Faculty Directory

Alejandro Villagra

Alejandro Villagra

Assistant Professor of Biochemistry and Molecular Medicine

Office Phone: 202-994-9547
Email: Email
Department: Biochemistry and Molecular Medicine

Education

  • BS Biochemistry, School of Pharmacy, University of Concepcion, Chile, 2000
  • PhD, School of Biological Sciences, University of Concepcion, Chile, 2004

Biography

Dr. Villagra's areas of expertise are tumor immunology and epigenetics. During his scientific career, Dr. Villagra has explored several aspects of these major areas including signaling pathways, and genomic and epigenetic regulation such as DNA methylation, ATP-dependent chromatin remodeling complexes, histone acetyltransferases, and histone deacetylases. His study models have been diverse and have included tissue-specific genes in myogenic and osteoblastic differentiation, cytokine genes, gene regulation during an anti-tumor immune response, gene expression in T cell activation and, most recently, cancer models including solid tumors and hematological malignancies. Overall, his current research areas are focused on the molecular and cellular roles of HDACs in tumor immunology using melanoma and other solid malignancies such as breast, lung, and ovarian cancer. His experimental approaches have essential translational components using animal models and human tissue samples, which gives him the possibility to further extend his investigations into the clinical area. These particular characteristics allowed Dr. Villagra to maintain continuous scientific feedback and keep focused goals on the relevant biomedical aspects of his research. 

Grants

NSF  1830941    PI: Alejandro Villagra, Emilia Entcheva, Shu Jia, Zhenyu Li, Ralph Mazitschek
Dates: 08/2018 – 07/2022
Source: National Science Foundation   Role: Co-PI
Title: EFRI CEE: Human cardiac opto-epigenetics with HDAC inhibitors
Goals: Optimization of photo-switchable HDACis to study temporal effects of epigenetic modifiers in cardiomyocytes.
 
MRF Team Award      PI: Alejandro Villagra  Dates: 11/01/2016 – 10/30/2019
Source: Melanoma Research Foundation              Role: PI
Title: Use of selective HDACi to improve blockade immunotherapy
Goals: To study the regulation of immune check-point molecules in melanoma cells and the effect of the combination of ACY1215 and immune check-point blockade over the activity of immune-related pathways in tumor cells.
 
CDRF  PI: Alejandro Villagra, Katherine Chiappinelli, Rohan Fernandes
Dates: 10/2018 – 09/2019
Source: GWU
Title: Reversing immune evasion in ovarian cancer through nanoparticle-directed epigenetic modulation
Goals: Evaluate the efficacy of epigenetic-loaded nanoparticles as neoadjuvant for ovarian cancer immunotherapy

Awards

1994-2000                   Presidential Scholarship for undergraduate students
2000-2001       Doctoral Fellowship, Chilean Program for Improvement of Quality and Equity in Higher Education (MECESUP)
2001                Awarded as the Best Undergraduate Thesis in Cell Biology, 2001. By The Chilean Foundation for Cell Biology and The Chilean Society for Cell Biology.
2002-2004       Doctoral Fellowship, National Commission for Scientific and Technological Research (CONICYT)
2009                Awarded as the Best Postdoctoral Fellow Presentation at Moffitt Cancer Center.
2017                The George Washington University Innovation Award

Teaching

Dr. Villagra has been actively involved in courses at the GW PhD program and the Biochemistry and Molecular Medicine master program. Additionally, he participates as external lecturer at the Biology graduate program at Georgetown.

Research

Enhancing Immunotherapy through selective HDAC inhibition

We recently reported that HDAC6 is involved in the regulation of a number of immunosuppressive checkpoint proteins, including the Program Death Receptor Ligand 1 (PD-L1). This protein is one of the natural ligands for the PD-1 receptor present on T-cells, consistently reported to suppress T-cell activation, proliferation, and induce T-cell exhaustion, anergy, and apoptosis. As a result, increased PD-L1 expression by cancer cells remains a fundamental escape mechanism from host immunity within the tumor microenvironment, and the understanding the molecular mechanisms modulating PD-L1 and other immunosuppressive mediators could lead to improved treatments for cancer patients. Several publications have linked the over-expression of PD-L1 in tumors and tumor microenvironment with a poor prognosis in several malignancies, including melanoma, ovarian, gastric and breast cancer, among many others. However, more detailed mechanistic information regarding the molecular events involved in the regulation of PD-L1 is still missing. Moreover, limited information is available about the participation of preclinical and clinical anti-cancer agents in the regulation of PD-L1 and other immunomodulatory pathways. As a result, this gap in knowledge is preventing the design of new immunotherapeutic combination therapies. Given the fact that HDAC6 is a potential regulator of immunosuppressive mediators, it opens up a new avenue for immunotherapy. By using selective HDAC6inh as adjuvants to ongoing immune blockade based treatments, we are aiming to further augment anti-tumor immune responses.   

Role of Histone Deacetylases in the regulation of pro- and anti-inflammatory cytokines

The role of HDACs in cell biology, initially limited to their effects upon histones, now encompasses more complex regulatory functions that vary with their tissue expression, cellular compartmentalization, and stage of cellular differentiation. Although there have been major advances in understanding the role of specific HDACs in cell proliferation and survival, their involvement in the regulation of inflammation and immune-related pathways remains poorly defined. In this regard, we reported that HDAC11 controls the expression of several anti-inflammatory cytokines in antigen presenting cells (APCs). Similarly, we have found that HDAC6 induces the transcriptional activation of IL-10 and the specific knock-down HDAC6 modifies the gene expression profile of APCs, including pro- and anti-inflammatory cytokine genes. Interestingly, we recently observed that several of the anti-inflammatory mediators regulated by HDAC6 in macrophages and dendritic cells (DCs) are regulated in the same fashion in microglia. However, pro-inflammatory mediators in microglia seem to be modulated differentially than APCs. Furthermore, selective HDAC6i impairs only the M1 inflammatory phenotype of microglia, suggesting that the molecular mechanisms present in this particular cell type are different from macrophages and DCs.

 

Selective HDAC inhibitors as anti-metastatic agents 

Inhibiting HDAC activity through pan HDAC inhibitors have shown variable results in different pre-clinical and clinical studies with metastatic tumors. HDAC6, having a unique substrate specificity towards non-histone molecules, shows the potential to regulate cell motility by regulating several cytoskeletal molecules, such as tubulin and cortactin. Using metastatic murine melanoma and breast cancer models, we are probing the potential of targeting HDAC6 selective inhibitors to inhibit metastasis along with primary tumor growth. Our preliminary in vitro and in vivo results show noticeable changes in the invasive property of the tumor cells. Within the breast cancer, we are extending our search to both triple negative and hormonal receptor-positive subtypes. We are also investigating if combining the HADC6inh with check point inhibitors may confer a synergistic benefit to the therapeutic efficacy of each of the agents, in both melanoma and breast cancer. Investigating the tumor microenvironment under different treatment regimens is another arm we are currently pursuing. 

Programs

  • GW Cancer Center

Publications

View publications by this faculty member from January 1, 2013 - present

Jie Chen, Eva Sahakian, John Powers, Maritza Lienlaf, Patricio Perez-Villarroel, Tessa Knox, and Alejandro Villagra. Functional Analysis of Histone Deacetylase 11. Methods Mol Biol. 2016;1436:147-65

John Powers, Jie Chen, Maritza Lienlaf, Patricio Perez-Villarroel, Tessa Knox, Alejandro Villagra, and Eva Sahakian. Expression and Function of Histone Deacetylase 10 (HDAC10) in B Cell Malignancies. Methods Mol Biol. 2016;1436:129-45

Lienlaf M, Perez-Villarroel P, Knox T, Woan K.V., Lee C., Cheng F., Sahakian E., Powers J., Deng S., Smalley K. S. M., Kozikowski A., Pinilla-Ibarz J., Sarnaik, A., Seto E., Weber J., Sotomayor E.M., and Villagra A. (2016). Essential role of HDAC6 in the regulation of PD-L1 in melanoma. Mol Oncol. 2016 May;10(5):735-50.

Preparation and Biochemical Analysis of Classical Histone Deacetylases. (2016) A. Villagra, E., Sahakian, E. Seto. Methods in Enzymology. Epub ahead

Woan K.V., Lienlaf M., Perez-Villaroel P., Lee C., Cheng F., Knox, T., Woods D.M., Barrios, K., Wang H.W., Canales, J., Marante, D., Sarnaik, A., Smalley, K., Bergman J., Kozikowski A., Celis E., Weber J., Sotomayor E.M., and Villagra A (2015). Targeting Histone Deacetylase 6 (HDAC6) mediates a dual anti-melanoma effect; enhanced antitumor immunity and impaired proliferation. Mol Oncol. 2015 Aug;9(7):1447-57

David M. Woods, Andressa L. Sodré, Alejandro Villagra, Eduardo M. Sotomayor, Jeffrey Weber (2015).HDAC Inhibition Upregulates PD­1 Ligands in Melanoma and Augments Immunotherapy with PD­1 Blockade. Cancer Immunol Res. 2015 Aug 21.

Paraiso KH, Thakur MD, Fang B, Koomen JM, Fedorenko IV, John JK, Tsao H, Flaherty KT, Sondak VK, Messina JL, Pasquale EB, Villagra A. Rao UN, Kirkwood JM, Meier F, Sloot S, Gibney GT, Stuart D, Tawbi H, Smalley KS. (2015). Ligand-Independent EPHA2 Signaling Drives the Adoption of a Targeted Therapy-Mediated Metastatic Melanoma Phenotype. Cancer Discovery, 2015 Mar;5(3):264-73.

Gonzalez-Zuñiga M., Contreras P., Estrada L., Chamorro D., Villagra A., Zanlungo S., Seto E., Alvarez A. Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer Disease. Molecular Cell. Mol Cell. 2014 Oct 2;56(1):163-73.

Kizuka Y, Kitazume S, Okahara K, Villagra A, Sotomayor EM, Taniguchi N. Epigenetic regulation of a brain-specific glycosyltransferase N-acetylglucosaminyltransferase-IX (GnT-IX) by specific chromatin modifiers. J. Biol. Chem. 2014 Apr 18;289(16):11253-61

Fengdong Cheng, Maritza Lienlaf, Patricio Perez-Villarroel, Hong-Wei Wang, Calvin Lee, Karrune Woan, David Woods, Tessa Knox, Joel Bergman, Javier Pinilla-Ibarz, Alan Kozikowski, Edward Seto, Eduardo M. Sotomayor and Alejandro Villagra. Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Molecular Immunology. 2014. 2014 Jul;60(1):44-53

Sahakian E, Powers J, Chen J, Deng S, Cheng F, Distler A, Woods D, Rock-Klotz J, Laino A, Youn J, Woan K, Villagra A, Gabrilovich D, Sotomayor E, Pinilla-Ibarz J. Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function. . Molecular Immunology. (2014) epub ahead.

Cheng F, Wang H, Woan K, Rock-Klotz J, Pinilla-Ibarz J, Seto E, Bhalla K, Kozikowski A, Sotomayor E, Villagra A. (2013). A novel role for histone deacetylase 6 (HDAC6) in the regulation of the tolerogenic STAT3/IL-10 pathway in antigen presenting cells. J. of Immunology. 2014 Sep 15;193(6):2850-62.

Woods, D.M., Woan, K., Cheng, F., Wang, H., Perez-Villarroel, P., Lee, C., Lienlaf, M., Atadja, P., Seto, E., Weber, J., Sotomayor, E.M. & Villagra, A. The anti-melanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by durect tumor cytotoxicity and increased tumor immunogenicity. Melanoma Research. ePub ahead (2013).

Youn J, Kumar V, Collazo M, Nefedova Y, Condamine T, Cheng P, Villagra A, Antonia S, McCaffrey J, Sarnaik A, Sotomayor E and Gabrilovich D. (2013). Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nature Immunology. 14(3):211-20.

Bai F, Villagra A, Zou JX, Painter J, Connolly K, Blaskovich M, Sokol L, Sebti S, Djeu J, Loughran T, Wei S, Sotomayor E, Epling-Burnette PK. (2012). Tipifarnib-mediated suppression of T-bet dependent signaling pathways. Cancer Immunology Immunotherapy. 61(4):523-33.

Woan KV, Sahakian E, Sotomayor EM, Seto E, Villagra A. (2012). Modulation of antigen-presenting cells by HDAC inhibitors: implications in autoimmunity and cancer. Immunol Cell Biol. 2012 Jan; 90(1):55-65.

Cheng F, Wang H, Horna P, Wang Z, Shah B, Sahakian E, Woan K, Villagra A, Pinilla-Ibarz J, Sebti S, Smith M, Tao J and Sotomayor E. (2012). Stat3 inhibition augments the immunogenicity of malignant B-Cells leading to effective antitumor immunity in B-Cell Lymphomas. Cancer Research. 72(17):4440-8.

Bergman J, Woan K, Perez-Villarroel P, Villagra A, Sotomayor E and Kozikowski A. (2012). Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth. Journal of Medicinal Chemistry. 55(22):9891-9.

Wang H, Cheng F, Woan K, Vicente-Suarez I, Pinilla-Ibarz J, Wright K, Seto E, Bhalla K, Villagra A, Sotomayor E. (2011). Histone deacetylase inhibitor LAQ824 augments inflammatory responses in antigen presenting cells and overcomes T-Cell tolerance through transcriptional regulation of IL-10. J. of Immunology. 186(7):3986-96.

Dubovsky JA, Villagra A, Powers JJ, Wang HW, Pinilla-Ibarz J, Sotomayor EM. (2010). Circumventing immune tolerance through epigenetic modification. Curr Pharm Des. 16(3):268-76.

Yuan Z, Villagra A, Peng L, Coppola D, Sotomayor E, Chen J, Lane W, Seto E. (2010). The ATDC (TRIM29) protein binds p53 and antagonizes p53-mediated functions. Mol. Cell. Biol. 30:3004-15.

Villagra A, Sotomayor EM, Seto E. (2010). Histone deacetylases and the immunological network: implications in cancer and inflammation. Oncogene, 14;29(2):157-73.

Yarde DN, Oliveira V, Mathews L, Wang X, Villagra A, Boulware D, Shain KH, Hazlehurst LA, Alsina M, Chen DT, Beg AA, Dalton WS. (2009). Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma. Cancer Res. 69(24):9367-75.

Vicente-Suarez I, Brayer J, Villagra A, Cheng F, Sotomayor EM. (2009). TLR5 ligation by flagellin converts tolerogenic dendritic cells into activating antigen-presenting cells that preferentially induce T-helper 1 responses. Immunol Lett. 125(2):114-8.

Cruzat F, Henriquez B, Villagra A, Hepp M, Lian JB, van Wijnen AJ, Stein JL, Imbalzano AN, Stein GS, Montecino MA. (2009). SWI/SNF-Independent nuclease hypersensitivity and increased histone acetylation at the P1 promoter accompany active transcription of the bone master gene RUNX2. Biochemistry. 48(30):7287-95.

Villagra A, Cheng F, Wang, H, Suarez I, Glozak M, Maurin M, Nguyen D, Wright K, Atadja AP, Bhalla K, Pinilla-Ibarz J, Seto E, Sotomayor E (2009). A novel role of histone deacetylase 11 (HDAC11) as transcriptional regulator of IL-10 and Immune tolerance. Nature Immunology, 10:92-100.

Villagra A, Ulloa N, Zhang X, Yuan Z, Sotomayor E, and Seto E. (2007). Histone Deacetylase 3 Down-regulates Cholesterol Synthesis through Repression of Lanosterol Synthase Gene Expression. J. Biol. Chem., 282(49):35457-470.

Lee, H., Sengupta, N., Villagra, A., Rezai-Zadeh, N. and Seto, E. (2006) HDAC8 safeguards the human Ever Shorter Telomeres 1B (hEST1B) protein from ubiquitin-mediated degradation. Mol. Cell. Biol. Jul, 26 (14): 5259-69.

Villagra A, Cruzat F, Carvallo L, Gutierrez S, Olate J, van Wijnen A, Lian J, Stein G, Stein J, Imbalzano A, Montecino M. (2006). Chromatin Remodeling and Transcriptional Activation of the Bone-specific Osteocalcin Gene requires SWI/SNF Activity. J. Biol. Chem., 281(32):22695-706.

Khanna P, Villagra A, Kim S, Seto E, Jaroszeski M, Kumar A, and Bhansali S. (2006) Use of nanocrystalline diamond for microfluidic lab-on-a-chip. Diamond and related materials, 15:2073-2077.

Sierra J, Villagra A, Paredes R, Cruzat F, Gutierrez S, Javed A, Arriagada G, Olate J, Imschenetzky M, Van Wijnen AJ, Lian JB, Stein GS, Stein JL, Montecino M. (2003). Regulation of the bone-specific osteocalcin gene by p300 requires Runx2/Cbfa1 and the vitamin D3 receptor but not p300 intrinsic histone acetyltransferase activity. Mol Cell Biol. 2003 May;23(9):3339-51.

Paredes R, Arriagada G, Cruzat F. Villagra A, Olate J, Zaidi K, van Wijnen A, Lian J, Stein G, Stein J, Montecino M. (2003). Bone-Specific Transcription Factor Runx2 Interacts with the 1{alpha},25-Dihydroxyvitamin D3 Receptor To Up-Regulate Rat Osteocalcin Gene Expression in Osteoblastic Cells. Mol Cell Biol. 2004 Oct;24(20):8847-8861.

Villagra A, Gutierrez J, Paredes R, Sierra J, Puchi M, Imschenetzky M, Wijnen Av A, Lian J, Stein G, Stein J, Monetcino M.(2002). Reduced CpG methylation is associated with transcriptional activation of the bone-specific rat osteocalcin gene in osteoblasts. J Cell Biochem. 2002;85(1):112-22.

Additional publications published before January 1, 2013 may be available within Himmelfarb Library's database.

Industry Relationships and Collaborations

This faculty member (or a member of their immediate family) has reported a financial interest with the healthcare related companies listed below. These relations have been reported to the University and, when appropriate, management plans are in place to address potential conflicts.

  • None