Our latest commentary on the importance of understanding and targeting all phases of metastasis is available on line.
Our knowledge of cancer progression has grown exponentially by 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 resulting in limited metastasis preventive therapies. Our work focuses on understanding the biology of residual cancer cells that persist in a dormant state after initial therapy. This knowledge will allow targeting minimal residual disease before it becomes clinically detectable and thus preventing recurrences. Our research is revealing ways to maintain residual cancer dormancy, kill dormant cancer cells and markers to determine the dormant or active state of disseminated disease.
Follow us on Twitter @ https://twitter.com/JAguirreGhiso
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. My lab focuses 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 is aimed at 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.
An important achievement was discovering that an imbalance in p38α/β and ERK1/2 signaling regulates lineage commitment transcription factors (NR2F1, DEC2) and en epigenetic network that determines dormancy induction. We also identified retinoic acid and TGFβ2 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 but still contributing to metastasis development. 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.
Movie: intravital imaging of MMTV-Her2-CFP mice revealing early dissemination. Nature. (2016) Dec 14. doi: 10.1038/nature20609. [Epub ahead of print] PMID:27974798.