Julio A Aguirre-Ghiso, PhD

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.