The overarching theme of my research program is the dissection of the role of proteins and networks (master regulators) that drive phenotypic states in normal and cancer cells of the brain. We use global and unbiased approaches to identify the genetic and transcriptional drivers of an obscure but incredibly important aberrant phenotype in brain tumors, the mesenchymal transformation of human high‐grade glioma. This phenotype endows one of the most lethal types of human cancer (the glioblastoma multiforme, GBM) with extremely aggressive features such as the ability to invade the normal brain and form new blood vessels.
In recent work we have identified and validated two transcription factors (Stat3 and C/EBP-beta) that, on their own, are necessary and sufficient to maintain the mesenchymal signature of high‐grade glioma. We now exploit Stat3 and C/EBP-beta as promising therapeutic targets in glioblastoma.
The dissection of transcriptional networks has provided us with invaluable information on the nature of the master regulators that control whole signatures of gene expression. However, cancer is a genetic disease and we recognized that the reconstruction of transcriptional networks should be integrated with the development of systems approaches aimed at identifying novel cancer‐driving genetic alterations. The availability of massively parallel sequencing technologies has revolutionized the field of cancer genetics. By analyzing the whole transcriptome of human glioblastoma, we recently discovered that a subgroup of GBM patients is defined by the presence of gene fusions of FGFR and TACC genes in their tumors.
The identification of FGFR‐TACC fusions in GBM patients and the elucidation of the mechanistic consequences triggered by the fusion proteins for development of brain tumors have allowed us to translate these findings to preclinical models of the disease and design clinical trials in GBM patients harboring FGFR‐TACC fusions. This work provides the first example of an oncogenic and recurrent gene fusion in human GBM and leads our research towards the goal of personalized cancer translation.
Current areas of research include the mechanism of oncogenic transformation by FGFR‐TACC fusion proteins, validation and modeling novel glioblastoma gene fusions in the mouse and identification of novel driver genetic alterations relevant to the maintenance of phenotypically recognizable subtypes of brain tumors.
1. Lasorella A., Benezra R., Iavarone A
. The Id proteins: master regulators of cancer stem cells and tumor aggressiveness Nature Reviews Cancer, February 2014.
2. 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].
3. Danussi C., Akavia U.D., Niola F., Jovic A. , Lasorella A., Pe'er D., Iavarone A
. RHPN2 Drives Mesenchymal Transformation in Malignant Glioma by Triggering RhoA Activation. Cancer Research, 73:5140-5150, 2013.
4. Niola F., Zhao X., Singh D., Sullivan R., Castano A., Verrico A., Zoppoli P., Friedmann-Morvinski D., Sulman E., Barrett L., Zhuang Y., Verma I., Benezra R., Aldape K., Iavarone A
., Lasorella A. The Id-RAP1 axis is essential for glioma maintenance and residency of glioma cells in the perivascular niche. J. Clin. Invest., 123:405-417, 2013.
5. 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.
6. Niola F, Zhao X, Singh D, Castano A, Sullivan R, Lauria M, Nam HS, Zhuang Y, Benezra R, Di Bernardo D, Iavarone A
, Lasorella A. Id proteins synchronize stemness and anchorage to the niche of neural stem cells. Nat. Cell. Biol. 14:477-487, 2012 (see also News and Views Nat Cell Biol. 2012, 14:450-452, Research Highlights Nat Rev Mol Cell Biol. 2012 13:278).
7. Barrett LE, Granot Z, Coker C, Iavarone A
, Hambardzumyan D, Holland EC, Nam HS, Benezra R. Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma. Cancer Cell 17;21(1):11-24, 2012.
8. Schreiber SL, Shamji AF, Clemons PA, Hon C, Koehler AN, Munoz B, Palmer M, Stern AM, Wagner BK, Powers S, Lowe SW, Guo X, Krasnitz A, Sawey ET, Sordella R, Stein L, Trotman LC, Califano A, Dalla-Favera R, Ferrando A, Iavarone A
, Pasqualucci L, Silva J, Stockwell BR, Hahn WC, Chin L, DePinho RA, Boehm JS, Gopal S, Huang A, Root DE, Weir BA, Gerhard DS, Zenklusen JC, Roth MG, White MA, Minna JD, MacMillan JB, Posner BA. Towards patient-based cancer therapeutics. Nat Biotechnol. 28:904-906, 2010.
9. 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 (Article), 463: 318-325, 2010 (see also Research Highlights, Network Spreading. Nature Reviews Cancer, 10:80-81, 2010).