u.s. science wars against cancer “inbred mice are the troops which literally by the tens of...
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U.S. Science Wars Against Cancer
“Inbred mice are the troops which literally by the tens of thousands occupy posts on the firing line of investigation [into the] nature and cure of cancer.“
Clarence Cook Little, Founder of The Jackson Laboratory1937
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The Jackson LaboratoryBar Harbor, Maine
• Non-profit mammalian genetics research
• Founded in 1929• 38 principal investigators• 1,300+ employees• Locations in Bar Harbor, Maine and
Sacramento, California• Expansion to Connecticut underway• NCI-designated Cancer Center
Bar Harbor, Maine Sacramento, California
Farmington, Connecticut
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Mission
We discover the genetic basis for preventing, treating and curing human disease, and we enable research and education for the global biomedical
community.
Mission
Research Resource Education
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JAX Quick Facts: Research Programs
• 38 Principal Investigator lead research groups in:
• Cancer• Neurobiology• Computational biology
and Bioinformatics• Developmental and
reproductive biology• Immunology• Complex trait genetics
ResearchResearch
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JAX Quick Facts: Research
• Distribute 4,000 lines of genetically defined mice to 16,000 laboratories around the world
• Provide unique services for developing and testing in vivo mouse models to advance drug discovery and pre-clinical testing
ResourceResource
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• Courses & Conferences• Precollege/College Internships• Pre- and Postdoctoral training• Graduate programs with the
University of Maine Graduate School for Biomedical Sciences (GSBS) & Tufts University Sackler School
• Visiting Investigator Program
OutreachOutreach and Education
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Why Mice?
• Mice get many of the same genetic disease as humans• Mammalian physiology is highly conserved• >95% of human genes have an ortholog in mouse• Conservation of gene content and organization• Experimentally tractable• Small, “easy” to breed• Short generation time
“The mouse is thebiomedical research platform for the
21st Century.”- Harold Varmus, Director, National
Cancer Institute
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genomics of normal lung development as a framework for understanding disease
processes
Carol Bult, Ph.D.Professor
Program Leader, JAX Cancer Center
Sr. Advisor for Research IT
A National Cancer Institute Designated Cancer Center
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development and disease
• is there a gene expression signature that is common to lung development and lung cancer?
• are developmental gene expression signatures tissue specific?
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Rudolf Virchow, 1859
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old question; new approaches
genomes
genomics
informatics
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• Embryonic (E9 – E12)– Primitive lung buds emerge from
ventral gut epithelium• Pseudoglandular (E12-E15)
– Stereo-specific branching of the lung bronchi. Differentiation of epithelial cells to form prealveolate saccules
• Canalicular (E15-E17)– Formation of terminal sacs and
vasculature • Saccular (Terminal Sac) (E17 – P0)
– Expansion in the numbers of terminal sacs and capillaries. Differentiation of Type I and II alveolar cells
• Alveolar (P1-P30)– terminal sacs develop into mature
alveolar ducts and alveoli
lung development in mouse
http://www.cincinnatichildrens.org/research/div/pulmonary-biology/faculty-research/whitsett-lab/projects.htm
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http://www.aups.org.au/Proceedings/36/9-13/
lung development stages are similar in mouse and human
Developmental Stage
Timeline for mouse
Timeline for human
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approach:compare global gene expression during of normal development (mouse) to global gene expression of
tumors (human)
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transcriptional profiling of lung development
E11.5 E13.5 E14.5 E16.5 P5
Images from Malpel S, Development (2000) 127:3057-67
E = embryonicP = postnatal
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Extract total mRNA from the target cell/tissue- presence of mRNA means a gene is “active”
Modify the mRNA with a tag
Hybridize modified mRNAs to the probes on the gene chip- successful hybridization generates a fluorescent signal
Scan for fluorescence
Quantitate expression
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1. Bright spots indicates positive hybridization events (i.e. active genes)
2. The analysis software “knows” the address of every gene and generates a report of gene activity (expression)
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time course analysis
Which genes have sustained transcriptional activity changes over time?
Expectations:• genes/pathways for cell division/cell cycle
should go down over time
• genes/pathways for differentiation and lung specific pathways go up over time
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http://www.cs.cmu.edu/~jernst/stem/
349312 196 141 431
320 139
Number of genes that match the expression profile
28,000+ genes on chip~20,000 genes don’t change~5,000 genes assigned to profiles
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1110005A23Rik, 1700009P03Rik, 1700020C11Rik, 1810058I14Rik, 2210018M11Rik, 2610301G19Rik, 2810407C02Rik, 4931406I20Rik, 4932432K03Rik, 5730467H21Rik, 5830411E10Rik, 6330581L23Rik, 9030612M13Rik, AI848100, Abca3, Abcc4, Abcd1, Acad10, Acads, Acsbg1, Acsl5, Adam12, Adamts20, Adamts5, Adamts9, Adcy3, Akap2, Alas1, Aldh1a1, Aldh1l1, Aldoc, Alg14, Alg6, Amph, Aox3, Aplp2, Appbp2, Aqp5, Arf2, Arf4, Arhgap6, Art3, Atf6, Atm, Atp1b1, Atp6v0b, Atp6v1e1, Atp7a, Atp8a1, Atp8b2, B230118G17Rik, BC016495, Bbs4, Bcat1, Bcl2l2, Bclaf1, Bid, Bpgm, Bphl, *Braf, Brunol4, Btbd4, Bzw1, C1qtnf3, C730048C13Rik, Cacna1d, Cadps2, Calm2, Camk2d, Camkk2, Cart1, Casp7, Cav1, Ccnb1, Ccni, Cd36, Cdc26, Cdca5, Cdkn1b, Cdkn1c, Cdkn3, Cdx2, Cebpg, Ches1, Cited1, Clca1, Clta, Clu, Cmpk, Cnot6, Cntn4, Col18a1, Col3a1, Col4a1, Col4a6, Col9a1, Cox6b2, Cpm, Cpne5, Crbn, Crls1, Cse1l, *Ctnnb1, Ctps2, Ctse, Cul3, Cyp11a1, D11Ertd333e, D1Ertd161e, D230025D16Rik, D830007F02Rik, Daam2, Dab1, Dach1, Dapk2, Dcamkl1, Dhfr, Dhrs8, Dnajc15, Dtymk, Dusp4, Dyrk1a, E2f7, Eda2r, Ednra, Ell2, Elmo3, Enah, Enpep, Enpp2, Epb4.1, Eps8, Esm1, Etv5, Eya1, Fabp3, Fabp5, Fank1, Fath, Fblim1, Fbxl20, Fbxl3, Fbxw7, Fem1c, Fgfr2, Fhit, Fhl2, Fkbp6, Folr1, Foxp1, Frk, Fusip1, Fxyd6, Fzd9, Gas7, Gata2, Gdpd2, Gja1, Gpc3, Gpx3, Gstk1, Gstp1, H2-Aa, H3f3a, Hdac9, Hel308, Hesx1, Heyl, Hhip, Hif3a, Hipk2, Hist1h2bc, Hnrpf, Hook1, Hoxd8, Hsd17b12, Hsp90b1, Hspa1b, Htra3, Ifitm3, Ifnar2, Igf1, Igfbp2, Igfbp3, Igfbp7, Ing3, Ipo7, Itga4, Itgb1, Itpr2, Jarid1d, Kcnab1, Kcnb1, Kcnip1, Kcnip4, Kcnj16, Kcns2, Kdr, Keap1, Kif2a, Klf6, Klf7, Klk1, Krt2-7, Krt2-8, Lama5, Lass6, Lcn2, Lgals7, Lgtn, Lhx1, Lhx9, Lmo4, Lrrc16, Lrrk1, Lsp1, Lss, Ltf, Madd, Mafa, Man1a2, Mapk1, Mapre1, Masp1, Mef2c, Mlph, Mmp19, Mod1, Morf4l1, Morf4l2, Mrpl18, Mrpl44, Mt1, Mt2, Mtdh, Mterf, Mthfd1, Mtm1, Mtr, Mtx2, Myef2, Myl1, Mylc2b, Mylk, Myo1b, Myo5b, Narg1, Nedd9, Neo1, Nfe2l2, Npc1, Npepl1, Npr2, Nr2f2, Nrg1, Nusap1, Ogt, Otx2, Pak1, Pak3, Papss2, Pard6b, Parp1, Pbx3, Pcbd1, Pcmtd1, Pcsk5, Pctk1, Pctk3, Pdcd6ip, Pdia3, Pfdn4, Pftk1, Phb2, Phca, Phf8, Phka1, Pitx2, Pja1, Pja2, Pnck, Pomgnt1, Porcn, Ppargc1a, Ppfibp1, Ppih, Ppp1r16b, Prc1, Prcp, Prkag2, Prkar2b, Prkcd, Psmb3, *Psrc1, Ptch1, Pten, Ptgds, Ptk2b, Ptp4a1, Ptp4a2, Ptp4a3, Ptpn13, Ptx3, Qscn6, Rab2b, Rab31, Rab3a, Rab3b, Rad51l3, Rec8L1, Ren2, Rims4, Rkhd3, Rnf11, Rnf20, Robo2, Rpl39, Rps6ka3, Runx1, Runx2, Rxrb, Ryr2, S100a6, S100a9, Sat1, Scd1, Scmh1, Scn3a, Scn7a, Scn8a, Scrn1, Sdk2, Sec24a, Sec61a2, Sema3a, Sept11, Serpina3g, Sesn3, Sf4, Sfrs1, Sgk3, Shb, Sin3b, Slc11a2, Slc16a10, Slc16a7, Slc18a2, Slc25a5, Slc26a1, Slc2a13, Slc38a5, Slc39a10, Slc41a2, Slc6a14, Slc6a15, Slc6a6, Slc7a4, Slc9a2, Smc2l1, Smg5, Snapap, Sncaip, Snrk, Soat1, Sorl1, Sox10, Sox11, Sox9, Spp1, Srp54, St3gal5, Star, Strbp, Stxbp1, Sulf1, Suv420h1, Sv2b, Sycp3, Syn2, Sypl, Tacc1, Tcea3, Tcf12, Tdgf1, Tesc, Tfrc, Tgfa, Tgfb2, Thap7, Timp1, Tinagl, Tm9sf3, Tmed7, Tmed9, Tmem23, Tmpo, Tmprss13, Tradd, Tram2, Trappc5, Trim23, Trim66, *Tsc1, Tspyl2, Txndc10, Txndc2, Tyro3, Uchl5, Uhrf2, Usp12, Usp7, Utp15, Uty, Vcpip1, Vim, Vldlr, *Yes1, Ywhaz, Zdhhc2, Zfhx1b, Zfp148, Zfp192, Zfp275, Zfp277, Zfp28, Zfp30, Zfp36, Zfp583, Zfp62, Zfp68
http://www.informatics.jax.org
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finding common biological themes in lists of genes
analyze biological systems and processes, not individual genes.
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biological systems represented by genes whose expression levels….
Cell Adhesion
System Development
Anatomical System Development
Vasculature Development
Blood Vessel Development
Angiogenesis
increase during murine lung development:
“Late expression group”
Cell Cycle
Cell Division
DNA Repair
Mitosis
Regulation of transcription
decrease during murine lung development:
“Early expression group”
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gene expression in human lung tumors
Which genes are differentially expressed in tumors compared to normal lung tissue?
Expectations:• genes/pathways for cell division/cell cycle
should go up over time
• genes/pathways for differentiation and lung specific pathways go down over time
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transcriptional profiling in human lung tumors compared to normal human lung
Adenocarcinoma Normal
Dehan and Kaminski, 2004. (GSE1987)NCBI’s GEO http://www.ncbi.nlm.nih.gov/geo/
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• Microarray Analysis of Variance (MAANOVA)**
differential gene expression: tumor vs normal
** http://www.jax.org/staff/churchill/labsite/software/anova/index.html
A vs N (q<0.05)
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1110005A23Rik, 1700009P03Rik, 1700020C11Rik, 1810058I14Rik, 2210018M11Rik, 2610301G19Rik, 2810407C02Rik, 4931406I20Rik, 4932432K03Rik, 5730467H21Rik, 5830411E10Rik, 6330581L23Rik, 9030612M13Rik, AI848100, Abca3, Abcc4, Abcd1, Acad10, Acads, Acsbg1, Acsl5, Adam12, Adamts20, Adamts5, Adamts9, Adcy3, Akap2, Alas1, Aldh1a1, Aldh1l1, Aldoc, Alg14, Alg6, Amph, Aox3, Aplp2, Appbp2, Aqp5, Arf2, Arf4, Arhgap6, Art3, Atf6, Atm, Atp1b1, Atp6v0b, Atp6v1e1, Atp7a, Atp8a1, Atp8b2, B230118G17Rik, BC016495, Bbs4, Bcat1, Bcl2l2, Bclaf1, Bid, Bpgm, Bphl, *Braf, Brunol4, Btbd4, Bzw1, C1qtnf3, C730048C13Rik, Cacna1d, Cadps2, Calm2, Camk2d, Camkk2, Cart1, Casp7, Cav1, Ccnb1, Ccni, Cd36, Cdc26, Cdca5, Cdkn1b, Cdkn1c, Cdkn3, Cdx2, Cebpg, Ches1, Cited1, Clca1, Clta, Clu, Cmpk, Cnot6, Cntn4, Col18a1, Col3a1, Col4a1, Col4a6, Col9a1, Cox6b2, Cpm, Cpne5, Crbn, Crls1, Cse1l, *Ctnnb1, Ctps2, Ctse, Cul3, Cyp11a1, D11Ertd333e, D1Ertd161e, D230025D16Rik, D830007F02Rik, Daam2, Dab1, Dach1, Dapk2, Dcamkl1, Dhfr, Dhrs8, Dnajc15, Dtymk, Dusp4, Dyrk1a, E2f7, Eda2r, Ednra, Ell2, Elmo3, Enah, Enpep, Enpp2, Epb4.1, Eps8, Esm1, Etv5, Eya1, Fabp3, Fabp5, Fank1, Fath, Fblim1, Fbxl20, Fbxl3, Fbxw7, Fem1c, Fgfr2, Fhit, Fhl2, Fkbp6, Folr1, Foxp1, Frk, Fusip1, Fxyd6, Fzd9, Gas7, Gata2, Gdpd2, Gja1, Gpc3, Gpx3, Gstk1, Gstp1, H2-Aa, H3f3a, Hdac9, Hel308, Hesx1, Heyl, Hhip, Hif3a, Hipk2, Hist1h2bc, Hnrpf, Hook1, Hoxd8, Hsd17b12, Hsp90b1, Hspa1b, Htra3, Ifitm3, Ifnar2, Igf1, Igfbp2, Igfbp3, Igfbp7, Ing3, Ipo7, Itga4, Itgb1, Itpr2, Jarid1d, Kcnab1, Kcnb1, Kcnip1, Kcnip4, Kcnj16, Kcns2, Kdr, Keap1, Kif2a, Klf6, Klf7, Klk1, Krt2-7, Krt2-8, Lama5, Lass6, Lcn2, Lgals7, Lgtn, Lhx1, Lhx9, Lmo4, Lrrc16, Lrrk1, Lsp1, Lss, Ltf, Madd, Mafa, Man1a2, Mapk1, Mapre1, Masp1, Mef2c, Mlph, Mmp19, Mod1, Morf4l1, Morf4l2, Mrpl18, Mrpl44, Mt1, Mt2, Mtdh, Mterf, Mthfd1, Mtm1, Mtr, Mtx2, Myef2, Myl1, Mylc2b, Mylk, Myo1b, Myo5b, Narg1, Nedd9, Neo1, Nfe2l2, Npc1, Npepl1, Npr2, Nr2f2, Nrg1, Nusap1, Ogt, Otx2, Pak1, Pak3, Papss2, Pard6b, Parp1, Pbx3, Pcbd1, Pcmtd1, Pcsk5, Pctk1, Pctk3, Pdcd6ip, Pdia3, Pfdn4, Pftk1, Phb2, Phca, Phf8, Phka1, Pitx2, Pja1, Pja2, Pnck, Pomgnt1, Porcn, Ppargc1a, Ppfibp1, Ppih, Ppp1r16b, Prc1, Prcp, Prkag2, Prkar2b, Prkcd, Psmb3, *Psrc1, Ptch1, Pten, Ptgds, Ptk2b, Ptp4a1, Ptp4a2, Ptp4a3, Ptpn13, Ptx3, Qscn6, Rab2b, Rab31, Rab3a, Rab3b, Rad51l3, Rec8L1, Ren2, Rims4, Rkhd3, Rnf11, Rnf20, Robo2, Rpl39, Rps6ka3, Runx1, Runx2, Rxrb, Ryr2, S100a6, S100a9, Sat1, Scd1, Scmh1, Scn3a, Scn7a, Scn8a, Scrn1, Sdk2, Sec24a, Sec61a2, Sema3a, Sept11, Serpina3g, Sesn3, Sf4, Sfrs1, Sgk3, Shb, Sin3b, Slc11a2, Slc16a10, Slc16a7, Slc18a2, Slc25a5, Slc26a1, Slc2a13, Slc38a5, Slc39a10, Slc41a2, Slc6a14, Slc6a15, Slc6a6, Slc7a4, Slc9a2, Smc2l1, Smg5, Snapap, Sncaip, Snrk, Soat1, Sorl1, Sox10, Sox11, Sox9, Spp1, Srp54, St3gal5, Star, Strbp, Stxbp1, Sulf1, Suv420h1, Sv2b, Sycp3, Syn2, Sypl, Tacc1, Tcea3, Tcf12, Tdgf1, Tesc, Tfrc, Tgfa, Tgfb2, Thap7, Timp1, Tinagl, Tm9sf3, Tmed7, Tmed9, Tmem23, Tmpo, Tmprss13, Tradd, Tram2, Trappc5, Trim23, Trim66, *Tsc1, Tspyl2, Txndc10, Txndc2, Tyro3, Uchl5, Uhrf2, Usp12, Usp7, Utp15, Uty, Vcpip1, Vim, Vldlr, *Yes1, Ywhaz, Zdhhc2, Zfhx1b, Zfp148, Zfp192, Zfp275, Zfp277, Zfp28, Zfp30, Zfp36, Zfp583, Zfp62, Zfp68
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Cell Cycle
Cell Division
Mitosis
Cell Adhesion
System Development
Anatomical System Development
Vasculature Development
Blood Vessel Development
Angiogenesis
human lung tumor(adenocarcinoma)
similar biological systems;
normal mouse lung development
“Late expression group”
Cell Cycle
Cell Division
DNA Repair
Mitosis
Regulation of transcription
Cell Adhesion
System Development
Anatomical System Development
Vasculature Development
Blood Vessel Development
Angiogenesis“Early expression group”
opposite gene expression trends
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• For genes regulated in lung tumors, when are the orthologous mouse genes expressed during development?
• For genes down regulated in lung tumors, when are the orthologous mouse genes expressed during development?
integrating development and cancer genomics
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Divide up the developmental timeline into segments, bin the ~5,000 or so genes that have expression levels related to development.
Determine the frequency of genes in each bin where the human ortholog is overexpressed in tumors.
Determine the frequency of genes in each bin where the human ortholog is underexpressed in tumors.
Developmental Timeline (DT)Early Late
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Fre
quen
cyF
requ
ency
Fre
quen
cy
No association
Strong association
Ambiguous association
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quantifying developmental gene expression signatures
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development and disease
• is there a gene expression signature that is common to lung development and lung cancer?
• are developmental gene expression signatures tissue specific?
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developmental gene expression signatures for cancer are not tissue specific
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not all cancers exhibit an early developmental gene expression signature
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10 developmental time series32 disease data sets (mostly cancer)
Naxerova et al. 2008. Genome Biology. 9:R108
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novel classification of tumors?
• group 1 – early development gene signatures– 46% of data sets tested fall into this group– lung cancer, Wilm’s tumor
• group 2 – ambiguous developmental signature– early developmental signature plus other
transcriptional programs– observed in CNS tumors, breast cancer
• group 3 – no early development signature– genes cluster on the late end of the DT– ovarian cancer, prostate cancer
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• group 1 and 2 tumors (early developmental signatures)– cell cycle, RNA splicing, DNA repair– cellular location largely in nucleus
• group 3 tumors (late development signatures)– immune response, cell adhesion, – cellular location largely in extracellular matrix and cell
membrane
functional differences in expression-based classifications
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summary
• genomics of normal lung development is a useful framework for identifying genes and networks that are dysregulated in lung cancer
• developmental gene signatures do not appear to be tissue specific
• not all cancers exhibit the same developmental gene signature
• the laboratory mouse allow us to investigate early genetic events in normal development and cancer that would not otherwise be possible
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ongoing studies
• developmental gene signatures in other lung tumor types
• developmental signatures in other lung diseases– Interstitial lung disease/ Pulmonary fibrosis
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possible clinical relevance
• correlate gene expression patterns of lung development genes with patient outcomes– Collaboration between JAX and Cancer Care of
Maine just funded by Maine Cancer Foundation to develop new models of lung cancer
• different transcriptional profiles may reflect a variety of strategies used by tumor cells for survival– New therapeutic targets?– Biomarkers?
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acknowledgements
Julie Wells
Cecily Swinburne
Jill Recla
Connie Birkenmeier
Kyle Beauchemin
Anne Peaston
Rita Thibodeau
Marge Strobel
Randy Babiuk
JAX Scientific Services
Isaac KohaneKamila NaxerovaAlvin Kho
Simon Kasif
Maine Cancer FoundationTJL Cancer Center Pilot Project FundsNational Cancer Institute
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