title: Single-cell dissection of transcriptional heterogeneity in human colon tumors.
abstract: Cancer is often viewed as a caricature of normal developmental processes, but the extent to which its cellular heterogeneity truly recapitulates multilineage differentiation processes of normal tissues remains unknown. Here we implement single-cell PCR gene-expression analysis to dissect the cellular composition of primary human normal colon and colon cancer epithelia. We show that human colon cancer tissues contain distinct cell populations whose transcriptional identities mirror those of the different cellular lineages of normal colon. By creating monoclonal tumor xenografts from injection of a single (n = 1) cell, we demonstrate that the transcriptional diversity of cancer tissues is largely explained by in vivo multilineage differentiation and not only by clonal genetic heterogeneity. Finally, we show that the different gene-expression programs linked to multilineage differentiation are strongly associated with patient survival. We develop two-gene classifier systems (KRT20 versus CA1, MS4A12, CD177, SLC26A3) that predict clinical outcomes with hazard ratios superior to those of pathological grade and comparable to those of microarray-derived multigene expression signatures.
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.
authors.forename: Piero
authors.initials: P
authors.lastname: Dalerba
authors.forename: Tomer
authors.initials: T
authors.lastname: Kalisky
authors.forename: Debashis
authors.initials: D
authors.lastname: Sahoo
authors.forename: Pradeep S
authors.initials: PS
authors.lastname: Rajendran
authors.forename: Michael E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Anne A
authors.initials: AA
authors.lastname: Leyrat
authors.forename: Sopheak
authors.initials: S
authors.lastname: Sim
authors.forename: Jennifer
authors.initials: J
authors.lastname: Okamoto
authors.forename: Darius M
authors.initials: DM
authors.lastname: Johnston
authors.forename: Dalong
authors.initials: D
authors.lastname: Qian
authors.forename: Maider
authors.initials: M
authors.lastname: Zabala
authors.forename: Janet
authors.initials: J
authors.lastname: Bueno
authors.forename: Norma F
authors.initials: NF
authors.lastname: Neff
authors.forename: Jianbin
authors.initials: J
authors.lastname: Wang
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Shelton
authors.forename: Brendan
authors.initials: B
authors.lastname: Visser
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hisamori
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shimono
authors.forename: Marc
authors.initials: M
authors.lastname: van de Wetering
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Michael F
authors.initials: MF
authors.lastname: Clarke
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D059010:Single-Cell Analysis / Q000379:methods*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
references.citation: Cell Stem Cell. 2009 Aug 7;5(2):168-77
references.pmid: 19664991
references.citation: J Clin Invest. 2010 Feb;120(2):636-44
references.pmid: 20101094
references.citation: Cell. 2009 Mar 20;136(6):1122-35
references.pmid: 19303854
references.citation: Cell Stem Cell. 2011 May 6;8(5):511-24
references.pmid: 21419747
references.citation: Nucleic Acids Res. 2007;35(11):3705-12
references.pmid: 17517782
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13427-32
references.pmid: 18765800
references.citation: Oncology. 2008;74(3-4):127-34
references.pmid: 18708730
references.citation: Nat Biotechnol. 2008 Mar;26(3):303-4
references.pmid: 18327243
references.citation: J Virol. 2000 Nov;74(21):10074-80
references.pmid: 11024136
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17807-12
references.pmid: 17098862
references.citation: ScientificWorldJournal. 2008 Nov 23;8:1168-76
references.pmid: 19030762
references.citation: Mod Pathol. 2008 Nov;21(11):1403-12
references.pmid: 18587323
references.citation: Nature. 1982 Sep 2;299(5878):61-3
references.pmid: 6955596
references.citation: Cell Cycle. 2007 Oct 1;6(19):2332-8
references.pmid: 17786053
references.citation: Nature. 2008 Dec 4;456(7222):593-8
references.pmid: 19052619
references.citation: Cell Stem Cell. 2010 Sep 3;7(3):279-82
references.pmid: 20804964
references.citation: BMC Physiol. 2001;1:1
references.pmid: 11231887
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10158-63
references.pmid: 17548814
references.citation: N Engl J Med. 2006 Sep 21;355(12):1253-61
references.pmid: 16990388
references.citation: Cell. 2009 Mar 6;136(5):903-12
references.pmid: 19269367
references.citation: Semin Oncol. 2010 Feb;37(1):39-46
references.pmid: 20172363
references.citation: Biochim Biophys Acta. 2010 Jan;1805(1):105-17
references.pmid: 19931353
references.citation: Nat Genet. 1996 Nov;14(3):316-9
references.pmid: 8896562
references.citation: Am J Pathol. 1999 Feb;154(2):515-23
references.pmid: 10027409
references.citation: Cancer Res. 2005 Mar 15;65(6):2321-9
references.pmid: 15781646
references.citation: Annu Rev Med. 2007;58:267-84
references.pmid: 17002552
references.citation: Cell Stem Cell. 2009 May 8;4(5):427-39
references.pmid: 19427292
references.citation: Cell Stem Cell. 2010 Jun 4;6(6):568-77
references.pmid: 20569694
references.citation: Exp Cell Res. 2010 Feb 1;316(3):452-65
references.pmid: 19786015
references.citation: Nucleic Acids Res. 2008 May;36(9):e49
references.pmid: 18411205
references.citation: Front Biosci. 2008 May 01;13:6820-33
references.pmid: 18508696
references.citation: Nat Genet. 2008 Jul;40(7):915-20
references.pmid: 18536716
references.citation: Dev Cell. 2010 Apr 20;18(4):675-85
references.pmid: 20412781
references.citation: Semin Oncol. 2009 Feb;36(1):8-37
references.pmid: 19179185
references.citation: Eur J Cancer. 2010 Oct;46(15):2788-98
references.pmid: 20627535
references.citation: Clin Cancer Res. 2009 Dec 15;15(24):7642-7651
references.pmid: 19996206
references.citation: Nature. 2003 May 15;423(6937):302-5
references.pmid: 12714971
references.citation: J Histochem Cytochem. 1996 Jan;44(1):35-41
references.pmid: 8543780
references.citation: Nature. 2007 Oct 25;449(7165):1003-7
references.pmid: 17934449
references.citation: Nature. 2011 Jan 20;469(7330):415-8
references.pmid: 21113151
references.citation: Cancer Res. 2008 May 1;68(9):3458-66
references.pmid: 18451174
references.citation: Nature. 2001 Nov 1;414(6859):105-11
references.pmid: 11689955
references.citation: Gastroenterology. 2009 Oct;137(4):1333-45.e1-3
references.pmid: 19549527
references.citation: Cancer. 1988 Apr 1;61(7):1359-63
references.pmid: 2449944
references.citation: Cell. 2009 Sep 4;138(5):822-9
references.pmid: 19737509
references.citation: Carcinogenesis. 2005 May;26(5):916-22
references.pmid: 15731168
references.citation: Cancer Res. 2008 Sep 1;68(17):6932-41
references.pmid: 18757407
references.citation: Genome Biol. 2008 Oct 30;9(10):R157
references.pmid: 18973690
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):13999-4004
references.pmid: 21808033
references.citation: Gastroenterology. 2010 Mar;138(3):958-68
references.pmid: 19914252