title: Patterns of basal signaling heterogeneity can distinguish cellular populations with different drug sensitivities.
abstract: Phenotypic heterogeneity has been widely observed in cellular populations. However, the extent to which heterogeneity contains biologically or clinically important information is not well understood. Here, we investigated whether patterns of basal signaling heterogeneity, in untreated cancer cell populations, could distinguish cellular populations with different drug sensitivities. We modeled cellular heterogeneity as a mixture of stereotyped signaling states, identified based on colocalization patterns of activated signaling molecules from microscopy images. We found that patterns of heterogeneity could be used to separate the most sensitive and resistant populations to paclitaxel within a set of H460 lung cancer clones and within the NCI-60 panel of cancer cell lines, but not for a set of less heterogeneous, immortalized noncancer human bronchial epithelial cell (HBEC) clones. Our results suggest that patterns of signaling heterogeneity, characterized as ensembles of a small number of distinct phenotypic states, can reveal functional differences among cellular populations.
authors.affiliation: Department of Pharmacology, Green Center for Systems Biology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
authors.forename: Dinesh Kumar
authors.initials: DK
authors.lastname: Singh
authors.forename: Chin-Jen
authors.initials: CJ
authors.lastname: Ku
authors.forename: Chonlarat
authors.initials: C
authors.lastname: Wichaidit
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Steininger
authors.forename: Lani F
authors.initials: LF
authors.lastname: Wu
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Altschuler
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D018740:Genetic Heterogeneity; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008856:Microscopy, Fluorescence; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D049490:Systems Biology
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D017239:Paclitaxel
references.citation: Cell Cycle. 2007 Oct 1;6(19):2332-8
references.pmid: 17786053
references.citation: Proc Natl Acad Sci U S A. 1984 Aug;81(16):5126-9
references.pmid: 6591183
references.citation: J Pathol. 2008 Sep;216(1):64-74
references.pmid: 18623623
references.citation: Science. 2008 Feb 1;319(5863):620-4
references.pmid: 18239126
references.citation: Cancer Metastasis Rev. 1990 Jul;9(1):1-20
references.pmid: 2208565
references.citation: Cancer Res. 2000 May 1;60(9):2535-40
references.pmid: 10811136
references.citation: BMC Genomics. 2009 Jun 23;10:277
references.pmid: 19549304
references.citation: Science. 2007 May 18;316(5827):1039-43
references.pmid: 17463250
references.citation: Bioinformatics. 2001 Dec;17(12):1213-23
references.pmid: 11751230
references.citation: Differentiation. 2006 Apr;74(4):141-8
references.pmid: 16683984
references.citation: Trends Mol Med. 2007 Jan;13(1):4-11
references.pmid: 17118707
references.citation: Nat Methods. 2009 Oct;6(10):759-65
references.pmid: 19767759
references.citation: Cell. 2006 Dec 1;127(5):905-15
references.pmid: 17129778
references.citation: Science. 2008 Dec 5;322(5907):1511-6
references.pmid: 19023046
references.citation: Cancer Res. 1984 Jun;44(6):2259-65
references.pmid: 6372991
references.citation: Science. 2004 Sep 10;305(5690):1622-5
references.pmid: 15308767
references.citation: Lung Cancer. 2002 May;36(2):115-24
references.pmid: 11955645
references.citation: Nature. 2007 Dec 20;450(7173):1235-9
references.pmid: 18097410
references.citation: Nature. 2002 Jan 31;415(6871):530-6
references.pmid: 11823860
references.citation: Cell. 2008 Dec 12;135(6):1118-29
references.pmid: 19062086
references.citation: Cancer Res. 2003 Sep 15;63(18):5821-8
references.pmid: 14522905
references.citation: Cell. 2005 Jul 1;121(7):1109-21
references.pmid: 15989959
references.citation: Science. 2008 Sep 26;321(5897):1807-12
references.pmid: 18772396
references.citation: BMC Bioinformatics. 2007 Jan 30;8:32
references.pmid: 17263881
references.citation: Mol Cell. 2007 Nov 30;28(4):584-97
references.pmid: 18042454
references.citation: Clin Cancer Res. 2005 Dec 1;11(23):8288-94
references.pmid: 16322287
references.citation: J Cell Biol. 2009 Nov 2;187(3):375-84
references.pmid: 19948481
references.citation: Genetics. 1943 Nov;28(6):491-511
references.pmid: 17247100
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19306-11
references.pmid: 19052231
references.citation: Science. 2008 Sep 5;321(5894):1361-5
references.pmid: 18703712
references.citation: Nat Methods. 2007 May;4(5):445-53
references.pmid: 17401369
references.citation: Nat Rev Genet. 2009 May;10(5):336-42
references.pmid: 19337290
references.citation: Cancer Cell. 2008 Aug 12;14(2):111-22
references.pmid: 18656424
references.citation: Nature. 2008 May 22;453(7194):544-7
references.pmid: 18497826
references.citation: N Engl J Med. 2004 Nov 25;351(22):2337-8
references.pmid: 15564551
references.citation: FASEB J. 2007 Dec;21(14):3777-85
references.pmid: 17625071
references.citation: Nature. 2005 Jun 9;435(7043):834-8
references.pmid: 15944708
references.citation: Nature. 2009 May 21;459(7245):428-32
references.pmid: 19363473
references.citation: Leuk Lymphoma. 2006 Oct;47(10):2017-27
references.pmid: 17071472
references.citation: Science. 2004 Nov 12;306(5699):1194-8
references.pmid: 15539606
references.citation: Science. 2008 Aug 22;321(5892):1081-4
references.pmid: 18719282
references.citation: Cancer Cell. 2008 Oct 7;14(4):335-43
references.pmid: 18835035
references.citation: Proc Natl Acad Sci U S A. 2009 May 26;106(21):8519-24
references.pmid: 19443687
references.citation: Nat Methods. 2006 Oct;3(10):807-15
references.pmid: 16990813
references.citation: J Cell Physiol. 2006 May;207(2):420-7
references.pmid: 16419029
references.citation: Nat Cell Biol. 2004 Oct;6(10):931-40
references.pmid: 15448698
references.citation: Blood. 2007 Jul 15;110(2):632-9
references.pmid: 17371950
references.citation: J Cogn Neurosci. 1991 Winter;3(1):71-86
references.pmid: 23964806
references.citation: Cancer Res. 1985 Jun;45(6):2913-23
references.pmid: 2985257
references.citation: Science. 2007 Mar 23;315(5819):1716-9
references.pmid: 17379809
references.citation: Science. 2008 Sep 26;321(5897):1801-6
references.pmid: 18772397
references.citation: Science. 1998 May 8;280(5365):895-8
references.pmid: 9572732
references.citation: BMC Bioinformatics. 2008 Jun 05;9:264
references.pmid: 18534020
references.citation: Semin Cell Dev Biol. 2009 Sep;20(7):869-76
references.pmid: 19595782
references.citation: Nature. 2009 Sep 24;461(7263):520-3
references.pmid: 19710653