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.
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.
|Sosa, María Soledad; Bragado, Paloma; Aguirre-Ghiso, Julio A (2014) Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14:611-22|
|Chéry, Lisly; Lam, Hung-Ming; Coleman, Ilsa et al. (2014) Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget 5:9939-51|
|Avivar-Valderas, A; Wen, H C; Aguirre-Ghiso, J A (2014) Stress signaling and the shaping of the mammary tissue in development and cancer. Oncogene 33:5483-90|
|Begley, Ulrike; Sosa, Maria Soledad; Avivar-Valderas, Alvaro et al. (2013) A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-*. EMBO Mol Med 5:366-83|
|Aguirre-Ghiso, Julio A; Bragado, Paloma; Sosa, Maria Soledad (2013) Metastasis awakening: targeting dormant cancer. Nat Med 19:276-7|
|Bragado, Paloma; Estrada, Yeriel; Parikh, Falguni et al. (2013) TGF-*2 dictates disseminated tumour cell fate in target organs through TGF-*-RIII and p38*/* signalling. Nat Cell Biol 15:1351-61|
|Sosa, Maria Soledad; Bragado, Paloma; Debnath, Jayanta et al. (2013) Regulation of tumor cell dormancy by tissue microenvironments and autophagy. Adv Exp Med Biol 734:73-89|
|Bragado, Paloma; Sosa, Maria Soledad; Keely, Patricia et al. (2012) Microenvironments dictating tumor cell dormancy. Recent Results Cancer Res 195:25-39|
|Bragado, Paloma; Estrada, Yeriel; Sosa, Maria Soledad et al. (2012) Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties. PLoS One 7:e29974|
|Kim, Ryung S; Avivar-Valderas, Alvaro; Estrada, Yeriel et al. (2012) Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. PLoS One 7:e35569|
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