Alejandro Sweet-Cordero

Clinical Focus

• Pediatric Hematology-Oncology

Honors and Awards

• Scholar Award, Rita Allen Foundation (2008-2011)
• Clinical Scientist Development Award, Doris Duke Foundation (2007-2010)
• Sidney Kimmel Scholar, Sidney Kimmel Foundation (2006-2008)

Professional Education

Postdoctoral Advisees

Alexandra Abrams,  Dana Gwinn,  Bethsaida Nieves,  David Simpson

Graduate & Fellowship Program Affiliations

• Cancer Biology
• Pediatrics

Internet Links

• Sweet-Cordero Laboratory

Current Research Interests

Our laboratory is devoted to the analysis of pathways involved in the initiation, progression, and maintenance of cancer. Utilizing the mouse as a model system, we strive to understand aberrant oncogenic signaling, the role of the tumor microenvironment and the mechanisms involved in chemotherapy response and resistance at the molecular, cellular, and organismal levels.

We use genome-wide analysis tools (microarrays, proteomics, etc) to understand the consequences of oncogenic mutations at a system-wide level. We have found that comparing genome-wide changes in a model system with those seen in primary human tumors is a fruitful approach for the discovery of novel genes and pathways important in oncogenesis. We continue to exploit such cross species comparisons as a tool for understanding cancer pathways and networks. We also rely heavily on shRNA technology both in vitro and in vivo to perform functional studies of genes identified in our genomic screens.

Specific Projects Include:

Kras signaling.

Kras is one of the most frequently mutated genes in human cancer. Many signaling pathways (MAPK, AKT, RALGDS) have been described as being necessary for Kras induced oncogenic transformation. However, the specific pathways required are strongly dependent on the tissue origin (fibroblast vs epithelial cell) and the species of the model system used.

Using cross-species microarray analysis, we have uncovered a gene expression profile associated with Kras mutation across species and in different tissues. We are using shRNA- based screens to study the functional significance of this signature. We are using this gene expression signature to understand how aberrant Kras signaling relays information to transcription factors that ultimately lead to changes in gene expression. Using a combination of biochemical, cell-based and in vivo studies, we are identifying novel genes involved in Kras induced oncogenesis and characterizing their function in the hopes of identifying novel therapeutic targets.


Chemotherapy response in vivo

Despite decades of use in clinical medicine, much is still unknown about the molecular and cellular determinants of chemotherapy response in cancer. Why are some tumors sensitive to chemotherapy treatment whereas others are highly resistant? To what extent are these properties due to genetic mutations in tumor cells (i.e, p53 loss) and to what extent are they determined by the cellular context and microenvironment in which the tumor exists? We believe that important differences exist between how tumor cells in a plastic dish respond to therapy and how tumors in an organism respond to therapy. Therefore, we rely on mouse models that closely recapitulate important aspects of human oncogenesis to study chemotherapy response. Using shRNA delivery in vivo, we are analyzing how specific signaling pathways modulate the response to chemotherapy in cancer cell. We are also interested in exploring whether “tumor stem cells” are intrinsically resistant to chemotherapy and to what extent self renewal pathways alter the molecular response to chemotherapy treatment.

Modeling solid tumor translocations in vivo and in vitro

Translocations are frequent genetic events in the genesis of many human cancers. They are particularly frequent in tumors common in pediatric patients (leukemias, sarcomas). We use gene targeting to produce mouse models in which translocation events can be activated temporally or in specific tissues. In particular, our laboratory is using gene targeting approaches in the mouse to study the oncogenesis mediated by fusion of the gene EWS with ets family transcription factors such as Fli-1 and Erg. Such translocations are seen in Ewing’s Sarcoma, a bone tumor found mostly in children.

Using human mesenchymal stem cells, we are also exploring what genetic events other than oncogenic translocation are required for tumor initiation and progression.

Clinical Trials

• Genomic Analysis of Pediatric Bone Tumors Recruiting

Publications

• Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Oliver TG, Mercer KL, Sayles LC, Burke JR, Mendus D, Lovejoy KS, Cheng MH, Subramanian A, Mu D, Powers S, Crowley D, Bronson RT, Whittaker CA, Bhutkar A, Lippard SJ, Golub T, Thomale J, Jacks T, Sweet-Cordero EA. Genes Dev. 2010; 24 (8): 837-52
• Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models. Vicent S, Chen R, Sayles LC, Lin C, Walker RG, Gillespie AK, Subramanian A, Hinkle G, Yang X, Saif S, Root DE, Huff V, Hahn WC, Sweet-Cordero EA. J Clin Invest. 2010; 120 (11): 3940-52
• An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Sweet-Cordero A, Mukherjee S, Subramanian A, You H, Roix JJ, Ladd-Acosta C, Mesirov J, Golub TR, Jacks T. Nat Genet. 2005; 37 (1): 48-55
• Expression and silencing of the microtubule-associated protein Tau in breast cancer cells. Spicakova T, O'Brien MM, Duran GE, Sweet-Cordero A, Sikic BI. Mol Cancer Ther. 2010; 9 (11): 2970-81
• Hypoxia in models of lung cancer: implications for targeted therapeutics. Graves EE, Vilalta M, Cecic IK, Erler JT, Tran PT, Felsher D, Sayles L, Sweet-Cordero A, Le QT, Giaccia AJ. Clin Cancer Res. 2010; 16 (19): 4843-52