Our knowledge of cancer progression has grown exponentially since the discovery of oncogenes and our ability to model cancer initiation. Still the major challenge faced by physicians is the prevention and treatment of metastasis, the main reason for cancer related deaths. Our understanding of metastasis has lagged behind that of primary tumor biology and even with a surge in metastasis research we are far behind grasping its complexities. Unfortunately, this lack of understanding of metastasis has resulted in limited success in metastasis preventive therapies.
Surprisingly, 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. Thus, despite cancer cells carrying genetic alterations micro-environmental and epigenetic mechanisms appear to induce tumor cell dormancy. 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 novel cancer 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. A major achievement of was discovering that imbalance in p38a/b and ERK1/2 signaling regulates lineage commitment transcription factors (TF) and en epigenetic network that determines dormancy induction. We also identified retinoic acid and TGFb2 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. My lab has also designed an epigenetic reprograming therapy to induce dormancy of DTCs, which is being developed into a clinical trial. We also discovered that UPR signaling can promote the survival of dormant tumor cells and that macrophages are key players in the regulation of early dissemination and dormancy. With multiple collaborators we run an NCI-Tumor Microenvironment Network Center that studies the microenvironmental stress and dormancy and develops new technologies to image and target metastasis. We also collaborate to characterize dormancy in human breast, prostate and head and neck cancer DTCs and we study the epigenetic regulation of DTC dormancy. A major effort in our lab is also to developed a translational program with the pharmaceutical inductry to identify potential drugs to target dormant disease.