TumorStroma
TamasAGonda,MDDivisionofDiges7veandLiverDiseases
ColumbiaUniversity
Outline
• Overviewofstromacomposi7on• FocusonCancerAssociatedFibroblasts(CAFs)
– OriginsofCAFs– Stromal–epithelialinterac7on– Gene7csandEpigene7csofCAFs– Prognos7cvalueofCAFs– SignificanceofCAFsintumorprogressionandmetastasis
• Therapeu7cimplica7onsandresults
Prac7calques7onsaboutthecancerassociatedstroma
• ChickenandEggdilemma– Docancercellsinduceadesmoplas7creac7onordoesanalteredmicroenvironmentprovideapermissivemilieufortumorforma7on?
• FriendorFoe(orFrenemy?)– Doesabla7onorreduc7onoftumorstromabenefit
• PrimaryTherapeu7cTargetorAdjunct?
Componentsofthetumorstromaortumormicroenvironment
• Componentsofthestroma• Vascularcells
– Endothelialcells– Pericytes
• Leukocytes– Myeloid– Lymphoid
• Neuralcells• ExtracellularMatrix• Mesenchymalcells
– (Myo)fibroblasts/CancerAssociated– Mesenchymalstemcells– Fibroblasts
Tumorsare“non-healingwounds”
FibroblastsandMyofibroblasts
• Themajorstromalcelltypeinmostcancers• Slenderfusiformsmoothnucleus• CancerAssociatedFibroblasts(CAFs)areoQenequatedwithac7vatedfibroblastsormyofibroblasts– Thecancerstromadoescontainbothfibroblastsandmyofibroblasts
• Myofibroblastsarecapable/responsiblefor7ssuecontrac7onandsecre7onofECM– ThehallmarkisαSMAexpression
Anearlyubiquitousfeatureofmostsolidcancers
ProstateCa BreastCa Pancrea7cCa
EsBmated%stroma
Esophagus(mostlySCC) 50-82%
Gastric 34%
Liver 50%
Pancreas 83%
Colon 34%
Breast 41-66%
Prostate 40%
Renal 10%
Glioblastoma 10%LiuLealPLOSOne2016GondaetalCellDev2010
Cervix Fibro CIN Cervix MF Cervix MF Cervix MF Cervix Fibro CIN Cervix Fibro CIN Cervix Fibro CIN Cervix Fibro CIN Colon MF Colon CAF Colon MF Colon MF Colon CAF Colon MF Colon CAF Colon CAF Colon MF Gastric CAF Gastric MF Gastric CAF Esoph CAF Esoph MF Esoph MF Esoph MF Esoph MF Esoph MF Esoph MF Gastric CAF Gastric CAF Esoph CAF Esoph CAF Esoph CAF Esoph CAF Gastric MF Esoph CAF Gastric MF Gastric MF
Low methylation High methylation
brai
n co
ntro
l SFG
708
1br
ain
cont
rol S
FG 5
982
brai
n co
ntro
l SFG
598
4br
ain
cont
rol S
FG 7
080
brai
n co
ntro
l SFG
598
3br
ain
cont
rol S
FG 5
986
brai
n co
ntro
l SFG
598
1br
ain
cont
rol S
FG 5
985
brai
n DS
SFG
596
6br
ain
DS S
FG 5
972
brai
n DS
SFG
597
4br
ain
DS S
FG 5
970
brai
n DS
SFG
597
6br
ain
DS S
FG 5
969
brai
n DS
SFG
596
5br
ain
DS S
FG 5
973
brai
n DS
SFG
597
9br
ain
DS S
FG 5
964
brai
n DS
SFG
596
7br
ain
DS S
FG 5
980
brai
n DS
SFG
597
5br
ain
DS S
FG 5
968
brai
n DS
SFG
597
7
cg08742575_21_47604166_C21orf56cg07747299_21_47604052_C21orf56cg25545878_21_47604361_C21orf56cg12016809_21_47604291_C21orf56cg14560110_17_20799470_CCDC144NLcg01532436_19_48983942_CYTH2cg12845177_19_8650523_ADAMTS10cg19662846_19_8650410_ADAMTS10cg01754525_8_43131353_cg07496545_5_140683737_SLC25A2cg03102494_1_147801721_cg04498198_17_27899966_TP53I13cg15025200_1_152161237_cg14325153_3_138763899_PRR23Ccg26520012_10_42672589_cg05563515_6_30039027_RNF39cg10568066_6_30039442_RNF39cg10930308_6_30039476_RNF39cg13731605_14_21660372_cg00994804_21_36259383_RUNX1cg05491587_18_77659695_KCNG2cg22790377_1_228291668_C1orf35cg08714433_4_132896736_cg27297025_19_47259588_FKRPcg09465703_16_733842_JMJD8cg01399317_8_144810339_FAM83Hcg25468618_8_144810034_FAM83Hcg02784823_19_49000897_LMTK3cg26280727_19_49000998_LMTK3cg02185216_8_145731186_GPTcg15640870_8_145731409_GPTcg01612292_8_144809598_FAM83Hcg07962934_8_144809621_FAM83Hcg25717917_3_9989555_PRRT3cg08302650_8_145750040_LRRC24cg19682134_8_145750363_LRRC14cg09594291_19_58879022_ZNF837cg24052338_19_58879059_ZNF837cg02749105_19_58879056_ZNF837cg03781262_19_58879871_ZNF837cg11707067_19_59073430_MZF1cg20194050_6_31939280_STK19cg04149916_6_31939319_STK19cg13069441_6_31939322_STK19cg00270625_22_51017019_CPT1Bcg06530441_22_51016950_CPT1Bcg10770023_22_51016644_CPT1Bcg08260245_22_51016501_CPT1Bcg24363820_22_51016703_CPT1Bcg10490842_22_51016604_CPT1Bcg05156901_22_51016646_CPT1Bcg19112186_22_51016638_CPT1Bcg13423383_9_139889616_CLIC3cg22993195_3_49756301_AMIGO3cg27168291_6_33282997_ZBTB22cg03441844_1_161368947_cg05475524_11_66326798_ACTN3cg07492045_5_180257795_LOC729678cg10187894_10_38015525_cg20995835_17_18528589_CCDC144Bcg26162794_17_18528568_CCDC144Bcg03049249_17_16593601_CCDC144Acg04316233_17_16593613_CCDC144Acg08570243_2_110969853_NCRNA00116cg26757221_17_21477761_cg26706163_19_59073369_MZF1cg13207630_7_32358064_cg19817652_17_36997420_C17orf98cg01218414_7_5937486_C7orf28Acg06221449_1_29102029_cg08402365_2_172945274_MAP1D
GenderPloidy(numeric)FOR AML PAPER_54 SAMPLESKaryotype Comments1Comments2Comments3Comments4Cell TypeBMIBWPSSPDQStress Cluster
N N N N N N N N N N N N N N N N N N N N N N N
b b b b b b b b b b b b b b b b b b b b b b b
-3.0 -2.8 -2.6 -2.4 -2.2 -2.0 -1.8 -1.6 -1.3 -1.1 -0.9 -0.7 -0.5 -0.3 -0.1 0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0
-3.0 +3.0 -2.0 +2.0 -.5 +.5
STDEV from mean
Differen7alMethylated
Differen7alExpression
ColonCAFvsColonMF
EsophCAFvsEsophMF
GastricCAFvsGastricMF
251
4 60
10
6
ColonCAFvsColonMF
EsophCAFvsEsophMF
GastricCAFvsGastricMF
166
65
2
0
69
37
1206
1789
SignificantorganspecificdifferencesexistbetweenCAFs
MarkersofCAFs
OhlundetalJEM2014
OthercellsthatexpressthesemarkersPericytessmoothmusclecellsNeuralcellsMacrophages
Stromalcellsarepresentinthepremalignantlesions
Chuetal.,JournalofCellularBiochemistry101:887–907(2007)
GastricNormal
GastricDysplasia
GastricCAinsitu
αSMA
OriginsofCAFs
• Ac7va7onortransforma7onofresidentcellsinthetumor– Ac7va7onoffibroblasts,smoothmusclecells,endothelialcells/pericytes
– EpithelialmesenchymalTransforma7on
• Recruitmentofbonemarrowderivedcells
OriginsofCAFs
Ac7va7onoffibroblasts-tumorcellderivedparacrinesignals
MezawaCelTissRes2016GondaSeminCellDev2012
Ac7va7onoffibroblasts-tumorcellderived&autocrinesignaling
KojimoPNAS2010
MCF7+fibroblasts->CAF CAF(+/-CXCR4shRNA+MCF7)
/CXCL12
CAF+MCF7
CAF+MCF7+CXCR4shRNAMCF7
EpithelialMesenchymalTransforma7on(EMT)
KalluriWeinbergJCI2009
Observedinnormaldevelopment/woundhealingandcancerPossiblyreversible(E->M->E;EMTtoMET)Phenotypicsimilari7eswithCSCsSignificantepigene7cregula7onofEMT-TFs
EMTTFSnail/SlugZeb1,2Twist