Francisco Vega-Vazquez, M.D., Ph.D.
Professor of Pathology
Description of Research
The research in Dr. Vega's laboratory focuses on the problem of chemoresistance in diffuse large B cell lymphoma (DLBCL). Approximately 40% of the DLBCL patients treated with current standard therapy will relapse and develop drug resistance. Indeed, resistance to chemotherapy is the most urgent challenge in the clinical management of DLBCL patients. In addition, a significant number of patients with relapsed DLBCL may have difficulty tolerating intensive second-line therapies due to age and/or comorbidities. At the same time, drug resistance is arguably one of the least understood aspects of cancer, especially when the emphasis is placed on the mechanisms leading towards resistance as opposed to the resulting changes in already established oncogenic pathways. The focus of his laboratory is on cellular adaptation at the membrane level and its contribution to drug resistance as well as cellular responses to established treatment modalities.
Smoothened (SMO) is a transmembrane protein that is overexpressed in lymphoma, and in other cancers. They found that SMO expression is highly induced in doxorubicin-resistant lymphoma cells. In addition, their findings revealed for the first time that SMO is a raft resident protein and that depletion of SMO results in a decrease of multiple cytokine/growth factor receptors in lymphoma and other cancer cells. Furthermore, silencing SMO quantitatively and qualitatively alters cell signaling involved in proliferation and cell survival such as PI3K/AKT. Currently, Dr. Vega’s laboratory is evaluating whether SMO levels and its activation state directly modulates the properties of lipid rafts with regard to expression of surface receptors or overall lipid raft composition. They are also exploring whether changes in SMO driven compartmentalization of signaling proteins enhances activation of survival pathways contributing to lymphoma progression and chemoresistance.
If their hypothesis is confirmed, the research in Dr. Vega's laboratory will provide a first glimpse of different players at the plasma cell membrane level that drive the adaptation process to chemotherapy and will allow the exploration of conceptually novel ways of therapeutic intervention. For the specific case of doxorubicin resistance, this will be the first time that SMO is implicated in lymphoma progression and drug resistance and thereby impacting DLBCL therapy.
A complete list of Dr. Vega's published work can be found in MyBibliography
- 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 »