Chief Scientific Officer, DarwinHealth
As a Fellow working under the mentorship of Andrea Califano I am interested in developing and applying cell regulatory models to identify genes and proteins that drive physiologic and pathologic cellular states. I joined the Califano Lab in 2006 as a postdoc with experience in both experimental and computational science, and with the goal of developing and applying systems biology-based approaches to dissect the mechanisms driving tumor initiation and progression. Since then, I have contributed to the development of several novel algorithms (such as CLEANER, MINDy, and MARINa) for assembling context-specific network models of cell regulation and inferring genes and proteins that drive specific phenotypic transitions. I applied this technology to dissect the regulatory logic of human high-grade glioma, identifying STAT3 and C/EBP as synergistic drivers of the mesenchymal subtype of human glioblastoma, and determining that FOXM1 and CENPF are synergistic regulators of the most aggressive subtype of prostate carcinoma.
I am currently using regulatory models to integrate functional genomics, epigenomics, and genetic information to identify combinations of genetic alterations that lead to the dysregulation of the cell regulatory logic in cancer. Specifically, I am studying the role of the cell regulatory logic in integrating a complex and heterogeneous array of genetics alterations into a finite set of distinct pathophysiologic phenotypes, thus accounting for a component of the genetic variability of cancer. Because dissecting tumor heterogeneity at the single patient or even at the single-clone level requires the development of novel methodologies, I recently developed the Virtual Protein-activity Inference by Enriched Regulon analysis (VIPER), an algorithm that leverages context-specific models of regulation to infer tumor-specific driving mechanisms from individual molecular profiles (R-package available from Bioconductor).
In addition to pursuing my primary interest in the elucidation of cancer drivers, I have extended the use of regulatory network models to predict small-molecule compounds that can reprogram cell state or elicit synergistic responses in the cell, with the aim of inferring determinants of drug sensitivity and drug mechanism of action, as well as to predict response to combination therapy. Indeed, dissecting mechanisms driving the neoplastic process and determining drug sensitivity at the single patient level is a critical step towards translational research in precision medicine.
PhD, University of Buenos Aires, Argentina
Biochemistry and Molecular Biology
MS, University of Lujan, Argentina
* Indicates authors contributed equally
Ikiz B, Alvarez MJ, Ré DB, Le Verche V, Politi K, Lotti F, Phani S, Pradhan R, Yu C, Croft GF, Jacquier A, Henderson CE, Califano A, Przedborski S. The regulatory machinery of neurodegeneration in in vitro models of amyotrophic lateral sclerosis. Cell Rep. 2015 Jul 1. pii: S2211-1247(15)00617-8.
Repunte-Canonigo V, Shin W, Vendruscolo LF, Lefebvre C, van der Stap L, Kawamura T, Schlosburg JE, Alvarez M, Koob GF, Califano A, Sanna PP. Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks. Genome Biol. 2015 Feb 2;16(1):68.
Shelanski M, Shin W, Aubry S, Sims P, Alvarez MJ, Califano A. A systems approach to drug discovery in Alzheimer's disease. Neurotherapeutics. 2015 Jan 22.
Bansal M, Yang J, Karan C, Menden MP, Costello JC, Tang H, Xiao G, Li Y, Allen J, Zhong R, Chen B, Kim M, Wang T, Heiser LM, Realubit R, Mattioli M, Alvarez MJ, Shen Y; NCI-DREAM Community, Gallahan D, Singer D, Saez-Rodriguez J, Xie Y, Stolovitzky G, Califano A; NCI-DREAM Community. A community computational challenge to predict the activity of pairs of compounds. Nat Biotechnol. 2014 Dec;32(12):1213-22.
Kushwaha R, Jagadish N, Kustagi M, Tomishima MJ, Mendiratta G, Bansal M, Kim HR, Sumazin P, Alvarez MJ, Lefebvre C, Villagrasa-Gonzalez P, Viale A, Korkola JE, Houldsworth J, Feldman DR, Bosl GJ, Califano A, Chaganti RS. Interrogation of a context-specific transcription factor network identifies novel regulators of pluripotency. Stem Cells. 2014 Oct 21.
Chen JC, Alvarez MJ, Talos F, Dhruv H, Rieckhof GE, Iyer A, Diefes KL, Aldape K, Berens M, Shen MM, Califano A. Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. Cell. 2014 Oct 9;159(2):402-14.
Aytes A, Mitrofanova A, Lefebvre C, Alvarez MJ, Castillo-Martin M, Zheng T, Eastham JA, Gopalan A, Pienta KJ, Shen MM, Califano A, Abate-Shen C. Cross-species analysis of genome-wide regulatory networks identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell. 2014 May 12;25(5):638-51.
Bilal E, Dutkowski J, Guinney J, Jang IS, Logsdon BA, Pandey G, Sauerwine BA, Shimoni Y, Moen Vollan HK, Mecham BH, Rueda OM, Tost J, Curtis C, Alvarez MJ, Kristensen VN, Aparicio S, Borresen-Dale AL, Caldas C, Califano A, Friend SH, Ideker T, Schadt EE, Stolovitzky GA, Margolin AA. Improving breast cancer survival analysis through competition-based multidimensional modeling. PLoS Comput Biol. 2013;9(5):e1003047.
Bisikirska BC, Adam SJ, Alvarez MJ, Rajbhandari P, Cox R, Lefebvre C, Wang K, Rieckhof GE, Felsher DW, Califano A. STK38 is a critical upstream regulator of MYC’s oncogenic activity in human B-cell lymphoma. Oncogene. 2013 Nov 7;32(45):5283-91.
Rodriguez Martinez M, Corradin A, Klein U, Alvarez MJ, Toffolo G, Di Camillo B, Califano A, Stolovitzky G. Quantitative modeling of the terminal differentiation of B cells and mechanisms of lymphomagenesis. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2672-7.
Iñigo S, Alvarez MJ, Strasser B, Califano A, Cerd ́an PD. PFT1, the MED25 subunit of the plant Mediator complex, promotes flowering through CONSTANS dependent and independent mechanisms in Arabidopsis. Plant J. 2012 Feb;69(4):601-12.
Kruithof-de Julio M, Alvarez MJ, Galli A, Chu J, Price SM, Califano A and Shen MM. Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling. Development. 2011 Sep;138(18):3885-95.
Lefebvre C, Rajbhandari P, Alvarez MJ, Bandaru P, Lim WK, Sato M, Wang K, Sumazin P, Kustagi M, Bisikirska BC, Basso K, Beltrao P, Krogan N, Gautier J, Dalla-Favera R, Califano A. A human B cell interactome identifies MYB and FOXM1 as master regulators of proliferation in germinal centers. Mol Syst Biol. 2010 Jun 8;6:377.
Carro MS*, Lim WK*, Alvarez MJ*, Bollo RJ, Zhao X, Snyder EY, Sulman EP, Anne SL, Doetsch F, Colman H, Lasorella A, Aldape K, Califano A, Iavarone A. The transcriptional network for mesenchymal transformation of brain tumors. Nature. 2010 Jan 21;463(7279):318-25.
Basso K*, Saito M*, Sumazin P*, Margolin AA, Wang K, Lim WK, Kitagawa Y, Schneider C, Alvarez MJ, Califano A, Dalla-Favera R (2010). Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal-center B cells. Blood. 2010 Feb 4;115(5):975-84.
Alvarez MJ*, Sumazin P*, Rajbhandari P, Califano A. Correlating measurements across samples improves accuracy of large-scale expression profile experiments. Genome Biol. 2009;10(12):R143.
Wang K, Saito M, Bisikirska BC, Alvarez MJ, Lim WK, Rajbhandari P, Shen Q, Nemenman I, Basso K, Margolin AA, Klein U, Dalla-Favera R, Califano A. Genome-wide identification of post-translational modulators of transcription factor activity in human B-cells. Nat Biotechnol. 2009 Sep;27(9):829-39.
Alvarez MJ*, Salibe MC*, Stolovitzky G, Rubinstein M, Pitossi FJ, Podhajcer OL. Distal tumors elicit distinctive gene expression changes in mouse brain, different from those induced by arthritis. Open Neurosci J. 2009;3:1-13. (*) These authors contributed equally.
Wang K, Alvarez MJ, Bisikirska BC, Linding R, Basso K, Dalla-Favera R, Califano A. Dissecting the interface between signaling and transcriptional regulation in human B cells. Pac Symp Biocomput. 2009:264-75.
Strasser B, Alvarez MJ, Califano A, Cerdan PD. A complementary role for ELF3 and TFL1 in the regulation of flowering time by ambient temperature. Plant J. 2009 May;58(4):629-40.
Prada F, Benedetti LG, Bravo AI, Alvarez MJ, Carbone C, Podhajcer OL. SPARC endogenous level, rather than fibroblast-produced SPARC or stroma reorganization induced by SPARC, is responsible for melanoma cell growth. J Invest Dermatol. 2007 Nov;127(11):2618-28.
Alvarez MJ, Vila-Ortiz GJ, Salibe MC, Podhajcer OL, Pitossi FJ. Model based analysis of real-time PCR data from DNA binding dye protocols. BMC Bioinformatics. 2007 Mar 9;8:85.
Lutzky VP, Carnevale RP, Alvarez MJ, Maffia PC, Zittermann SI, Podhajcer OL, Fainboim L, Issekutz AC, Chuluyan HE. Platelet-endothelial cell adhesion molecule-1 (CD31) recycles and induces cell growth inhibition on human tumor cell lines. J Cell Biochem. 2006 Aug 1;98(5):1334-50.
Alvarez MJ, Prada F, Salvatierra E, Bravo AI, Lutzky VP, Carbone C, Pitossi FJ, Chuluyan HE, Podhajcer OL. Secreted protein acidic and rich in cysteine produced by human melanoma cells modulates polymorphonuclear leukocytes recruitment and anti-tumor cytotoxic capacity. Cancer Res. 2005 Jun 15;65(12):5123-32.
Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege. Cancer Cell. 2004 Mar;5(3):241-51.
Alvarez MJ, Depino AM, Podhajcer OL, Pitossi FJ. Bias in estimations of DNA content by competitive polymerase chain reaction. Anal Biochem. 2000 Dec 1;287(1):87-94.
Momo FR, Alvarez M, Alvarez MJ. Species richness in fluctuating environments: a model involving interespecific competition and physiological stress. J Biological Syst. 1997;5(4):537-46.