Disseminated tumor cells and cancer dormancy
More than half of cancer patients will die from metastatic disease that invariably arises from disseminated tumor cells (DTCs) months, years or even decades after primary tumor removal. While in many cases cells can resume growth immediately, in some situations cells may enter a state of dormancy. It appears that dormancy of DTCs may be due to the ability of these cells to reprogram and enter a state of quiescence. The mechanisms that allow DTCs, which were competent for survival and proliferation in the primary site, to suddenly become growth arrested and dormant in target organs, are poorly understood. Our long-term goal is to understand the biology of DTCs. In particular we are interested in the mechanisms that favor survival, dormancy and switch into growth of loco-regional or secondary organ DTCs.
As part of the Head and Neck Cancer Multidisciplinary Research Program, we are exploring these mechanisms in the context of HNSCC but we anticipate these findings to be applicable to other tumors. In fact our research and translational programs have strong interactions and collaborations with the Breast Cancer and Hematological Malignancies Research Programs. Understanding the biology driving growth, survival and dormancy of DTCs is essential to identify new therapies to induce and/or maintain dormancy of DTCs or to eradicate dormant DTCs before they resume growth. This research will allow identifying markers indicative of the behavior of residual disease leading to a better staging of patients and better choices for therapy.
Modeling Tumor Dormancy General Hypothesis:
Our research hypothesis is that stress signaling imposed by micro-environmental cues or by exogenous stress such as that imposed by chemo- or radiation-therapy can induce stress adaptation programs. We hypothesize that stress signaling through a quiescence program allows disseminated tumor cells (DTCs) to survive in different microenvironments (i.e. target organs) and resist therapies. Thus, prolonged dormancy may be a manifestation of a survival program conserved through evolution for cells to adapt to strenuous conditions imposed by their surroundings. Stress signaling and tumor cell dormancy in HNSCC. We have studied head and neck squamous cell carcinoma (HNSCC) HEp3 cells retain their malignancy only upon in vivo serial transplantation. In contrast, the same cells placed in culture as pools of primary tumor-derived cells or as individual clones representing the primary tumor heterogeneity, extinguish their malignancy after in vitro adaptation over several generations. This is caused by the acquisition of a quiescent phenotype in vivo that results in protracted dormancy. Mechanistic analysis showed that the loss of malignancy is in part due to the activation of p38 stress signaling, which antagonizes ERK activation (a low ERK/p38 signaling ratio), among other critical players. Induction of quiescence by p38 involves the regulation of transcriptional and post-transcriptional programs as well as attenuation of translation initiation. Further, dormant tumor cell survival and resistance to chemotherapy, was found to be depend! ent on the chaperon Grp78/BiP and on the transcription factor ATF6. This model has allowed us to learn how stress signaling can induce quiescence and survival of otherwise proliferating malignant cells. Our lab is also interested how cancer therapies may activate these survival stress adaptation programs. We are particularly interested in how conventional chemo- and radiation-therapy induces stress adaptation in HNSCC and how it may be applicable to other cancers including breast cancer and multiple myeloma (Aguirre-Ghiso Nat Rev Cancer. 2007 Nov;7(11):834-46). We are also interested in determining whether these mechanisms are operational in DTCs in patients. We are particularly interested in determining whether bone marrow and/or lymph node DTCs in HNSCC patients express markers of progression vs. dormancy and whether these have prognostic value. Stress signaling, mammary morphogenesis and early dissemination of tumor cells: We have studied how stress signaling through the endoplasmic reticulum kinase PERK and p38 regulate mammary acinar morphogenesis. We have shown that these stress-signaling pathways are essential to limit the growth of acinar structures and maintain proper acinar architecture. This occurs through the coordinated regulation of growth arrest and apoptosis by PERK and p38. We are also exploring how loss of stress signaling mechanisms may favor disruption of acinar architecture favoring early dissemination of mammary epithelial cells. This in turn may contribute to dormancy of DTCs in this type of cancer (Klein and Holzel, Cell Cycle. 2006 Aug;5(16):1788-98 and Aguirre-Ghiso Nat Rev Cancer. 2007 Nov;7(11):834-46).
Julio. A. Aguirre-Ghiso, MSc, PhD
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New York NY 10029