- PROFESSOR Medicine, Hematology and Medical Oncology
- PROFESSOR Otolaryngology
- PROFESSOR Oncological Sciences
Ph.D., University of Buenos Aires
The Mount Sinai School of Medicine
M.Sc, University of Buenos Aires
Charles Revson Foundation
- Director, Head and Neck Cancer Basic Research.
Director of Solid Tumor and Metastasis Research.
Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Mount Sinai School of Medicine.
Visit Dr. Aguirre-Ghiso's laboratory website.
Florencio Fiorini Foundation Award
Argentine League for the Fight Against Cancer (LALCEC), Argentina
Charles H. Revson Postdoctoral Fellowship in Biomedical Research
Charles Revson Foundation, New York, USA
Florencio Fiorini Foundation Award
Argentine League for the Fight Against Cancer (LALCEC), Argentina
ResearchCurrent Students: Kathryn Harper
Postdoctoral Fellows: Paloma Bragado, Alvaro Avivar Valderas, Maria Soledad Sosa, Alfred Adomako, Nina Linde
Research Personnel: Yeriel Estrada, Falguni Parikh
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. 2007 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).
Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C, Farina HG, Schewe DM, Aguirre-Ghiso JA. TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling. Nature cell biology 2013 Nov; 15(11).
Avivar-Valderas A, Bobrovnikova-Marjon E, Alan Diehl J, Bardeesy N, Debnath J, Aguirre-Ghiso JA. Regulation of autophagy during ECM detachment is linked to a selective inhibition of mTORC1 by PERK. Oncogene 2012 Nov;.
Sosa MS, Bragado P, Debnath J, Aguirre-Ghiso JA. Regulation of tumor cell dormancy by tissue microenvironments and autophagy. Advances in experimental medicine and biology 2013; 734.
Kim RS, Avivar-Valderas A, Estrada Y, Bragado P, Sosa MS, Aguirre-Ghiso JA, Segall JE. Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. PloS one 2012; 7(4).
Bragado P, Sosa MS, Keely P, Condeelis J, Aguirre-Ghiso JA. Microenvironments dictating tumor cell dormancy. Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 2012; 195.
Bragado P, Estrada Y, Sosa MS, Avivar-Valderas A, Cannan D, Genden E, Teng M, Ranganathan AC, Wen HC, Kapoor A, Bernstein E, Aguirre-Ghiso JA. Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties. PloS one 2012; 7(1).
Gutiérrez-Uzquiza Á, Arechederra M, Bragado P, Aguirre-Ghiso JA, Porras A. p38α mediates cell survival in response to oxidative stress via induction of antioxidant genes: effect on the p70S6K pathway. The Journal of biological chemistry 2012 Jan; 287(4).
Avivar-Valderas A, Salas E, Bobrovnikova-Marjon E, Diehl JA, Nagi C, Debnath J, Aguirre-Ghiso JA. PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment. Molecular and cellular biology 2011 Sep; 31(17).
Sosa MS, Avivar-Valderas A, Bragado P, Wen HC, Aguirre-Ghiso JA. ERK1/2 and p38α/β signaling in tumor cell quiescence: opportunities to control dormant residual disease. Clinical cancer research : an official journal of the American Association for Cancer Research 2011 Sep; 17(18).
Wen HC, Avivar-Valderas A, Sosa MS, Girnius N, Farias EF, Davis RJ, Aguirre-Ghiso JA. p38α Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis. Science signaling 2011; 4(174).
Adam AP, George A, Schewe D, Bragado P, Iglesias BV, Ranganathan AC, Kourtidis A, Conklin DS, Aguirre-Ghiso JA. Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence. Cancer research 2009 Jul; 69(14).
Schewe DM, Aguirre-Ghiso JA. Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy. Cancer research 2009 Feb; 69(4).
Schewe DM, Aguirre-Ghiso JA. ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proceedings of the National Academy of Sciences of the United States of America 2008 Jul; 105(30).
Ranganathan AC, Ojha S, Kourtidis A, Conklin DS, Aguirre-Ghiso JA. Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. Cancer research 2008 May; 68(9).
Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nature reviews. Cancer 2007 Nov; 7(11).
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; 2(7).
Ranganathan AC, Zhang L, Adam AP, Aguirre-Ghiso JA. Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer research 2006 Feb; 66(3).
Aguirre-Ghiso JA, Ossowski L, Rosenbaum SK. Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth. Cancer research 2004 Oct; 64(20).
Liu D, Aguirre Ghiso J, Estrada Y, Ossowski L. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer cell 2002 Jun; 1(5).
Aguirre Ghiso JA. Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. Oncogene 2002 Apr; 21(16).
Aguirre Ghiso JA, Kovalski K, Ossowski L. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. The Journal of cell biology 1999 Oct; 147(1).
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Below are financial relationships with industry reported by Dr. Aguirre-Ghiso during 2014 and/or 2015. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
Other Activities: Examples include, but are not limited to, committee participation, data safety monitoring board (DSMB) membership.
- Eli Lilly and Company
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