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