Francisco Vega-Vazquez, M.D., Ph.D.
Professor of Pathology
Description of Research
The research in Dr. Vega's laboratory is directed at exploring the role of Hedgehog (Hh) signaling in the pathobiology of malignant lymphomas, in particular diffuse large B-cell lymphoma (DLBCL).
DLBCL is the most common lymphoid malignancy in adults accounting for approximately 30,000 new cases each year. Many aspects of the pathophysiology of DLBCL, particularly regarding tumor cell growth, survival and chemotolerance, are still poorly understood, hampering new therapeutic approaches. Although DLBCL is potentially curable with conventional anthracycline-based therapy, variability in response is often observed, and eventually many (~50%) patients relapse and ultimately die of their disease. The cellular mechanisms contributing in drug resistance and treatment failure in DLBCL are poorly understood and their elucidation could lead to development of new therapeutic approaches. Therefore, new advances in the molecular pathobiology of DLBCL are needed and they are expected to contribute to the development of new therapeutic approaches.
Dr. Vega's lab has demonstrated that the canonical Hh ligand-PTCH1- smoothened (SMO)-GLI1 axis is functional in DLBCL. Activated Hh signaling was identified in our laboratory to contribute to cell survival, proliferation and stroma-induced chemotolerance of DLBCL suggesting that targeting Hh signaling may be of therapeutic value in DLBCL (Leukemia 2010, Oncogene 2011). Regarding SMO (Hh signal transducer subunit), the lab found that SMO recruits and activates trimeric G proteins to activate PKCb/CARMA1/TRAF6/NEMO axis, followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO resulting in NF-kB activation (Blood 2013). This finding defines a novel mechanism of NF-kB activation in DLBCL and is of clinical interest as effective inhibitors of SMO and NF-kB are currently available for clinical use.
The lab has also demonstrated that GLI1 is aberrantly activated in a subset of DLBCL and that GLI1 is essential for cell proliferation and survival in DLBCL (J Biol Chem 2013). This activation results from integration of deregulated oncogenic signaling inputs converging into Hh signaling (Leuk Res 2012). To address how GLI1 affects the biology of DLBCL, we have searched for GLI1-target gene promoters using chromatin immunoprecipitation (ChiP) assays followed by gene sequencing. The lab has validated some of the identified GLI1-target gene promoters as novel direct downstream targets of GLI1. We confirmed that GLI1 directly regulates the transcription of AKT1, 2 and 3 genes (J Biol Chem 2013).
Dr. Vega and his lab are now investigating the transcriptional regulation of GLI1 as well its transcriptional signature with the final goal of finding novel therapeutic approaches to treat DLBCL.
- Provided evidence that Hh signaling pathway is functional in DLBCL cells and that promotes DLBCL growth, survival and chemotolerance.
- Discovered that the ATP binding cassette sub family G member 2 (ABCG2) and AKT genes are direct transcriptional targets of GLI1.
- Discovered that NPM-ALK, through activation of PI3K/AKT, contributes to activation of Hh signaling, which in turn contributes to cell proliferation and survival in ALK-positive anaplastic large cell lymphoma.
- Discovered that SMO modulates the activity of NF-kB independently of GLI. We found that SMO activates trimeric G proteins and CARMA-1 associated signaling complex, leading to NF-kB activation.
- Agarwal NK, Qu C, Kunkalla K, Liu Y, Vega F. Transcriptional regulation of Serine/threonine protein kinase (AKT) genes by glioma-associated oncogene homolog 1. J Biol Chem 2013; 288:15390-401. PMCID: 23580656 Read more »
- Qu C, Liu Y, Kunkalla K, Sing RR, Blonska, M, Lin X, Agarwal NK, Vega F. Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-KB activation in diffuse large B-cell lymphoma. Blood 2013; 121:4718-28. PMCID: 23632891 Read more »
- Kunkalla K, Liu Y, Changju Q, Leventaki V, Agarwal NK, Singh R, Vega F. Functional Inhibition of BCL2 is needed to Increase the Susceptibility to Apoptosis to SMO Inhibitors in Diffuse Large B-Cell Lymphoma of Germinal Center Subtype. Ann Hematol 92:777-87, 2013. PMCID: 23370596 Read more »
- Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller LL, Younes A, Lannutti BJ. PI3Kδ inhibitor, GS-1101(CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 2012; 119:1897-900. PMCID: 22210877 Read more »
- Greaves WO, Xiao L, Sanchez-Espiridion B, Kunkalla K, Dave KS, Liang CS, Singh RR, Younes A, Medeiros LJ, Vega F. Detection of ABCC1 expression in classical Hodgkin lymphoma is associated with increased risk of treatment failure using standard chemotherapy protocols. J Hematol Oncol 2012; 5:47. PMCID: 22871336 Read more »
- Ok CH, Singh RR, Vega F. Aberrant activation of hedgehog signaling pathway in hematological neoplasms. Am J Pathol 2012; 180:2-11. PMCID: 22056910 Read more »
- Ramirez E, Singh RR, Kunkalla K, Liu Y, Cain C, Multani AS, Lennon PA, Jackacky J, Dawud S, Gu J, Yang S, Hu PC, Vega F. Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma. Leuk Res 36:1267-73, 2012. PMID: 22809693 Read more »
- Drakos E, Singh RR, Rassidakis GZ, Schlette E, LI J, Claret FX, Ford RJ Jr, Vega F, Medeiros LJ. Activation of the p53 pathway by the MDM2 inhibitor nutlin-3ª overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21). Leukemia 2011; 25:856-67. PMCID: 21394100 Read more »
- Greaves WO, Kim JE, Singh RR, Drakos E, Kunkalla K, Garcia JF, Medeiros LJ, Vega F. Glioma associated oncogene homologue 3 (GLI3) a Hedgehog transcription factor, is highly expressed in Hodglin and Reed-Sternberg cells of classical Hodgkin lymphoma. Hum Pathol 2011;42:1643-52. NIHMS294697. Read more »
- Singh RR, Kunkalla K, Qu C, Schlette E, Neelapu S, Samaniego F, Vega F. ABCG2 is a Direct Transcriptional Target of Hedgehog Signaling and Involved in Stroma-Induced Drug Tolerance in Diffuse Large B-Cell Lymphoma. Oncogene 2011; 30:4874-86. NIHMS290938. Read more »
- Vega F, Davuluri Y, Cho-Vega JH, Ma S, Wang RU, Multani AS, Drakos I, Pham L, Shen L, Ambrus J, Medeiros LJ, Ford R. Side Population Contains Cells with "Tumor-Initiating Cell" Features Responsible for Lymphoma Maintenance and Systemic Dissemination. J Cell Mol Med 2010; 6B:1532-45. PMCID: 19656242 Read more »
- Singh RR, Kim JE, Davuluri Y, Drakos-E, Cho-Vega JH, Amin H, Vega F. Hedgehog-Signaling Pathway Contributes to Tumor Cell Survival and Proliferation in Diffuse Large B-Cell Lymphoma. Leukemia 2010:5:1025-36. PMCID: 20200556 Read more »
Selected Cancer-Related Publications
Collaborating in the Multidisciplinary Research Program(s):