Julio A Aguirre-Ghiso, PhD Email Julio Aguirre-Ghiso

2014
Co-Chair, Plenary Lecture Session
2nd Advances in Circulating Tumour Cells Meeting
Crete, Greece

2014
Editorial Board
International Journal of Stem Cell Research

2013
Advisor
The National Breast Cancer Coalition Artemis Project on Breast Cancer Dormancy

2012
Speaker and Chair
Princess Takamatsu Cancer Research Symposium
Tokyo, Japan

2012
Speaker
Herrenhausen Symposium on Metastasis, Nature Medicine Kloster
Seeon, Germany

2012
Co-Chair
Plenary Lecture Session, 1st Advances in Circulating Tumour Cells Meeting
Athens, Greece

2012
Speaker Symposium
AACR Meeting: Dormant and Stem Cells in Tumor Heterogeneity
Chicago, Illinois

Editorial Board of Cancer Research, Breaking Advances Editor
cancerres.aacrjournals.org/site/misc/edboard.xhtml

Current Students: Kathryn Harper, Miguel Vizarreta Sandoval Postdoctoral Fellows: Maria Soledad Sosa, Georg Fleugen, Veronica Calvo Vidal, Nina Linde Research Personnel: Julie Cheung Lab Administrator: Jolanda Mernacej Overview Surprisingly cancer patients presumed cured can carry non-proliferating ‘dormant’ disseminated tumor cells (DTCs) for years before they activate to form incurable metastasis. We focused on understanding the biology of dormant DTCs to target them and prevent relapse. This contrasts to the vast majority of cancer research, which focuses on understanding constant cancer growth. My team led a paradigm shift that is revealing novel cancer biology. By a multidisciplinary approach integrating mechanisms of basic stress and mitogenic signaling, adult stem cell, intra-vital imaging and micro-environmental biology, we discovered that reciprocal crosstalk between DTCs and the microenvironment regulates the inter-conversion between dormancy and proliferation. A major achievement of my team was discovering that imbalance in p38 and ERK1/2 signaling regulates lineage commitment transcription factor (TF) networks determining dormancy induction. I also identified retinoic acid and TGF2 in the microenvironment as inducers of the high p38/ERK signaling ratio and that dormancy (quiescent phenotype) is controlled by mechanisms driving adult and embryonic stem cell biology. Translating this biology to medicine we identified a “dormancy signature” enriched in dormant DTCs from patients asymptomatic for >10 years, predicting prolonged metastasis-free periods in different cancers. Our work has propelled new questions to the forefront of cancer research, with the unexpected discovery of the mechanisms that regulate early dissemination and that dormant DTCs can originate very early during cancer evolution, disseminating during pre-malignant stages of cancer. My team has also studied the role of endoplasmic reticulum stress signaling in tissue morphogenesis and DTC biology and we discovered that UPR signaling can promote the survival of dormant tumor cells. We also study how UPR signaling triggered by therapies in multiple myeloma can induce residual disease dormancy and how can we target these residual cancer cell. We have also studied the role of host cells specifically macrophages in regulating early dissemination and DTC fate. We found that macrophages are key players in the regulation of early dissemination and dormancy. My lab is part of a NCI-Tumor Microenvironment Network Center along with Einstein (John Condeelis), Univ. Of Wisconsin (Patricia Keely) and the College of Nanoscale Sciences (James Castracane). This Center studies the role of microenvironmental stress and dormancy and the development of new technologies to image and target metastasis. My lab also collaborates with Christoph Klein’s lab (Univ. of Regensburg), Nicholas Steocklein (Univ. of Duddeldorf) and Colm Morrissey’s lab at the University Of Washington, to characterize dormancy in human DTCs. We also collaborate with Dr. Emily Bersntein, an expert in melanoma epigenetics on the epigenetic regulation of DTC dormancy, among others. This translational focus is strengthened by my roles in clinical programs and as Research Leader of the Metastasis Center at Mount Sinai. Our lab has a long term interest in translational efforts and we have thus developed a pre-clinical and translational program in with Eli Lilly to identify drugs to target dormant disease. This multidisciplinary program has allowed us to develop basic mechanistic work, but also translational research on DTC biology and metastasis, which has an important impact in our understanding of cancer biology.

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).