Eva Hernando, PhD
Assistant Professor of Pathology
PhD, 2009 University Autonoma Madrid, Spain.
550 First Avenue
Smilow- Room 305
New York, NY 10016
Office Tel: (212) 263 9054
Lab Tel: (212) 263-9057
Fax: (212) 263 8211
Research Theme(s): Tumor cell-of-origin, Cellular Differentiation, Tumor Initiation, Metastasis, Targeted Therapy
Keywords: Melanoma, Leiomyosarcoma, Sarcoma, Metastasis, PTEN, microRNA, miR-182
Traditionally, mature cells in specific tissues and organs have been regarded as the cell-of-origin of the corresponding tumors. However, the observation that tumor cells need to accumulate genetic and phenotypic alterations over extended time periods has turned the view to stem cells or progenitors with a prolonged lifespan, which are broadly distributed in local reservoirs. These cells, in charge of maintaining tissue homeostasis, are contemplated as the target of neoplastic transformation.
Our laboratory is investigating the cell-of-origin and the molecular bases of two tumor types: melanoma and sarcoma. We hypothesize that alterations in the normal differentiation and tissue homeostasis act at early stages of tumor initiation, and that the retention or reactivation of stem cell properties may contribute to tumor progression and aggressive behavior (i.e., resistance to therapy, metastasis). A limitation for these studies is our partial understanding of the normal differentiation process of these two lineages.
To overcome this limitation, our laboratory has established and characterized the in vitro differentiation of human Mesenchymal Stem Cells (hMSCs) into smooth-muscle (SMC), the lineage of origin of Leiomyosarcomas (LMS), tumors that appear in the uterus and the retroperitoneum. Using multiple computational analyses, we determined that LMS are more similar to hMSCs than to mature SMCs and myometrium (Danielson et al., Am J Path 2010). Also, we found that some miRNAs down-regulated during hMSC differentiation are overexpressed in uterine LMS compared to normal myometrium. We are currently investigating whether these candidate miRNAs play an active role in SM differentiation in vitro and in vivo and whether their alteration contributes to LMS genesis and/or progression.
In addition, we have conditionally inactivated p53 and/or Pten in mice in an early smooth-muscle progenitor (using the transgelin promoter, Tgln). These mice develop high-grade undifferentiated sarcomas which are able to spontaneously metastasize to distal organs. Moreover, MSCs isolated from bone marrow of Tgln-cre/Ptenlox/wt/p53lox/wt mice have increased clonogenic and proliferative potential than those from Tgln-cre/Ptenwt/wt/p53lox/wt mice and they have impaired differentiation.
Melanoma is the most aggressive form of skin cancer; it is, in fact, the paradigmatic metastatic tumor. While the incidence and mortality of melanoma are rapidly increasing, progress in treatment has stalled at surgery for primary tumors. There is currently no successful treatment for melanoma metastases, and little understanding of the disease’s aggressiveness. Accumulating evidence, however, indicates that the processes involved in metastasis are closely related to developmental programmes. Two lines of evidence that point to such a link are of particular interest to us. First, several studies over the past few years have shown that alterations in microRNA (miRNA) expression, which serve important regulatory functions during development, are crucial in promoting tumorogenicity in different cancers. Second, recent work in several different cancers has suggested the existence of Cancer Stem Cells (CSC), a sub-population of malignant cells endowed with the capacity to self-renew. Although the idea of melanoma stem cells remains controversial, melanoma cells often express developmental genes, display multidifferentiation potential, and seem to recapitulate the migratory nature of neural crest stem cells from which melanocytes arise. Our group discovered that the miRNA cluster miR-183-96-182 is frequently overexpressed in melanoma tissues and cell lines, it promotes migration in vitro and metastasis in vivo, and it does so in part by targeting MITF, a master regulator of melanocyte differentiation(Segura et al., 2009). More recently, we have found that both human embryonic stem cells (hESCs) and quiescent mouse melanocyte stem cells (mMSCs) express miR-183-96-182 at high levels comparable to those of some melanoma cell lines, while expression of this cluster decreases during in vitro melanocyte differentiation in inverse correlation with levels of MITF. Based on these data, we propose that miR-183-96-182 expression is an important part of both normal melanocyte development and melanoma metastasis, and we are investigating if modulation of its expression confers stem cell-like properties onto melanoma cells, thereby promoting the chemoresistant and metastatic behavior of these tumors.
Research is supported by the Melanoma Research Foundation, the Melanoma Research Alliance, the Liddy Shriver Sarcoma initiative, the Edna’s Foundation of Hope, the American Cancer Society, the Department of Defense, and the National Cancer Institute.
- The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma. Huynh C, Poliseno L, Segura MF, Medicherla R, Haimovic A, Menendez S, Shang S, Pavlick A, Shao Y, Darvishian F, Boylan JF, Osman I, Hernando E. PLoS One. 2011;6(9):e25264. Epub 2011 Sep 29. PMID: 21980408
- miR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Gaziel-Sovran A, Segura MF, Di Micco R, Collins MK, Hanniford D, Vega-Saenz de Miera E, Rakus JF, Dankert JF, Shang S, Kerbel RS, Bhardwaj N, Shao Y, Darvishian F, Zavadil J, Erlebacher A, Mahal LK, Osman I, Hernando E. Cancer Cell. 2011 Jul 12;20(1):104-18. PMID: 21741600
- Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival. Zakrzewski J, Geraghty LN, Rose AE, Christos PJ, Mazumdar M, Polsky D, Shapiro R, Berman R, Darvishian F, Hernando E, Pavlick A, Osman I. Cancer. 2011 Apr 15;117(8):1711-20. doi: 10.1002/cncr.25643. Epub 2010 Nov 8. PMID: 21472718
- Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression. Rose AE, Poliseno L, Wang J, Clark M, Pearlman A, Wang G, Vega Y Saenz de Miera EC, Medicherla R, Christos PJ, Shapiro R, Pavlick A, Darvishian F, Zavadil J, Polsky D, Hernando E, Ostrer H, Osman I. Cancer Res. 2011 Apr 1;71(7):2561-71. Epub 2011 Feb 22. PMID: 21343389
- HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes. Wu J, Liu Z, Shao C, Gong Y, Hernando E, Lee P, Narita M, Muller W, Liu J, Wei JJ. Cancer Res. 2011 Jan 15;71(2):349-59. Epub 2011 Jan 11. PMID: 21224353
- Efficient in vivo microRNA targeting of liver metastasis. C. Huynh, M.F. Segura, A. Gaziel, S. Menendez, F. Darvishian, L. Chiriboga, B. Levin, D. Meruelo, I. Osman, J. Zavadil, E. G. Marcusson and E. Hernando Oncogene. 30(12):1481-8 (2011).PMID: 21102518
- MicroRNA signature predicts melanoma post-recurrence survival. MF Segura, I Belitskaya-Lévy, AE Rose, J Zakrzewski, A Gaziel, D Hanniford, F Darvishian, I Osman, and E Hernando. Clin Can Res 16(5): 1577-1586 (2010). PMID: 2017923.
- A differentiation-based miRNA signature identifies leiomyosarcomas as a mesenchymal-stem cell related malignancy. L.S. Danielson, S. Menendez, C. Stephan-Otto Attolini, M.V. Guijarro, M. Bisogna, J.J. Wei, N.D. Socci, D.A. Levine, F. Michor and E. Hernando. Am J Pathol. 177(2):908-17 (2010). PMID: 20558575.
- The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. A. Kapoor, M.S. Goldberg, L. Cumberland, K. Ratnakumar, M. F. Segura, P.O. Emanuel, S. Menendez, C. Vardabasso, G. LeRoy, C.I. Vidal, D. Polsky, I. Osman, B.A. Garcia, E. Hernando, E. Bernstein. Nature, 468(7327):1105-9 (2010). PMID: 21179167.
- Aberrant miR-182 expression promotes melanoma metastasis by repressing Foxo3 and MITF. MF Segura, D Hanniford, S Menendez, L Reavie, X Zou, S Alvarez-Diaz, J Zakrzewski, E Blochin, A Rose, D Bogunovic, D Polsky, JJ Wei, P Lee, I Belitskaya-Levy, N Bhardwaj, I Osman, and E Hernando. PNAS 106 (6), 1814-1819 (2009). PMID: 19188590