Research Faculty

Address
ICRC, room 404
1130 St. Nicholas Ave.
New York NY 10032

Phone: 212-851-5240
Fax:

al2179@cumc.columbia.edu
Affiliations
Pathobiology
Anna Lasorella,
Associate Professor of Pediatrics and Pathology and Cell Biology
Institute of Cancer Genetics
Research Summary

My laboratory uses the nervous system as a paradigm model to gain molecular and mechanistic insights into the coordination of cell growth and differentiation. We use biochemical approaches, mouse genetics and bioinformatics to identify genes and cellular pathways that function in embryonic cells to coordinate cell growth and differentiation and are aberrantly recruited by tumor cells. The main concept is that cancer is a disease of differentiation, which translates in aberrant cell proliferation and survival signals and restoring differentiation mechanisms is a potential strategy to treat human cancer.

We have focused on the role of transcription factors that operate during normal development to preserve the neural stem cell (NSC) state and prevent premature differentiation. We have postulated that these factors will be hijacked during oncogenic transformation to lock cancer cells in an irreversible stem‐like state. The molecules that better helped us to understand this paradigm are the Id (Inhibitor of differentiation) proteins and the N‐myc proto‐oncogene. Our work revealed that Id proteins are master regulators of NSCs, where they operate to coordinate the stem cell state with the anchorage to a specialized niche microenvironment but are recruited by brain tumor cells to initiate and maintain their most aggressive features.

Over the last few years we studied the regulation of N‐Myc in neural stem cells we
identified the natural protein complexes engaged by N‐Myc using a state‐of‐the‐art proteomic approach. Among the N‐myc protein partners we identified the ubiquitin ligase Huwe1. Huwe1 targets N‐myc protein for degradation during differentiation and cell cycle arrest in the developing nervous system and neuroblastoma cells. The most exciting novel finding that originated from the identification of the Huwe1‐N‐myc pathway in neural cells is that primary neural tumors in humans carry focal genetic deletions of the Huwe1 gene. These results identify Huwe1 as a new tumor suppressor gene in neural tumors and establish an unprecedented link between neural stem cell renewal and tumor development.
Selected Publications

1. Frattini V., Trifonov V., Chan J.M., Castano A., Lia M., Abate F., Keir S.T., Ji A.X., Zoppoli P., Niola F., Danussi C., Dolgalev I., Porrati P., Pellegatta S., Heguy A., Gupta G., Pisapia D.J., Canoll P., Bruce J.N., McLendon R.E., Yan H., Aldape K., Finocchiaro G., Mikkelsen T., Privé G.G., Bigner D.D., Lasorella A., Rabadan R., Iavarone A. The integrated landscape of driver genomic alterations in glioblastoma. Nature Genetics, 45:1141-1149, 2013 [see also Nat Genet. NEWS and VIEWS 2013;45:1105-7. Genomics informs glioblastoma biology. Nature Reviews Clinical Oncology RESEARCH HIGHLIGHTS. 10:547, 2013 Glioblastoma landscape revealed; Cancer Discovery RESEARCH WATCH. 3:OF19, 2013. Driver alterations in glioblastoma suggest new therapeutic targets; Nature Reviews Neurology NEWS and VIEWS. 9:612-613, 2013]. PMCID: PMC3799953

2. Niola F., Zhao X., Singh D., Sullivan R, Castano A, Verrico A., Zoppoli P., Friedmann-Morvinski D., Sulman E., Barret L., Zhuang Y., Verma I.,Benezra R., Aldape K., Iavarone A, Lasorella A. Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis. J. Clin. Invest. 123:405-417, 2013. PMCID: PMC3635493

3. Singh D., Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Liu EM, Reichel J, Porrati P, Pellegatta S, Qiu K, Gao Z, Ceccarelli M, Riccardi R, Brat DJ, Guha A, Aldape K, Golfinos JG, Zagzag D, Mikkelsen T, Finocchiaro G, Lasorella A., Rabadan R, Iavarone A. Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma Science 337:1231-1235, 2012. [see also Nature Reviews Cancer (12: 585, 2012). RESEARCH HIGHLIGHTS “Glioblastoma: Transforming fusions induce aneuploidy”, Cancer Discovery (2: 761, 2012). RESEARCH WATCH “FGFR–TACC Fusion Proteins Are Oncogenic in Glioblastoma”, Nature Medicine (18: 1472, 2012). RESEARCH HIGHLIGHTS “Finding Fusions”, Science Signaling (5: ec238, 2012). EDITORS’ CHOICE “Oncogenic TACC-tics”, Nature Reviews Clinical Oncology (9: 550, 2012). RESEARCH HIGHLIGHT “Constitutive fusion-protein kinase activity identified in GBM”, SciBX: Science-Business eXchange 5(34); doi:10.1038/scibx.2012.893, Neurology Today (12: P 27, 2012). ARTICLE IN BRIEF “Two New Mutations Identified as Potential Therapeutic Targets for Glioblastoma Multiforme”, HemOnc Today (September 10, 2012). NEWS “Some cases of glioblastoma caused by two fused genes, The Wall Street Journal (July 26, 2012) BY RON WISLOW “Some Brain Tumors Are Linked to a Gene Defect”, NCI-The Cancer Genome Atlas (December 18, 2012) BY PRITTY PATEL JOSHI “Researchers use TCGA Glioblastoma data in the discovery of a novel fusion gene implicated in a subset of brain tumors”, NCI Cancer Bulletin 9(16) page 3, August 7, 2012 “Discovery of fused genes in brain cancer points to possible treatment”, Discover Magazine January/February 2013 THE 100 TOP SCIENCE STORIES OF 2012 “#40 Brain cancer traced back to fused genes” page 49. PMCID: PMC3677224

4. Jones-Mason ME, Zhao X, Kappes D, Lasorella A., Iavarone A, Zhuang Y. E protein transcription factors are required for the development of CD4(+) lineage T cells. Immunity. Mar 23;36(3):348-61, 2012. PMCID: PMC3431168

5. Niola F., Zhao X., Singh D., Castano A., Sullivan R., Lauria M., Num Y., Zhuang Y., Benezra R., Di Bernardo D., Iavarone A, Lasorella A.. Id proteins synchronize stemness and anchorage to the niche of neural stem cells. Nature Cell Biol. 14:477-87, 2012. (see also News and Views Nat Cell Biol. 2012, 14:450-452, Research Highlights Nat Rev Mol Cell Biol. 2012 13:278). PMCID: PMC3635493

6. Carro M.S., Lim W.K., Alvarez M.J., Bollo R.J., Zhao X., Snyder E.Y., Sulman E.P., Anne S. L., Doetsch F., Colman H., Lasorella A., Aldape K., Califano A., Iavarone A. A transcriptional module synergistically initiates and maintains mesenchymal transformation in the brain. Nature, 463(7279): 318-25, 2010.

7. Zhao X, D' Arca D, Lim WK, Brahmachary M, Carro MS, Ludwig T, Cardo CC, Guillemot F, Aldape K, Califano A, Iavarone A, Lasorella A. The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain. Dev Cell. (2009) Aug;17(2):210-21.

8. Zhao X, Heng JI, Guardavaccaro D, Jiang R, Pagano M, Guillemot F, Iavarone A, Lasorella A. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat Cell Biol. (2008) Jun;10(6):643-53. Epub 2008 May 18.

9. Iavarone A, Lasorella A. ID proteins as targets in cancer and tools in neurobiology. Trends Mol Med. (2006) Dec;12(12):588-94. Epub 2006 Oct 30. Review.

10. Lasorella A., Stegmuller J, Guardavaccaro D, Liu G, Carro MS, Rothschild G, de la Torre-Ubieta L, Pagano M, Bonni A, Iavarone A. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature. (2006) Jul 27;442(7101):471-4. Epub 2006 Jun 28.

11. Rothschild G, Zhao X, Iavarone A, Lasorella A.. E Proteins and Id2 converge on p57Kip2 to regulate cell cycle in neural cells. Mol Cell Biol. (2006) Jun;26(11):4351-61.

12. Lasorella A., Rothschild G, Yokota Y, Russell RG, Iavarone A. Id2 mediates tumor initiation, proliferation, and angiogenesis in Rb mutant mice. Mol Cell Biol. (2005) May;25(9):3563-74.
Current Projects

Current areas of research include the mechanism of oncogenic transformation by Id proteins and the identification of novel Id protein targets relevant to the maintenance of stem cell properties using conditional compound knockout mice for the Id genes. We also study novel Huwe1 substrates in neural development and cancer.


Keywords

Brain development, brain tumors, cancer stem cells, ID proteins

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