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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 Laboratory 1937. U.S. Science Wars Against Cancer. The Jackson Laboratory

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U.S. Science Wars Against Cancer

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  1. “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 Laboratory 1937 U.S. Science Wars Against Cancer

  2. The Jackson Laboratory Bar Harbor, Maine Bar Harbor, Maine Sacramento, California • 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 Farmington, Connecticut

  3. Mission Mission We discover the genetic basis for preventing, treating and curing human disease, and we enable research and education for the global biomedical community. Research Resource Education

  4. Research Research 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

  5. Resource Resource 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

  6. Outreach and Education Outreach • 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

  7. 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 the • biomedical research platform for the • 21st Century.” • Harold Varmus, Director, National Cancer Institute

  8. 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

  9. 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?

  10. Rudolf Virchow, 1859

  11. old question; new approaches genomes genomics informatics

  12. lung development in mouse • 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 prealveolatesaccules • 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 http://www.cincinnatichildrens.org/research/div/pulmonary-biology/faculty-research/whitsett-lab/projects.htm

  13. lung development stages are similar in mouse and human Developmental Stage Timeline for mouse Timeline for human http://www.aups.org.au/Proceedings/36/9-13/

  14. approach: compare global gene expression during of normal development (mouse) to global gene expression of tumors (human)

  15. transcriptional profiling of lung development E11.5 E13.5 E14.5 E16.5 P5 E = embryonic P = postnatal Images from Malpel S, Development (2000) 127:3057-67

  16. 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

  17. Bright spots indicates positive hybridization events (i.e. active genes) • The analysis software “knows” the address of every gene and generates a report of gene activity (expression)

  18. 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

  19. Number of genes that match the expression profile 312 349 196 141 431 320 139 28,000+ genes on chip ~20,000 genes don’t change ~5,000 genes assigned to profiles http://www.cs.cmu.edu/~jernst/stem/

  20. 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

  21. finding common biological themes in lists of genes analyze biological systems and processes, not individual genes.

  22. biological systems represented by genes whose expression levels…. increase during murine lung development: decrease during murine lung development: Cell Adhesion System Development Anatomical System Development Vasculature Development Blood Vessel Development Angiogenesis Cell Cycle Cell Division DNA Repair Mitosis Regulation of transcription “Early expression group” “Late expression group”

  23. 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

  24. 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/

  25. differential gene expression: tumor vs normal • Microarray Analysis of Variance (MAANOVA)** A vs N (q<0.05) ** http://www.jax.org/staff/churchill/labsite/software/anova/index.html

  26. 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

  27. opposite gene expression trends similar biological systems; human lung tumor (adenocarcinoma) Cell Adhesion System Development Anatomical System Development Vasculature Development Blood Vessel Development Angiogenesis Cell Cycle Cell Division Mitosis normal mouse lung development Cell Adhesion System Development Anatomical System Development Vasculature Development Blood Vessel Development Angiogenesis Cell Cycle Cell Division DNA Repair Mitosis Regulation of transcription “Early expression group” “Late expression group”

  28. integrating development and cancer genomics • 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?

  29. Divide up the developmental timeline into segments, bin the ~5,000 or so genes that have expression levels related to development. Developmental Timeline (DT) Early Late 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.

  30. Frequency No association Ambiguous association Frequency Frequency Strong association

  31. quantifying developmental gene expression signatures

  32. 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?

  33. developmental gene expression signatures for cancer are not tissue specific

  34. not all cancers exhibit an early developmental gene expression signature

  35. 10 developmental time series 32 disease data sets (mostly cancer) Naxerova et al. 2008. Genome Biology. 9:R108

  36. 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

  37. functional differences in expression-based classifications • 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

  38. 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

  39. ongoing studies • developmental gene signatures in other lung tumor types • developmental signatures in other lung diseases • Interstitial lung disease/ Pulmonary fibrosis

  40. 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?

  41. acknowledgements Julie Wells Cecily Swinburne Jill Recla Connie Birkenmeier Kyle Beauchemin Anne Peaston Rita Thibodeau Marge Strobel Randy Babiuk JAX Scientific Services Isaac Kohane KamilaNaxerova Alvin Kho Simon Kasif Maine Cancer Foundation TJL Cancer Center Pilot Project Funds National Cancer Institute

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