cancerres.aacrjournals.org · Web viewZebrafish: Speeding up the Cancer Drug Discovery Process...

Zebrafish: Speeding up the Cancer Drug Discovery

Process

Patricia Letrado1,2, Irene de Miguel2, Iranzu Lamberto1, Roberto Díez-Martínez1,*

and Julen Oyarzabal2,*

1 Ikan Biotech SL, The Zebrafish Lab Department, Centro Europeo de Empresas e

Innovación de Navarra (CEIN), Plaza CEIN 5 D9-A4, 31110 Noain, Spain.

2 Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for

Applied Medical Research (CIMA), University of Navarra, Avenida Pio XII 55, E-

31008 Pamplona, Spain.

Table of Contents

S5.1. Supplementary Table S5....................................................................................................S2

S5.2. References S5......................................................................................................................... S3


S6.2. References S6......................................................................................................................... S8


S7.2. References S7.......................................................................................................................S10

S8.1. Supplementary Table S8.................................................................................................S14

S8.2. References S8.......................................................................................................................S15

S1

Supplementary Table S5. Cancer models carried out in zebrafish using genetics approaches.

Cancer Gene Methodology (ref)

Ewing´s sarcomaHRASV12 Transgenesis (1)

hsp70 or β-actin-EWSR1-FLI1

Transgenesis (2)

GliomaRAS(G12D) Transgenesis (3)

Nf1, nf2 Mutagenesis (4)

Hepatocarcinoma

Mycsrc

Transgenesis (5)

UHRF1 Transgenesis (6)fabp10:beta-catenin Transgenesis (7)

apc Mutagenesis (8)

Hemangiosarcoma pten Mutagenesis (9)

Leukemia (T-ALL)

Myc Transgenesis (10-13)

akt Transgenesis (14)

Noch1 Transgenesis (12,15)

Leukemia (B-ALL) TEL-AML1 Transgenesis (16)

Leukemia (AML)Mycn Transgenesis (5)

MOZ/TIF2, -MYST3/NCOA2 Transgenesis (17)Malignant peripheral neural sheath tumor

(MPNST)

tp53 Mutagenesis (18)Nf1 Mutagenesis (4)

KRAS(G12D) Transgenesis (19)

MelanomaBRAF(V600E) Transgenesis (20,21)

HRAS(G12V) Transgenesis (22,23)NRAS(Q61K) Transgenesis (21,24)

Myeloproliferative neoplams

NUP98-HOXA9 (NHA9) Transgenesis (25)

KIT-D816V Transgenesis (26)sp1-NUP98-HOXA9 Transgenesis (27)

Ocular tumors pten Mutagenesis (28)

PancreaticKRAS(G12D) Transgenesis (29)

apc Mutagenesis (8)

Rabdomyosarcoma KRAS(G12D) Transgenesis (30,31)

S2

References S5

1. Burger A, Vasilyev A, Tomar R, Selig MK, Nielsen GP, Peterson RT, et al. A

zebrafish model of chordoma initiated by notochord-driven expression of

HRASV12. Dis Model Mech 2014;7:907–13.

2. Leacock SW, Basse AN, Chandler GL, Kirk AM, Rakheja D, Amatruda JF. A

zebrafish transgenic model of Ewing’s sarcoma reveals conserved mediators of

EWS-FLI1 tumorigenesis. Dis Model Mech;5:95–106.

3. Ju B, Chen W, Orr BA, Spitsbergen JM, Jia S, Eden CJ, et al. Oncogenic KRAS

promotes malignant brain tumors in zebrafish. Mol Cancer 2015;14:18.

4. Shin J, Padmanabhan A, de Groh ED, Lee J-S, Haidar S, Dahlberg S, et al.

Zebrafish neurofibromatosis type 1 genes have redundant functions in

tumorigenesis and embryonic development. Dis Model Mech 2012;5:881–94.

5. Shen LJ, Chen FY, Zhang Y, Cao LF, Kuang Y, Zhong M, et al. MYCN Transgenic

Zebrafish Model with the Characterization of Acute Myeloid Leukemia and

Altered Hematopoiesis. PLoS One 2013;8:1–12.

6. Mudbhary R, Hoshida Y, Chernyavskaya Y, Jacob V, Villanueva A, Fiel MI, et al.

UHRF1 overexpression drives DNA hypomethylation and hepatocellular

carcinoma. Cancer Cell 2014;25:196–209.

7. Evason KJ, Francisco MT, Juric V, Balakrishnan S, Lopez Pazmino M del P, Gordan

JD, et al. Identification of Chemical Inhibitors of β-Catenin-Driven Liver

Tumorigenesis in Zebrafish. PLoS Genet 2015;11:e1005305.

8. Haramis APG, Hurlstone A, van der Velden Y, Begthel H, van den Born M,

Offerhaus GJA, et al. Adenomatous polyposis coli-deficient zebrafish are

susceptible to digestive tract neoplasia. EMBO Rep 2006;7:444–9.

S3

9. Choorapoikayil S, Kuiper R V, de Bruin A, den Hertog J. Haploinsufficiency of the

genes encoding the tumor suppressor Pten predisposes zebrafish to

hemangiosarcoma. Dis Model Mech 2012;5:241–7.

10. Langenau DM, Feng H, Berghmans S, Kanki JP, Kutok JL, Look AT. Cre/lox-

regulated transgenic zebrafish model with conditional myc-induced T cell acute

lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2005;102(17):6068-6073.

11. Gutierrez A, Pan L, Groen RWJ, et al. Phenothiazines induce PP2A-mediated

apoptosis in T cell acute lymphoblastic leukemia. J Clin Investig.

2014;124(2):644-655.

12. Blackburn JS, Liu S, Wilder JL, et al. Clonal evolution enhances leukemia

propagating cell frequency in T-cell acute lymphoblastic leukemia through

akt/mtorc1 pathway activation. Cancer Cell. 2014;25(3):366-378.

13. Ridges S, Heaton WL, Joshi D, et al. Zebrafish screen identifies novel compound

with selective toxicity against leukemia. Blood. 2012;119(24):5621-5631.

14. Gutierrez A, Grebliunaite R, Feng H, et al. Pten mediates Myc oncogene

dependence in a conditional zebrafish model of T cell acute lymphoblastic

leukemia. J Exp Med. 2011;208(8):1595-1603.

15. Chen J, Jette C, Kanki JP, Aster JC, Look AT, Griffin JD. NOTCH1-induced T-cell

leukemia in transgenic zebrafish. Leukemia. 2007;21(3):462-471.

16. Sabaawy HE, Azuma M, Embree LJ, Tsai H-J, Starost MF, Hickstein DD. TEL-AML1

transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia.

Proc Natl Acad Sci U S A. 2006;103(41):15166-15171.

17. Zhuravleva J, Paggetti J, Martin L, Hammann A, Solary E, Bastie J-N, et al.

MOZ/TIF2-induced acute myeloid leukaemia in transgenic fish. Br J Haematol

S4

2008;143:378–82.

18. Berghmans S, Murphey RD, Wienholds E, Neuberg D. tp53 mutant zebrafish

develop malignant peripheral nerve sheath tumors. Proc Natl Acad Sci

2005;102:407–12.

19. Patton, E. Elizabeth, Windlund, Hans R, Kutok Jeffery L, Kopani KR. BRAF

Mutations Are Sufficient to Promote Nevi Formation and Cooperate with p53 in

the Genesis of Melanoma. Curr Biol 2005;15:249–54.

20. Lister JA, Capper A, Zeng Z, Mathers ME, Richardson J, Paranthaman K, et al. A

conditional zebrafish MITF mutation reveals MITF levels are critical for

melanoma promotion vs. regression in vivo. J Invest Dermatol 2014;134:133–40.

21. Yen J, White RM, Wedge DC, Van Loo P, de Ridder J, Capper A, et al. The genetic

heterogeneity and mutational burden of engineered melanomas in zebrafish

models. Genome Biol 2013;14:R113.

22. Michailidou C, Jones M, Walker P, Kamarashev J, Kelly A, Hurlstone AFL.

Dissecting the roles of Raf- and PI3K-signalling pathways in melanoma formation

and progression in a zebrafish model. Dis Model Mech 2009;2:399–411.

23. Anelli V, Santoriello C, Distel M, Köster RW, Ciccarelli FD, Mione M. Global

Repression of Cancer Gene Expression in a Zebrafish Model of Melanoma Is

Linked to Epigenetic Regulation. Zebrafish 2009;6:417–24.

24. Dovey M, White RM, Zon LI. Oncogenic NRAS Cooperates with p53 Loss to

Generate Melanoma in Zebrafish. Zebrafish 2009;6:397–404.

25. Deveau AP, Forrester AM, Coombs AJ, Wagner GS, Grabher C, Chute IC, et al.

Epigenetic therapy restores normal hematopoiesis in a zebrafish model of

NUP98–HOXA9-induced myeloid disease. Leukemia 2015;29:2086–97.

S5

26. Balci TB, Prykhozhij S V., Teh EM, Da’as SI, McBride E, Liwski R, et al. A

transgenic zebrafish model expressing KIT -D816V recapitulates features of

aggressive systemic mastocytosis. Br J Haematol 2014;167:48–61.

27. Forrester AM, Grabher C, McBride ER, Boyd ER, Vigerstad MH, Edgar A, et al.

NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and

provide new insight into mechanisms of myeloid leukaemogenesis. Br J

Haematol 2011;155:167–81.

28. Faucherre A, Taylor GS, Overvoorde J, Dixon JE, Den Hertog J. Zebrafish pten

genes have overlapping and non-redundant functions in tumorigenesis and

embryonic development. Oncogene 2008;27:1079–86.

29. Provost E, Bailey JM, Aldrugh S, Liu S, Iacobuzio-Donahue C, Leach SD. The

tumor suppressor rpl36 restrains KRAS(G12V)-induced pancreatic cancer.

Zebrafish 2014;11:551–9.

30. Storer NY, White RM, Uong A, Price E, Nielsen GP, Langenau DM, et al. Zebrafish

rhabdomyosarcoma reflects the developmental stage of oncogene expression

during myogenesis. Development 2013;140:3040–50.

31. Ignatius MS, Chen EY, Elpek NM, Fuller A, Tenente IM, Clagg R, et al. NIH Public

Access. Cancer Cell 2012;21:680–93.

S6

Supplementary Table S6. Allograft assays carried out in zebrafish.

Cancer type (ref)

Donor zebrafish

Cancer origin

Receptor zebrafish

Immuno-suppresio

nStage

ERMS (1)

rag2-Myc orrag2-kRASG12D

Transgenesis

rag2E450fs Immuno-suppresed mutant

Not needed Adult

Hepatocarcinoma (2)

MutantDEN mutagenesis

Syngenic Not needed Adult

Hepatocarcinoma (3)

MutantDEN mutagenesis

Syngenic Not neededAdult, embryo

Leukemia (ALL) (4)

TransgenicTEL-AMIL1

Transgenesis

Wild-type Irradiation Adult

Leukemia(TALL y TLBL)

(5)Mutant

ENU mutagenesis


Leukemia (TALL) (6)

TransgenicNotch1 induced

Transgenesis

AB Wild-type

Irradiation Adult

Leukemia (TALL) (7)

Transgenic

Transgenesis

Syngenic CG1-strain,Wild-type

Not needed, irradiation

Adult

Leukemia (TALL) (8)


Transgenesis

rag2E450fs,immuno-suppresed mutant

Not needed Adult

Melanoma (9)Transgenic BRAF

Transgenesis


Melanoma (8)


Transgenesis

rag2E450fs, immuno-suppresed mutant

Not needed Adult

Pancreatic (3) MutantDEN mutagenesis

Syngenic Not neededAdult, embryo

Rhabdo-Myosarcoma

(7)

Transgenic

Transgenesis

Syngenic CG1-strain, Wild-type

Not needed, irradiation

Adult

S7

References S6

1. Tang Q, Abdelfattah NS, Blackburn JS, Moore JC. Optimized cell transplantation

using adult rag2 mutant zebrafish. Nat Methods 2014;11:821–4.

2. Mizgirev I, Revskoy S. Generation of clonal zebrafish lines and transplantable

hepatic tumors. Nat Protoc 2010;5:383–94.

3. Mizgireuv I V., Revskoy SY. Transplantable Tumor Lines Generated in Clonal

Zebrafish. Cancer Res 2006;66:3120–5.

4. Sabaawy HE, Azuma M, Embree LJ, Tsai H-J, Starost MF, Hickstein DD. TEL-AML1

transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia.

Proc Natl Acad Sci 2006;103:15166–71.

5. Frazer JK, Meeker ND, Rudner L, Bradley DF, Smith ACH, Demarest B, et al.

Heritable T-cell malignancy models established in a zebrafish phenotypic screen.

Leukemia 2009;23:1825–35.

6. Chen J, Jette C, Kanki JP, Aster JC, Look AT, Griffin JD. NOTCH1-induced T-cell

leukemia in transgenic zebrafish. Leukemia 2007;21:462–71.

7. Smith ACH, Raimondi AR, Salthouse CD, Ignatius MS, Blackburn JS, Mizgirev I V,

et al. High-throughput cell transplantation establishes that tumor-initiating cells

are abundant in zebrafish T-cell acute lymphoblastic leukemia. Blood

2010;115:3296–303.

8. Tang Q, Abdelfattah NS, Blackburn JS, Moore JC. Optimized cell transplantation

S8

using adult rag2 mutant zebrafish. Nat Methods 2014;11:821–4.

9. Patton, E. Elizabeth, Windlund, Hans R, Kutok Jeffery L, Kopani KR. BRAF

Mutations Are Sufficient to Promote Nevi Formation and Cooperate with p53 in

the Genesis of Melanoma. Curr Biol 2005;15:249–54.

Supplementary Table S7. Xenograft assays performed in embryo zebrafish.

Cancer type Cell line Process studied (ref) Monitoring

Breast cancer

MDA-MB-231

Angiogenesis, drug testing (1)

Fluorescence imagingMetastasis, vascularization (2)

Dissemination (3)

MCF7Angiogenesis (4) Fluorescence imaging

Dissemination (5) Confocal imagingMDA-MB-23, M1, M2, M4

Metastasis (6)Confocal imaging, immunohistology

MDA-MB-23, MCF-7 Metastasis (7) Fluorescence imaging

Colon cancer

HCT116DLD-1

Drug screening (8) Fluorescence imaging

SW620HT29

Metastasis (9) Confocal imaging

Fibrosarcoma HT1080 Drug testing (10) Confocal imagingGastric cancer AGS, MGC80-3 Tumor growth (11) Fluorescencen imaging

GlioblastomaU87

Invasion (12)Confocal imaging, flow

citometryGrowth and invasion (13) Bioluminiscence

X12, GBM9 Proliferation (14) Confocal imagingHepatocarcinoma

JHH6Drug testing (15) Fluorescence imaging

Leukemia K562, NB4, Jukart Drug screening (16-18)ImmunofluorescenceFluorescence imaging

Confocal imaging

Lung cancerA549 Metastasis (19) Fluorescence imaging

H1299, H1437 Drug testing (20) Immunofluorescence

Melanoma

C8161 Dissemination (21) Confocal imagingA375 Tumor growth (22) Immunofluorescence

UACC62, 888mel, WM266-4, 501mel

Invasion (23) Confocal imaging

Mieloma MM.1S, BCWM.1, Dissemination (24) Fluorescence imaging

Ovarian cancer

A2780 Angiogenesis (25) Epifluorescence

OVOCAR 8Dissemination, metastasis

(3)Fluoresecence imaging

SKOV3 Drug testing (10) Confocal imagingPancreatic

cancerPANC-1,

PaTu8988TMetastasis, angiogénesis

(26)Confocal imaging

FA6, PaTu 8988s, Dissemination (27) Epifluorescence imaging

S9

CFPAC1, BxPC3AsPC-1, BxPC3 Metastasis (28) Confocal imaging

Prostate cancer

PC3Metastasis, vascularization

(2)Confocal imaging

DU145, PC3, LNCap, CWR22 PCa

Angiogenesis, tumor growth (29)

Fluorescence imaging

LnCAP, PC3 Dissemination (5) Confocal imaging

PC3, DU145 Adhesion (30) Fluorescence imaging

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2. He S, Lamers GEM, Beenakker JWM, Cui C, Ghotra VPS, Danen EHJ, et al.

Neutrophil-mediated experimental metastasis is enhanced by VEGFR inhibition

in a zebrafish xenograft model. J Pathol 2012;227:431–45.

3. Lee SLC, Rouhi P, Dahl Jensen L, Zhang D, Ji H, Hauptmann G, et al. Hypoxia-

induced pathological angiogenesis mediates tumor cell dissemination, invasion,

and metastasis in a zebrafish tumor model. Proc Natl Acad Sci 2009;106:19485–

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4. Zhao C, Yang H, Shi H, Wang X, Chen X, Yuan Y, et al. Distinct contributions of

angiogenesis and vascular co-option during the initiation of primary

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5. Ghotra VPS, He S, de Bont H, van der Ent W, Spaink HP, van de Water B, et al.

Automated Whole Animal Bio-Imaging Assay for Human Cancer Dissemination.

PLoS One 2012;7:e31281.

6. Drabsch Y, He S, Zhang L, Snaar-Jagalska BE, ten Dijke P. Transforming growth

factor-β signalling controls human breast cancer metastasis in a zebrafish

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S10

7. Tulotta C, Stefanescu C, Beletkaia E, Bussmann J, Tarbashevich K, Schmidt T, et

al. Inhibition of signaling between human CXCR4 and zebrafish ligands by the

small molecule IT1t impairs the formation of triple-negative breast cancer early

metastases in a zebrafish xenograft model. Dis Model Mech 2016;9:141–53.

8. Jung D-W, Oh E-S, Park S-H, Chang Y-T, Kim C-H, Choi S-Y, et al. A novel zebrafish

human tumor xenograft model validated for anti-cancer drug screening. Mol

Biosyst 2012;8:1930.

9. Haldi M, Ton C, Seng WL, McGrath P. Human melanoma cells transplanted into

zebrafish proliferate, migrate, produce melanin, form masses and stimulate

angiogenesis in zebrafish. Angiogenesis 2006;9:139–51.

10. Cheng J, Gu Y-J, Wang Y, Cheng SH, Wong W-T. Nanotherapeutics in

angiogenesis: synthesis and in vivo assessment of drug efficacy and

biocompatibility in zebrafish embryos. Int J Nanomedicine 2011;6:2007–21.

11. Zhang B, Xuan C, Ji Y, Zhang W, Wang D. Zebrafish xenotransplantation as a tool

for in vivo cancer study. Fam Cancer. 2015;14:487–93.

12. Yang X, Cui W, Gu A, Xu C, Yu S, Li T, et al. A Novel Zebrafish Xenotransplantation

Model for Study of Glioma Stem Cell Invasion. Ribatti D, editor. PLoS One

2013;8:e61801.

13. Zhao H, Tang C, Cui K, Ang B-T, Wong STC. A screening platform for glioma

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14. Welker AM, Jaros BD, Puduvalli VK, Imitola J, Kaur B, Beattie CE. Standardized

orthotopic xenografts in zebrafish reveal glioma cell-line-specific characteristics

and tumor cell heterogeneity. Dis Model Mech 2016;9:199–210.

S11

15. Tonon F, Zennaro C, Dapas B, Carraro M, Mariotti M, Grassi G. Rapid and cost-

effective xenograft hepatocellular carcinoma model in Zebrafish for drug testing.

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therapeutic platform for T-cell acute lymphoblastic leukemia. Haematologica

2015;100:70–6.

17. Corkery DP, Dellaire G, Berman JN. Leukaemia xenotransplantation in zebrafish -

chemotherapy response assay in vivo. Br J Haematol 2011;153:786–9.

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Leukemic cell xenograft in zebrafish embryo for investigating drug efficacy.

Haematologica 2011;96:612–6.

19. Lara R, Mauri FA, Taylor H, Derua R, Shia A, Gray C, et al. An siRNA screen

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20. Chiu C, Chou H, Chen B, Chang K, Tseng C, Fong Y. BPIQ , a novel synthetic

quinoline derivative , inhibits growth and induces mitochondrial apoptosis of

lung cancer cells in vitro and in zebrafish xenograft model. BMC Cancer

2015;15:962.

21. Lee LMJ, Seftor EA, Bonde G, Cornell RA, Hendrix MJC. The fate of human

malignant melanoma cells transplanted into zebrafish embryos: Assessment of

migration and cell division in the absence of tumor formation. Dev Dyn.

2005;233:1560–1570.

22. Zhao C, Zhang W, Zhao Y, Yang Y, Luo H, Ji G, et al. Endothelial Cords Promote

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Tumor Initial Growth prior to Vascular Function through a Paracrine Mechanism.

Sci Rep 2016;6:1–13.

23. Chapman A, del Ama LF, Ferguson J, Kamarashev J, Wellbrock C, Hurlstone A.

Heterogeneous tumor subpopulations cooperate to drive invasion. Cell Rep

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24. Sacco A, Roccaro AM, Ma D, Shi J, Mishima Y, Moschetta M, et al. Cancer Cell

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25. Nicoli S, Ribatti D, Cotelli F, Presta M. Mammalian Tumor Xenografts Induce

Neovascularization in Zebrafish Embryos. Cancer Res 2007;67:2927–31.

26. Vlecken DH, Bagowski CP. LIMK1 and LIMK2 Are Important for Metastatic

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27. Dumartin L, Whiteman HJ, Weeks ME, Hariharan D, Dmitrovic B, Iacobuzio-

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dissemination of pancreatic cancer cells through regulation of cathepsins B and

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28. Teng Y, Xie X, Walker S, White DT, Mumm JS, Cowell JK. Evaluating human

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Enrichment of human prostate cancer cells with tumor initiating properties in

mouse and zebrafish xenografts by differential adhesion. Prostate 2014;74:187–

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200.

Supplementary Table S8. Orthotopic transplantation in embryo zebrafish.

Tumor type Cell line (ref) Process studied Tumor monitoring

Glioblastoma

X12, GBM9 (1) ProliferationConfocal imaging,

HistologyU87MG, U251MG,

HT1080 (2)Proliferation Confocal imaging

U3013MG (3)Cell

interactionMicroscopy

U87, U373 (4)Invasion,

Cell interactionConfocal imaging

U87MG (5) Cell interaction Confocal imagingHuman tumor

cells isolated (6)Cell differentiation Confocal imaging

Pancreatic cancer

PaTu-S, PaTu-T (PaTu8988-S and PaTu8988-T) (7)

MetastasisConfocal imaging,

Inmunofluorescence

RetinoblastomaRB355, WERI-

Rb1(8)Invasiveness, metastasis Fluorescence imaging

SNUOT-Rb1 (9) Drug screening Confocal imaging

Uveal melanoma

92.1, Mel270, OMM2.3, OMM2.5,

OMM1 (10)

Proliferation,Migration,

Drug testingConfocal imaging

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References S8

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orthotopic xenografts in zebrafish reveal glioma cell-line-specific characteristics

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2. Hamilton L, Astell KR, Velikova G, Sieger D. A Zebrafish Live Imaging Model

Reveals Differential Responses of Microglia Toward Glioblastoma Cells In Vivo.

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8. Chen X, Wang J, Cao Z, Hosaka K, Jensen L, Yang H, et al. Invasiveness and

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9. Jo DH, Son D, Na Y, Jang M, Choi JH, Kim JH, et al. Orthotopic transplantation of

retinoblastoma cells into vitreous cavity of zebrafish for screening of anticancer

drugs. Mol Cancer 2013;12:71.

10. van der Ent W, Burrello C, Teunisse AFAS, Ksander BR, van der Velden PA, Jager

MJ, et al. Modeling of Human Uveal Melanoma in Zebrafish Xenograft Embryos.

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