Genomes and Genes
Functional determinants of metastatic dormancy
Principal Investigator: Julio A Aguirre-Ghiso
Abstract: DESCRIPTION (provided by applicant): Majority of cancer patients will die of metastases that develop from disseminated tumor cells (DTCs) sometimes decades after treatment, suggesting that DTCs survive in a dormant, non-proliferative state. Our long-term goal is to identify the mechanisms regulating dormancy of DTCs. We hypothesize that (i) tumor cell dormancy (i.e. growth arrest) may happen during and/or after dissemination in response to stress signals imposed by an inhospitable tissue microenvironment and/or by therapy and that (ii) stress signaling in turn activates a robust survival program that favors prolonged survival during the dormancy periods. Using an experimental model, HEp3 head and neck squamous carcinoma cells, our laboratory has identified novel mechanisms regulating the growth arrest and survival capacity of dormant tumor cells. These depend on the signaling balance between ERK1/2 (mitogenic) and p38a/b (stress) pathways and a specific downstream gene expression program. We showed that during adaptation from in vivo to culture conditions HEp3 carcinoma cells reprogram to acquire a dormant phenotype characterized by a prolonged G0/G1 arrest when re-injected in vivo. We discovered that (i) the growth arrest of dormant HEp3 cells is due to p38a-dependent regulation of a complex transcription factor (TF) network. In this network p53 and BHLHB3 are transcriptionally induced by p38 and they contribute to quiescence. The G0/G1 arrest is further enforced by p38a-dependent inhibition of the TFs FoxM1 and c-Jun;the latter antagonizes p53. We also found that (ii) the TF ATF6a regulates the survival component of dormancy by controlling an alternative pathway to mTOR activation Indeed, ATF6a upregulates the small GTPase Rheb, which in turn induces mTOR-S6K activation, resistance to Rapamycin and survival of dormant tumor cells in vivo. Thus, we have pinpointed genes and mechanisms contributing to both the quiescence and survival of dormant tumor cells. We also discovered that HEp3 DTCs but in the bone marrow microenvironment are unable to resume proliferation, while growth ensues in the primary site and lungs. This remarkable difference seems to be a program of dormancy. The basis for this is that upon recovery from the bone marrow and expansion in culture these cells are unable to form tumors when re-injected in animals. Instead they undergo a dormancy phase before resuming growth. We hypothesize that similar mechanisms to those described above allow DTCs to resist therapy- or microenvironment-induced cell death and to survive in a dormant state, providing a source of metastatic recurrences in patients. Clearly, inducing and or extending the growth arrest of DTCs would be beneficial for patients, but blocking their survival mechanisms would allow their eradication before recurrences can develop. Because eventual success of anti- cancer therapy depends strictly on curing or preventing metastases, progress in this field is urgently needed to improve the therapeutic eradication of metastatic precursors. We believe these findings are of significance, as knowledge on DTC dormancy will have an important impact on how we understand and treat cancer. PUBLIC HEALTH RELEVANCE: We will explore the gene programs regulating the induction of quiescence, the prolonged survival and chemotherapy resistance of dormant tumor cells. We will also study the activation of these mechanisms in disseminated tumor cells. These studies will provide insight into how to stop metastasis development.
Funding Period: 2004-07-01 - 2015-12-31
more information: NIH RePORT
- Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cellsAparna C Ranganathan
Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, Rensselaer, NY 12144, USA
Cancer Res 66:1702-11. 2006..We propose that stress-dependent activation of p38 via BiP up-regulation and PERK activation protects dormant tumor cells from stress insults, such as chemotherapy...
- Bortezomib enhances the efficacy of fulvestrant by amplifying the aggregation of the estrogen receptor, which leads to a proapoptotic unfolded protein responseYuki Ishii
Division of Hematology Oncology, Tisch Cancer Institute and Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, New York, USA
Clin Cancer Res 17:2292-300. 2011..We tested whether combining fulvestrant with the proteasome inhibitor, bortezomib, could enhance the accumulation of ER aggregates and cause apoptotic cell death...
- p38α Signaling Induces Anoikis and Lumen Formation During Mammary MorphogenesisHuei Chi Wen
Department of Medicine, Tisch Cancer Institute at Mount Sinai, Mount Sinai School of Medicine, New York, USA
Sci Signal 4:ra34. 2011..We conclude that p38α is crucial for the development of hollow ducts during mammary gland development, a function that may be crucial to its ability to suppress breast cancer...
- ERK1/2 and p38α/β signaling in tumor cell quiescence: opportunities to control dormant residual diseaseMaria Soledad Sosa
Department of Medicine, Division of Hematology and Oncology, Tisch Cancer Institute at Mount Sinai, New York, New York, USA
Clin Cancer Res 17:5850-7. 2011..Finally, we draw caution on the use of p38 inhibitors currently in clinical trials for different diseases as these may accelerate metastasis development...
- PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachmentAlvaro Avivar-Valderas
Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA
Mol Cell Biol 31:3616-29. 2011..We propose that the normal proautophagic and antioxidant PERK functions may be hijacked to promote the survival of ECM-detached tumor cells in DCIS lesions...
- p38α mediates cell survival in response to oxidative stress via induction of antioxidant genes: effect on the p70S6K pathwayAlvaro Gutiérrez-Uzquiza
Departamento de Bioquímica y Biología Molecular II Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Ciudad Universitaria, 28040 Madrid, Spain
J Biol Chem 287:2632-42. 2012..Therefore, our results reveal a novel homeostatic role for p38α in response to oxidative stress, where ROS removal is favored by antioxidant enzymes up-regulation, allowing cell survival and mTOR/p70S6K activation...
- Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating propertiesPaloma Bragado
Division of Hematology and Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America
PLoS ONE 7:e29974. 2012..This allows multiple tumor cell subpopulations to drive tumor growth suggesting that their dynamic nature renders them a "moving target" and their eradication might require more persistent strategies...
- Microenvironments dictating tumor cell dormancyPaloma Bragado
Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Mount Sinai School of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, New York, NY, USA
Recent Results Cancer Res 195:25-39. 2012..For these non-mutually exclusive scenarios we review experimental and clinical evidence in their support...
- Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancerRyung S Kim
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America
PLoS ONE 7:e35569. 2012..Furthermore, genes identified with this approach might provide insight into the mechanisms of dormancy onset and maintenance as well as dormancy models using human breast cancer cell lines...
- Regulation of tumor cell dormancy by tissue microenvironments and autophagyMaria Soledad Sosa
Department of Medicine and Otolaryngology, Mount Sinai School of Medicine, New York, NY, USA
Adv Exp Med Biol 734:73-89. 2013..We also explore how therapy may cause the onset of dormancy in the surviving fraction of cells after treatment and how autophagy may be a mechanism that maintains the residual cells that are viable for prolonged periods...
- Regulation of autophagy during ECM detachment is linked to a selective inhibition of mTORC1 by PERKA Avivar-Valderas
Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY, USA
Oncogene 32:4932-40. 2013..We propose that increased autophagy, secondary to persistent PERK and LKB1-AMPK signaling, can robustly protect cells from anoikis and promote luminal filling during early carcinoma progression...
- A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-αUlrike Begley
College of Nanoscale Science and Engineering, University at Albany, State University of New York, Albany, NY, USA
EMBO Mol Med 5:366-83. 2013..Our study links hTRM9L and tRNA modifications to inhibition of tumour growth via LIN9 and HIF1-α-dependent mechanisms. It also suggests that aminoglycoside antibiotics may be useful to treat hTRM9L-deficient tumours...
- TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signallingPaloma Bragado
Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York 10029, USA
Nat Cell Biol 15:1351-61. 2013..Our work reveals a 'seed and soil' mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis. ..
- On the theory of tumor self-seeding: implications for metastasis progression in humansJulio A Aguirre-Ghiso
Department of Medicine and Department of Otolaryngology, Division of Hematology and Oncology, Tisch Cancer Institute at Mount Sinai, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA
Breast Cancer Res 12:304. 2010..A viewpoint presented here addresses the implications of these studies for human cancer metastasis...
- Dormancy of metastatic melanomaLiliana Ossowski
Division of Hematology and Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA
Pigment Cell Melanoma Res 23:41-56. 2010..Ultimately, understanding the biology of dormancy and the mechanisms of dormant cell survival, might allow for their specific targeting and elimination...
- Tumor cell dormancy induced by p38SAPK and ER-stress signaling: an adaptive advantage for metastatic cells?Aparna C Ranganathan
Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, Rensselaer, NY 12144 3456, USA
Cancer Biol Ther 5:729-35. 2006..Finally, we propose that this response may recapitulate an evolutionarily conserved program of life-span extension through adaptation and tolerance to stress...
- The problem of cancer dormancy: understanding the basic mechanisms and identifying therapeutic opportunitiesJulio A Aguirre-Ghiso
Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, NY, USA
Cell Cycle 5:1740-3. 2006..We anticipate that this will initiate a forum of discussion on the problem of cancer dormancy and stimulate investigators to study this rather unexplored but undeniably relevant clinical stage of cancer progression...
- Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancyAparna C Ranganathan
Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, New York, USA
Cell Cycle 5:1799-807. 2006....
- Extracellular signal-regulated kinase 1/2 activity is not required in mammalian cells during late G2 for timely entry into or exit from mitosisMio Shinohara
Division of Molecular Medicine, Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA
Mol Biol Cell 17:5227-40. 2006..Together, our data reveal that ERK1/2 activity is required in early G2 for a timely entry into mitosis but that it does not directly regulate cell cycle progression from late G2 through mitosis in normal or transformed mammalian cells...
- Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formationSharon J Sequeira
Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, Rensselaer, New York, United States of America
PLoS ONE 2:e615. 2007..The possibility that deficiencies in PERK signaling could lead to hyperproliferation of the mammary epithelium and increase the likelihood of tumor formation, is of significance to the understanding of breast cancer...
- Models, mechanisms and clinical evidence for cancer dormancyJulio A Aguirre-Ghiso
Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, One Discovery Drive, Rensselaer, New York 12144 3456, USA
Nat Rev Cancer 7:834-46. 2007..The advances in this field provide an emerging picture of how cancer dormancy can ensue and how it could be therapeutically targeted...
- Ribonomic and short hairpin RNA gene silencing methods to explore functional gene programs associated with tumor growth arrestTimothy E Baroni
Gen NY Sis Center for Excellence in Cancer Genomics, Department of Biomedical Sciences, School of Public Health, University of Albany, SUNY, Rensselaer, NY, USA
Methods Mol Biol 383:227-44. 2007..Finally, this library of gene candidates is evaluated in vivo to address their functional role in the induction or maintenance of dormancy...
- Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survivalAparna C Ranganathan
Department of Biomedical Sciences, School of Public Health, Center for Excellence in Cancer Genomics, University at Albany, State University of New York, Rensselaer, New York, USA
Cancer Res 68:3260-8. 2008..This is an important consideration in the development of PERK-based therapies, as its inhibition may facilitate the proliferation of slow-cycling or dormant tumor cells...
- ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivoDenis M Schewe
Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, One Discovery Drive, Rensselaer, NY 12144, USA
Proc Natl Acad Sci U S A 105:10519-24. 2008..Targeting survival signaling by the ATF6alpha-Rheb-mTOR pathway in dormant tumor cells may favor the eradication of residual disease during dormancy periods...
- The urokinase receptor (u-PAR)--a link between tumor cell dormancy and minimal residual disease in bone marrow?Heike Allgayer
Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Medical Faculty Mannheim, University of Heidelberg, and DKFZ German Cancer Research Center Heidelberg, Germany
APMIS 116:602-14. 2008..Finally, we discuss the hypothesis that u-PAR might be an essential molecule in bone marrow disseminated tumor cells for long-term survival during dormancy, and/or reactivation of their proliferation years after primary treatment...
- Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapyDenis M Schewe
Department of Medicine, Division of Hematology and Oncology, Mount Sinai School of Medicine, New York, New York, USA
Cancer Res 69:1545-52. 2009..Thus, strategies that maintain eIF2alpha in a hyperphosphorylated state may be a novel therapeutic approach to maximize bortezomib-induced apoptosis and reduce residual disease and recurrences in this type of cancer...
- Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescenceAlejandro P Adam
Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, SUNY Albany, Rensselaer, New York, USA
Cancer Res 69:5664-72. 2009..Our results identify components of the regulatory mechanisms driving p38-induced cancer cell quiescence. These may regulate dormancy of residual disease that usually precedes the onset of metastasis in many cancers...
- Inhibition of eIF2alpha dephosphorylation inhibits ErbB2-induced deregulation of mammary acinar morphogenesisSharon J Sequeira
Department of Medicine, Division of Hematology and Oncology, Tisch Cancer Institute at Mount Sinai, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA
BMC Cell Biol 10:64. 2009..Here we explore whether ErbB2 modulates eIF2alpha phosphorylation and whether forced phosphorylation of the latter can antagonize ErbB2 deregulation of mammary acinar morphogenesis...
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