Id proteins are master regulators of cell proliferation, differentiation and self-renewal of stem cells. Development of the adult organism requires suppression of Id function whereas persistent Id activation leads to tumor formation. Aberrant expression of Id proteins has been detected in most types of human cancer, in which it sustains key hallmarks of tumor progression such as unrestrained proliferation, anaplasia and tumor angiogenesis. During the past funding cycle, we demonstrated that the proliferative and angiogenic responses induced by Id are rate limiting for tumor development. Using a mouse tumor model in which pituitary cancer is initiated by loss of the Rb tumor suppressor gene, we discovered that each of the crucial traits of tumor growth (initiation, tumor cell proliferation and angiogenesis) requires Id activity. Collectively, these findings suggest that targeting Id proteins may have widespread benefit in preventing tumor initiation and maintenance. All analyses described above were performed using tissues and cells from Id2 knockout mice in which the Id2 gene had been constitutively inactivated throughout embryogenesis. What is the requirement for Id function after the acute and combined deletion of all the Id genes? The embryonic lethality of compound Id null mice precluded us from addressing this question. We are in the process of generating conditional Id1/2/3 triple-knockout mice.
In Aim 1, we will use cells and tissues from these mice to by-pass the embryonic lethality and study Id function in the neural stem cell compartment. We previously showed that Id2-null cells showed greatly reduced susceptibility to oncogenic transformation. A critical, unresolved question is whether ablation of Id genes in already transformed cells would revert the transformed phenotype. Given the pervasive and aggressive nature of the """"""""angiogenic switch"""""""" in neuroectodermal tumors and its dependency on Id expression, we have focused on this cellular system. Thus, we will address this issue in Aim 2 by testing the requirement for Id function in a mouse model for malignant glioma. This issue is very important from a clinical standpoint, and it must be resolved before anti-Id therapy in human cancer patients is entertained. We found that Id proteins enhance tumor angiogenesis by increasing the production of Vascular Endothelial Growth Factor (VEGF) through stabilization of the Hypoxia Inducible Factor alpha (HIF?), the main inducer of VEGF expression in human cancer. We have begun exploring the mechanistic basis of this observation. We have now found that Id proteins interfere with the assembly of the Von Hippel Lindau (VHL) ubiquitin ligase, a multi- subunit tumor suppressor complex whose primary function is destruction of HIF? in oxygenated cells. In the work described in Aim 3, we will follow up on these observations with detailed mechanistic analyses. Thus, the proposed study for the next funding cycle will conclusively address the role of Id proteins in the initiation and progression of malignant brain tumors and validate Id as targets for therapeutic intervention in this incurable cancer.

Public Health Relevance

Id proteins are master regulators of cell proliferation, differentiation and self-renewal of stem cells. Development of the adult organism requires suppression of Id function whereas persistent Id activation leads to tumor formation. Malignant gliomas are among the most lethal human cancers. In this proposal, we will study how Id proteins promote relentless tumor cell proliferation and angiogenesis, key hallmarks of tumor progression in the brain. Ultimate goal of our work is to provide novel therapeutic targets to attack this intractable disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Frattini, VĂ©ronique; Pagnotta, Stefano M; Tala et al. (2018) A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature 553:222-227
Wang, Jiguang; Cazzato, Emanuela; Ladewig, Erik et al. (2016) Clonal evolution of glioblastoma under therapy. Nat Genet 48:768-76
Lee, Sang Bae; Frattini, Veronique; Bansal, Mukesh et al. (2016) An ID2-dependent mechanism for VHL inactivation in cancer. Nature 529:172-7
Di Stefano, Anna Luisa; Fucci, Alessandra; Frattini, Veronique et al. (2015) Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma. Clin Cancer Res 21:3307-17
Iavarone, Antonio; Lasorella, Anna (2014) Myc and differentiation: going against the current. EMBO Rep 15:324-5
Frattini, Veronique; Trifonov, Vladimir; Chan, Joseph Minhow et al. (2013) The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45:1141-9
Danussi, Carla; Akavia, Uri David; Niola, Francesco et al. (2013) RHPN2 drives mesenchymal transformation in malignant glioma by triggering RhoA activation. Cancer Res 73:5140-50
Niola, Francesco; Zhao, Xudong; Singh, Devendra et al. (2013) Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis. J Clin Invest 123:405-17
Niola, Francesco; Zhao, Xudong; Singh, Devendra et al. (2012) Id proteins synchronize stemness and anchorage to the niche of neural stem cells. Nat Cell Biol 14:477-87
Singh, Devendra; Chan, Joseph Minhow; Zoppoli, Pietro et al. (2012) Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337:1231-5

Showing the most recent 10 out of 16 publications