Cancer patients presumed cured after primary tumor removal and therapy, can carry non-proliferating ‘dormant’ disseminated tumor cells (DTCs) for years before reactivating to form incurable metastasis. I focused on understanding the biology of dormant DTCs and their reactivation, 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 a novel cancer dormancy biology. We integrated mechanisms of basic stress and mitogenic signaling, adult stem cell and micro-environmental biology and discovered that a reciprocal crosstalk between DTCs and the microenvironment regulates the inter-conversion between dormancy and proliferation. We discovered that an imbalance in p38a/b and ERK1/2 signaling regulates lineage commitment transcription factors and en epigenetic network that induces dormancy. We also identified retinoic acid and TGF2 in the microenvironment as inducers of the high p38/ERK-signaling ratio and that dormancy (quiescent phenotype) is controlled by mechanisms driving adult stem cell biology. Translating this biology to medicine we identified a “dormancy signature” enriched in dormant DTCs from patients asymptomatic for up to 18 years and that predicts for prolonged metastasis-free periods in different cancers. Our work has propelled new questions to the forefront of cancer research, with the unexpected discovery that dormant DTCs can originate very early during cancer evolution, disseminating during pre-malignant stages of cancer. We have also designed an epigenetic reprograming therapy to induce dormancy of DTCs and developed a translational program with Eli Lilly to target dormant disease.
Julio Aguirre-Ghiso, MSc., Ph.D.
Director, Division of Hematology and Oncology
Department of Medicine and Department of Otolaryngology
Mount Sinai School of Medicine
12:00 pm at Van Andel Institute
Conference Room 3104/3105
For questions, please contact Kim Cousineau at 616.234.5684.