Gender	Male
E-mail	julio.aguirre-ghiso@mssm.edu
Education and Training	M.Sc, University of Buenos Aires
	Ph.D., University of Buenos Aires
	Postdoctoral Training, The Mount Sinai School of Medicine
	Charles H. Revson Fellowship in Biomedical Research, Charles Revson Foundation
Awards	2003 Florencio Fiorini Foundation Award Argentine League for the Fight Against Cancer (LALCEC), Argentina
	2001 Charles H. Revson Postdoctoral Fellowship in Biomedical Research Charles Revson Foundation, New York, USA
	1998 Florencio Fiorini Foundation Award Argentine League for the Fight Against Cancer (LALCEC), Argentina

Director, Head and Neck Cancer Basic Research. Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Mount Sinai School of Medicine - NYU.

Education and Training	M.Sc, University of Buenos Aires
	Ph.D., University of Buenos Aires
	Postdoctoral Training, The Mount Sinai School of Medicine
	Charles H. Revson Fellowship in Biomedical Research, Charles Revson Foundation

Current Students: Wen Huei Chi

Postdoctoral Fellows: Paloma Bragado Domingo, Yang Zheng, Alvaro Avivar Valderas

Research Personnel: Yeriel Estrada

Overview:
DISSEMINATED TUMOR CELLS AND CANCER DORMANCY More than half of cancer patients will die from metastatic disease that invariably arises from disseminated tumor cells (DTCs) months, years or even decades after primary tumor removal. While in many cases cells can resume growth immediately, in some situations cells may enter a state of dormancy. It appears that dormancy of DTCs may be due to the ability of these cells to reprogram and enter a state of quiescence. The mechanisms that allow DTCs, which were competent for survival and proliferation in the primary site, to suddenly become growth arrested and dormant in target organs, are poorly understood. Our long-term goal is to understand the biology of DTCs. In particular we are interested in the mechanisms that favor survival, dormancy and switch into growth of loco-regional or secondary organ DTCs.

As part of the Head and Neck Cancer Multidisciplinary Research Program, we are exploring these mechanisms in the context of HNSCC but we anticipate these findings to be applic! able to other tumors. Understanding the biology driving growth, survival and dormancy of DTCs is essential to identify new therapies to induce and/or maintain dormancy of DTCs or to eradicate dormant DTCs before they resume growth. This research will allow identifying markers indicative of the behavior of residual disease leading to a better staging of patients and better choices for therapy.

Summary of Research Studies:
MODELING TUMOR DORMANCY General hypothesis: Our research hypothesis is that stress signaling imposed by micro-environmental cues or by exogenous stress such as that imposed by chemo- or radiation-therapy can induce stress adaptation programs. We hypothesize that stress signaling through a quiescence program allows disseminated tumor cells (DTCs) to survive in different microenvironments (i.e. target organs) and resist therapies. Thus, prolonged dormancy may be a manifestation of a survival program conserved through evolution for cells to adapt to strenuous conditions imposed by their surroundings. Stress signaling and tumor cell dormancy in HNSCC. We have studied head and neck squamous cell carcinoma (HNSCC) HEp3 cells retain their malignancy only upon in vivo serial transplantation. In contrast, the same cells placed in culture as pools of primary tumor-derived cells or as individual clones representing the primary tumor heterogeneity, extinguish their malignancy after in vitro adaptation over several generations. This is caused by the acquisition of a quiescent phenotype in vivo that results in protracted dormancy. Mechanistic analysis showed that the loss of malignancy is in part due to the activation of p38 stress signaling, which antagonizes ERK activation (a low ERK/p38 signaling ratio), among other critical players. Induction of quiescence by p38 involves the regulation of transcriptional and post-transcriptional programs as well as attenuation of translation initiation. Further, dormant tumor cell survival and resistance to chemotherapy, was found to be depend! ent on the chaperon Grp78/BiP and on the transcription factor ATF6. This model has allowed us to learn how stress signaling can induce quiescence and survival of otherwise proliferating malignant cells. Our lab is also interested how cancer therapies may activate these survival stress adaptation programs. We are particularly interested in how conventional chemo- and radiation-therapy induces stress adaptation in HNSCC and how it may be applicable to other cancers including breast cancer and multiple myeloma (Aguirre-Ghiso Nat Rev Cancer. 2 007 Nov;7(11):834-46). We are also interested in determining whether these mechanisms are operational in DTCs in patients. We are particularly interested in determining whether bone marrow and/or lymph node DTCs in HNSCC patients express markers of progression vs. dormancy and whether these have prognostic value. Stress signaling, mammary morphogenesis and early dissemination of tumor cells: We have studied how stress signaling through the endoplasmic reticulum kinase PERK and p38 regulate mammary acinar morphogenesis. We have shown that these stress-signaling pathways are essential to limit the growth of acinar structures and maintain proper acinar architecture. This occurs through the coordinated regulation of growth arrest and apoptosis by PERK and p38. We are also exploring how loss of stress signaling mechanisms may favor disruption of acinar architecture favoring early dissemination of mammary epithelial cells. This in turn may contribute to dormancy of DTCs in this type of cancer (Klein and Holzel, Cell Cycle. 2006 Aug;5(16):1788-98 and Aguirre-Ghiso Nat Rev Cancer. 2007 Nov;7(11):834-46).

Schewe DM, Aguirre-Ghiso JA, . ATF6a-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc Natl Acad Sci U S A 2008 Jul 29; 105(30): 10519-10524.

Ranganathan AC, Ohja S, Kourtidis A, Conkilin D, Aguirre-Ghiso JA, . Dual function of PERK in tumor cell growth arrest and survival. Cancer Res 2008; 68(9): 1-9.

Aguirre-Ghiso JA, . Models, mechanisms and clinical evidence for cancer dormancy. Nature Reviews Cancer 2007; 7(11): 834-846.

Sequeira SJ, Ranganathan AC, Adam AP, Iglesias BV, Farias EF, Aguirre-Ghiso JA. Inhibition of Proliferation by PERK Regulates Mammary Acinar Morphogenesis and Tumor Formation. PLoS ONE 2007 Jul 18; 2: e615.

Shinohara M, Mikhailov AV, Aguirre-Ghiso JA, Rieder CL. ERK1/2 activation is required for timely progress through early G2 but it is not directly involved in the G2/M or M/A transitions in mammalian cells. Molecular Biology of the Cell 2006 Dec 1; 17: 5227-5240.

Aguirre-Ghiso JA. The problem of cancer dormancy: understanding the basic mechanisms and identifying therapeutic opportunities [editorial]. Cell Cycle 2006 Aug; 5(16): 1740-1743.

Ranganathan AC, Adam AP, Aguirre-Ghiso JA. Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy. Cell Cycle 2006 Aug 5(16):1799-1807.

Ranganathan AC, Adam AP, Zhang L, Aguirre-Ghiso JA. Tumor cell dormancy induced by p38SAPK and ER-stress signaling; an adaptive advantage for metastatic cells? [review]. Cancer Biology & Therapy 2006 Jul; 5(7): 729-735.

Chaurasia P, Aguirre-Ghiso JA, Liang OD, Gardsvoll H, Ploug M, Ossowski L. A region in uPAR domain III controlling a functional association with a5b1 integrin and tumor growth. J. Biol. Chem 2006 May 26; 281(21): 14852-14863.

Ranganathan AC, Zhang L, Adam AP, Aguirre-Ghiso JA. Functional coupling of p38-induced upregulation of BiP and activation of RNA-dependent protein kinase-like ER kinase (PERK) to drug resistance of dormant carcinoma cells. Cancer Research 2006; 66(3): 1702-1711.