PROJECT 2: Majority of cancer patients will die of metastases originating from disseminated tumor cells (DTCs), years or even decades after treatment. This suggests that DTCs survive in a dormant, non-proliferative state. However, because the biology of DTCs is poorly understood it is critical to ask basic mechanistic questions to further develop translational approaches. Our goal is to identify these mechanisms by combining powerful In vivo models and novel imaging and nano-device technologies available through this collaboration. This consortium provides unprecedented synergy to study dormancy and address three emphasis areas of this RFA: 1) tumor dormancy, activation of dormant cells and the tumor microenvironment (SAI), and dormancy in response to cancer treatment (SA2);2) imaging the tumor microenvironment during tumor metastasis, and dormancy (SAI), as well as in response to therapies (SA2) and 3) characterization and functional relevance of the tumor microenvironment extracellular matrix (ECM) and how tumor cells stroma interactions (i.e. niches) establish metastatic cell fate (SA2). We hypothesize that at least two scenarios influence DTC dormancy. Scenario 1: DTCs from invasive cancers activate stress signals in response to a growth-restrictive target organ microenvironment inducing dormancy. Scenario 2: therapy and/or micro-environmental stress conditions (e.g. hypoxia) acting on primary tumor cells carrying a """"""""dormancy signature"""""""" primes newly DTCs to enter dormancy. Based on these two scenarios we propose to 1) isolate DTCs and identify microenvironment-specific gene programs driving DTC dormancy (Scenario 1) and 2) determine whether primary tumor """"""""stress microenvironments"""""""" trigger long-term dormancy of DTCs (Scenario 2). Findings in both aims will be validated using archived human primary and metastatic tumors. using human squamous (HEp3) and mouse breast carcinoma models (MMTV-Neu), we found that low ERK1/2 (mitogenic) and high p38a/p (stress) signaling activated dormancy of DTCs. Tumor cells spontaneously disseminated to lungs, lymph nodes (LN) and bone marrow (BM). A short-term dormancy period (2-3 weeks) preceded expansion of lung DTCs. However, BM DTCs persisted in a dormant state (Scenario 1). Systemic inhibition of p38a/p eliminated the short-term dormancy of lungs DTCs and also fueled growth even in sites where it is never observed like spleen, liver and BM. Thus, DTCs might remain occult and dormant in growth restrictive sites (Scenario 1). We also identified a specific gene expression program (signature) in dormant HEp3 cells that is present in cell lines derived from BM DTCs. Importantly, patients whose breast primary tumors carried this dormancy gene signature remained metastasis free for longer periods than those negative for the signature (Scenario 2). We also found that exposure to sub-lethal doses of y-radiation or oxidative stress ignited in surviving cells a dormancy state (Scenario 2). These preliminary data further support the important progress we have made in understanding the scenarios we propose to explore in our specific aims.
We will use novel imaging and nano-device technologies to tag, track and isolate disseminating tumor cells departing from primary tumors and proliferating or entering dormancy in target organs. We will discover their metabolic, genomic and transcription profiles to identify a cancer dormancy gene signature relevant to patients.
|Williams, James K; Entenberg, David; Wang, Yarong et al. (2016) Validation of a device for the active manipulation of the tumor microenvironment during intravital imaging. Intravital 5:|
|Hosseini, Hedayatollah; ObradoviÄ‡, Milan M S; Hoffmann, Martin et al. (2016) Early dissemination seeds metastasis in breast cancer. Nature :|
|Alsadeq, A; Strube, S; Krause, S et al. (2015) Effects of p38Î±/Î² inhibition on acute lymphoblastic leukemia proliferation and survival in vivo. Leukemia 29:2307-16|
|Curran, Colleen S; Carrillo, Esteban R; Ponik, Suzanne M et al. (2015) Collagen density regulates xenobiotic and hypoxic response of mammary epithelial cells. Environ Toxicol Pharmacol 39:114-24|
|Sosa, Maria Soledad; Parikh, Falguni; Maia, Alexandre Gaspar et al. (2015) NR2F1 controls tumour cell dormancy via SOX9- and RARÎ²-driven quiescence programmes. Nat Commun 6:6170|
|Hasegawa, Daisuke; Calvo, Veronica; Avivar-Valderas, Alvaro et al. (2015) Epithelial Xbp1 is required for cellular proliferation and differentiation during mammary gland development. Mol Cell Biol 35:1543-56|
|Sosa, MarÃa Soledad; Bragado, Paloma; Aguirre-Ghiso, Julio A (2014) Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14:611-22|
|ChÃ©ry, 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|
|Roh-Johnson, M; Bravo-Cordero, J J; Patsialou, A et al. (2014) Macrophage contact induces RhoA GTPase signaling to trigger tumor cell intravasation. Oncogene 33:4203-12|
|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|
Showing the most recent 10 out of 34 publications