Molecular and Cellular Basis of Oncogene Addiction

Summary

Principal Investigator: Dean Felsher
Abstract: Cancer is caused by the activation of oncogenes and the inactivation of tumor suppressor genes. The targeted inactivation and repair of these gene products may be a specific and effective therapy for cancer. Previously, we have shown that the inactivation of the MYC oncogene is sufficient to induce sustained regression of hematopoietic tumors [2]. Subsequently, we reported that even brief inactivation of MYC is sufficient to induce sustained tumor regression of osteosarcoma [3, 4]. Our results support the general hypothesis that tumors exhibit the phenomena of oncogene addiction [5, 6]. To explain our findings, we reasoned that MYC inactivation induces a permanent change in the ability of cells to induce a cancer-associated gene expressionprogram. Upon MYC inactivation, there are specific and sustained changes in gene expression [Wu et al, PLoS Genetics [1];and see Appendix, Shachaf et al, Cancer Research, 2008]. These changes in gene expression are frequently accompanied by permanent changes in the ability of MYC binding to promoter loci, as shown by ChIP. We performed a preliminary ChIP-on-chip analysis for MYC and interrogated changes in binding of other transcription factors in a genome-wide scale. Moreover, we also found that changes in gene expression are associated with specific alterations in chromatin modifications. Importantly, MYC appears to regulate gene expression not just through interactions with the canonical DNA binding sequence (E-Box), but additionally, its binding specificity may be regulated by DNA methylation. We provide new results that illustrate that the TGF-n signaling pathway may play an important role in the mechanism by which MYC inactivation induces changes in gene expression and cellular senescence. Moreover, we provide evidence that MYC regulates DNA methylation. Hence, we hypothesize that MYC inactivation restores auto-regulatory programs, including the induction of CDKIs, through effects on DNA methylation, resulting in the induction of a cellular senescence program. Hence, both cell extrinsic receptor based mechanisms, including TGF-U signaling, as well as cell intrinsic mechanisms, including regulation of DNA methylation, may be critical to oncogene addiction. We now propose experiments and request salary and grant support for a team of 1 principal investigator, 2 post-doctoral fellows and 1 graduate student and a research associates to delineate the role of TGF-13 signaling and DNA methylation on the mechanism of tumor regression upon MYC inactivation. Our results are consistent with the notion that MYC may directly regulate the global chromatin structure;and suggest the surprising idea that MYC-induced tumor cells remain unaware or "amnesic" - as we have recently described [10] - of their cancerous state, yet remain poised to undergo senescence. The results of our proposed experiments will have important implications for the mechanisms by which the MYC oncogene maintains tumorigenesis and the development of new therapies for the treatment of cancer.
Funding Period: ----------------2004 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi CDK2 is required by MYC to induce apoptosis
    Debabrita Deb-Basu
    Division of Oncology, Department of Medicine, Stanford University, Stanford, California 94305 5151, USA
    Cell Cycle 5:1342-7. 2006
  2. pmc A quantitative PCR method to detect blood microRNAs associated with tumorigenesis in transgenic mice
    Alice C Fan
    Stanford University, School of Medicine, Division of Oncology, Department of Medicine, Stanford, CA 94305 5151, USA
    Mol Cancer 7:74. 2008
  3. pmc (18)F and (18)FDG PET imaging of osteosarcoma to non-invasively monitor in situ changes in cellular proliferation and bone differentiation upon MYC inactivation
    Constadina Arvanitis
    Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford, California 94403, USA
    Cancer Biol Ther 7:1947-51. 2008
  4. pmc Inactivation of MYC reverses tumorigenesis
    Y Li
    Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USA
    J Intern Med 276:52-60. 2014
  5. pmc Survival and death signals can predict tumor response to therapy after oncogene inactivation
    Phuoc T Tran
    Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Sci Transl Med 3:103ra99. 2011
  6. pmc CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis
    Bikul Das
    Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Sci Transl Med 5:170ra13. 2013
  7. pmc Characterization of MYC-Induced Tumorigenesis by in Situ Lipid Profiling
    Richard H Perry
    Department of Chemistry, Stanford University, Stanford, California 94305 5080, United States
    Anal Chem 85:4259-62. 2013
  8. pmc Noncanonical roles of the immune system in eliciting oncogene addiction
    Stephanie C Casey
    Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    Curr Opin Immunol 25:246-58. 2013
  9. ncbi Generation of a tetracycline regulated mouse model of MYC-induced T-cell acute lymphoblastic leukemia
    Kavya Rakhra
    Department of Medicine Oncology and Pathology, Stanford University School of Medicine, Stanford, CA, USA
    Methods Mol Biol 1012:221-35. 2013
  10. pmc An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice
    Milena Traykova-Brauch
    Department of Cellular and Molecular Pathology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
    Nat Med 14:979-84. 2008

Scientific Experts

  • PAUL ANTHONY WENDER
  • Dean W Felsher
  • Alice C Fan
  • David I Bellovin
  • Kavya Rakhra
  • Pavan Bachireddy
  • Debabrita Deb-Basu
  • Phuoc T Tran
  • Shelly Beer
  • Catherine M Shachaf
  • Chi Hwa Wu
  • Pavan K Bendapudi
  • Joy Chen
  • Constadina Arvanitis
  • Jan van Riggelen
  • Sylvie Giuriato
  • Y Li
  • Stephanie C Casey
  • Bikul Das
  • Richard H Perry
  • Brian A DeChristopher
  • Tahera Zabuawala
  • Zhongwei Cao
  • Peter S Choi
  • Qiwei Yang
  • George Horng
  • Sanjiv Sam Gambhir
  • Andrew J Gentles
  • Sylvia K Plevritis
  • Shan Koh
  • Kimberly Komatsubara
  • Milena Traykova-Brauch
  • Sandra Ryeom
  • Debashis Sahoo
  • Omar D Perez
  • Maria Chang
  • Garry P Nolan
  • Sailaja Elchuri
  • Orr Sharpe
  • Suma Ray
  • S C Casey
  • D W Felsher
  • Emelyn H Shroff
  • Antonio Campos-Neto
  • Ista Pulu
  • Vijay Swami
  • Deepjyoti Kalita
  • Suely S Kashino
  • Richard N Zare
  • Herman Yeger
  • Ali I Ismail
  • Lawrence H Schwartz
  • Julia Arzeno
  • Stacey J Adam
  • Nicholas P Hughes
  • Aleksey Yevtodiyenko
  • H Jill Lin
  • Peter Choi
  • Hua Fan-Minogue
  • Toshio Kitamura
  • David Paik
  • Toshiyuki Kawashima
  • Vincent A Miller
  • Mark A Kay
  • Corrine R Davis
  • Lora S Wang
  • Kathleen Börner
  • Andrew Kopelman
  • Erika Crosby
  • Theresa A Storm
  • Liwen Xu
  • Huishan Koh
  • Dirk Grimm
  • Robert Zeiser
  • Lior Braunstein
  • Joyce S Lee
  • Kim Komatsubara
  • Hermann Josef Grone
  • Adam B Glick
  • Jennifer Ho
  • Jurgen Horst
  • Kai Schonig
  • Oliver Greiner
  • Jeffrey R Tseng
  • David Dill
  • William H Robinson
  • Magnus von Knebel Doeberitz
  • MARIANNA M GOLDRICK
  • Anna Jauch
  • Tewfik Miloud

Detail Information

Publications26

  1. ncbi CDK2 is required by MYC to induce apoptosis
    Debabrita Deb-Basu
    Division of Oncology, Department of Medicine, Stanford University, Stanford, California 94305 5151, USA
    Cell Cycle 5:1342-7. 2006
    ..The inhibition of CDK2 did not prevent apoptosis induced by the DNA damaging agent etoposide. Our results surprisingly suggest that CDK2 defines whether MYC induction causes apoptosis...
  2. pmc A quantitative PCR method to detect blood microRNAs associated with tumorigenesis in transgenic mice
    Alice C Fan
    Stanford University, School of Medicine, Division of Oncology, Department of Medicine, Stanford, CA 94305 5151, USA
    Mol Cancer 7:74. 2008
    ..Our results suggest that specific changes in blood miRNA can be detected during tumorigenesis and tumor regression...
  3. pmc (18)F and (18)FDG PET imaging of osteosarcoma to non-invasively monitor in situ changes in cellular proliferation and bone differentiation upon MYC inactivation
    Constadina Arvanitis
    Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford, California 94403, USA
    Cancer Biol Ther 7:1947-51. 2008
    ....
  4. pmc Inactivation of MYC reverses tumorigenesis
    Y Li
    Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USA
    J Intern Med 276:52-60. 2014
    ..Hence, tumours appear to be addicted to the MYC oncogene because of both tumour cell intrinsic and host-dependent mechanisms. MYC is important for the regulation of both the initiation and maintenance of tumorigenesis. ..
  5. pmc Survival and death signals can predict tumor response to therapy after oncogene inactivation
    Phuoc T Tran
    Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Sci Transl Med 3:103ra99. 2011
    ....
  6. pmc CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis
    Bikul Das
    Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Sci Transl Med 5:170ra13. 2013
    ..These results suggest that CD271(+) BM-MSCs may provide a long-term protective intracellular niche in the host in which dormant Mtb can reside...
  7. pmc Characterization of MYC-Induced Tumorigenesis by in Situ Lipid Profiling
    Richard H Perry
    Department of Chemistry, Stanford University, Stanford, California 94305 5080, United States
    Anal Chem 85:4259-62. 2013
    ..Our approach provides a strategy to define a precise molecular picture at a resolution of about 200 μm that may be useful in identifying lipid molecules that define how the MYC oncogene initiates and maintains tumorigenesis. ..
  8. pmc Noncanonical roles of the immune system in eliciting oncogene addiction
    Stephanie C Casey
    Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    Curr Opin Immunol 25:246-58. 2013
    ..The combination of oncogene-targeted therapy together with immunomodulatory therapy may be ideal for the development of both robust tumor intrinsic and immunological responses, effectively leading to sustained tumor regression...
  9. ncbi Generation of a tetracycline regulated mouse model of MYC-induced T-cell acute lymphoblastic leukemia
    Kavya Rakhra
    Department of Medicine Oncology and Pathology, Stanford University School of Medicine, Stanford, CA, USA
    Methods Mol Biol 1012:221-35. 2013
    ..In this protocol, we describe the methods involved in the development of a conditional mouse model of MYC-induced T-cell acute lymphoblastic leukemia...
  10. pmc An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice
    Milena Traykova-Brauch
    Department of Cellular and Molecular Pathology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
    Nat Med 14:979-84. 2008
    ..These experiments establish Pax8-rtTA mice as a powerful tool for modeling renal diseases in transgenic mice...
  11. pmc Genomic and proteomic analysis reveals a threshold level of MYC required for tumor maintenance
    Catherine M Shachaf
    Department of Medicine and Pathology, Division of Medical Oncology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA
    Cancer Res 68:5132-42. 2008
    ..Thus, at the MYC threshold, there is a loss of its ability to maintain tumorigenesis, with associated shifts in gene and protein expression that reestablish cell cycle checkpoints, halt protein translation, and promote apoptosis...
  12. pmc Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis
    Catherine M Shachaf
    Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, CA 94305 5151, USA
    Blood 110:2674-84. 2007
    ..Thus, atorvastatin, by inhibiting HMGcoA reductase, induces changes in phosphoprotein signaling that in turn prevent MYC-induced lymphomagenesis...
  13. pmc Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch
    Sylvie Giuriato
    Departments of Medicine and Pathology, Division of Oncology, Stanford University School of Medicine, CCSR Building, Room 1120, 269 Campus Drive, Stanford, CA 94305 5151, USA
    Proc Natl Acad Sci U S A 103:16266-71. 2006
    ..Therefore, the combined inactivation of oncogenes and angiogenesis may be a more clinically effective treatment of cancer. We conclude that angiogenesis is an essential component of oncogene addiction...
  14. ncbi MYC can induce DNA breaks in vivo and in vitro independent of reactive oxygen species
    Suma Ray
    Division of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA
    Cancer Res 66:6598-605. 2006
    ..Hence, MYC overexpression can induce ROS and SSBs under some conditions, but generally induces widespread DSBs in vivo and in vitro independent of ROS production...
  15. ncbi MYC can enforce cell cycle transit from G1 to S and G2 to S, but not mitotic cellular division, independent of p27-mediated inihibition of cyclin E/CDK2
    Debabrita Deb-Basu
    Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, California, USA
    Cell Cycle 5:1348-55. 2006
    ..Our results have implications for the mechanisms by which MYC overexpression dysregulates cell cycle transit, causes genomic destabilization and is restrained from causing tumorigenesis...
  16. pmc Combined Inactivation of MYC and K-Ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas
    Phuoc T Tran
    Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, United States of America
    PLoS ONE 3:e2125. 2008
    ..However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment...
  17. pmc Combined analysis of murine and human microarrays and ChIP analysis reveals genes associated with the ability of MYC to maintain tumorigenesis
    Chi Hwa Wu
    Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California, United States of America
    PLoS Genet 4:e1000090. 2008
    ..Hence, through our analysis of gene expression in murine tumor models and human lymphomas, we have identified a novel gene signature correlated with the ability of MYC to maintain tumorigenesis...
  18. pmc Hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis
    Shelly Beer
    Department of Medicine, Division of Oncology, School of Medicine, Center for Clinical Sciences Research, Stanford University, Stanford, California, United States of America
    PLoS ONE 3:e2493. 2008
    ....
  19. pmc Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation
    Chi Hwa Wu
    Department of Medicine, Division of Oncology, Stanford University School of Medicine, CA 94305, USA
    Proc Natl Acad Sci U S A 104:13028-33. 2007
    ..Our results suggest that cellular senescence programs remain latently functional, even in established tumors, and can become reactivated, serving as a critical mechanism of oncogene addiction associated with MYC inactivation...
  20. pmc "Picolog," a synthetically-available bryostatin analog, inhibits growth of MYC-induced lymphoma in vivo
    Brian A DeChristopher
    Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, CA 94305 5080
    Oncotarget 3:58-66. 2012
    ..We provide the first in vivo validation that the bryostatin analog, picolog, is a potential therapeutic agent for the treatment of cancer and other diseases...
  21. pmc Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction
    Peter S Choi
    Division of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 108:17432-7. 2011
    ..These results suggest that tumors induced by MYC remain addicted to overexpression of this oncogene...
  22. pmc MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase
    Zhongwei Cao
    Division of Medical Oncology, Department of Medicine and Pathology, Molecular Imaging Program at Stanford, Stanford University, Stanford, California 94305, USA
    Cancer Res 71:2286-97. 2011
    ..The inhibition of HMG-CoA reductase may be a useful target for the treatment of MYC-associated HCC as well as other tumors...
  23. pmc MYC Inactivation Elicits Oncogene Addiction through Both Tumor Cell-Intrinsic and Host-Dependent Mechanisms
    Dean W Felsher
    Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA, USA
    Genes Cancer 1:597-604. 2010
    ..Hence, targeting the inactivation of MYC appears to elicit oncogene addiction and, thereby, tumor regression through both tumor cell-intrinsic and host-dependent mechanisms...
  24. pmc CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation
    Kavya Rakhra
    Division of Oncology, Departments of Medicine, Pathology and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305, USA
    Cancer Cell 18:485-98. 2010
    ..Hence, CD4(+) T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction...
  25. pmc Low-level shRNA cytotoxicity can contribute to MYC-induced hepatocellular carcinoma in adult mice
    Shelly Beer
    Department of Medicine, Division of Oncology, School of Medicine, Center for Clinical Sciences Research, Stanford University, Stanford, California 94305 5151, USA
    Mol Ther 18:161-70. 2010
    ..Our data warrant caution regarding the possible carcinogenic potential of shRNAs when used as clinical agent, particularly in circumstances where tissues are genetically predisposed to cellular transformation and proliferation...