancer Res. 2008 Jan 15;68(2):498-505
references.pmid: 18199545
references.citation: Nat Rev Mol Cell Biol. 2008 Jan;9(1):11-21
references.pmid: 18097443
references.citation: Blood. 2012 Jan 19;119(3):817-25
references.pmid: 21937694
references.citation: Development. 2003 Dec;130(25):6283-94
references.pmid: 14623818
references.citation: FEBS Lett. 2012 Jul 4;586(14):1836-45
references.pmid: 22306319
references.citation: Nat Genet. 2008 May;40(5):499-507
references.pmid: 18443585
references.citation: Cell Stem Cell. 2011 Oct 4;9(4):330-44
references.pmid: 21982233
references.citation: Breast Cancer Res. 2011 May 25;13(3):108
references.pmid: 21635708
references.citation: Differentiation. 2003 Jan;71(1):1-17
references.pmid: 12558599
references.citation: PLoS Biol. 2013;11(8):e1001630
references.pmid: 23966837
references.citation: J Biol Chem. 2010 May 14;285(20):15065-15075
references.pmid: 20208072
references.citation: Am J Pathol. 2010 Aug;177(2):532-40
references.pmid: 20616345
references.citation: Vet Pathol. 2006 Jan;43(1):36-49
references.pmid: 16407485
references.citation: Nature. 2006 Jan 5;439(7072):84-8
references.pmid: 16397499
references.citation: J Biol Chem. 2008 Feb 22;283(8):4490-500
references.pmid: 18089557
references.citation: Genes Dev. 2003 May 15;17(10):1253-70
references.pmid: 12756227
references.citation: Breast Cancer Res. 2009;11(4):R62
references.pmid: 19706193
references.citation: Mol Cell Biol. 2006 Aug;26(15):5688-97
references.pmid: 16847323
references.citation: Nat Biotechnol. 2007 Jul;25(7):803-16
references.pmid: 17572666
references.citation: J Biomed Biotechnol. 2001;1(3):133-143
references.pmid: 12488607
references.citation: Eur J Surg Oncol. 2007 May;33(4):438-43
references.pmid: 17125961
references.citation: Mol Cell. 2001 May;7(5):949-57
references.pmid: 11389842