Dormancy gene signatures that predict for late relapse in ER+ breast cancer patients:
Gene expression profiles of dormant HNSCC tumor cells:
Optimized IHC/IF protocols to detect dormancy markers:
RNAseq profiles of dormant HNSCC tumor cells derived from bone marrow dormant DTCs compared to proliferative DTCs from lung and primary tumor cells. (Pending accession numbers – available direct request)
5/4/18 Protocol update: for those that are using NR2F1 as a marker of dormancy – we have recently optimized the following antibody for immunofluorescence. It shows as a nuclear puncta which depending on the degree of expression/activity occupies different size areas in the nucleus https://www.rndsystems.com/products/human-coup-tf-i-nr2f1-mab-clone-h8132-h8132_pp-h8132-00
Microscope Work Stations
Avian embryo system for PDX and metastasis studies.
Our lab has used for over more than 15 years an optimized system for growing human patient derived and cancer cell line tumors in the avian chick embryo system. This system also allows for engrafting mouse tumors and it can be used to study tumor cell invasion, intravasation, dissemination and extravasation in lung, liver, brain and bone marrow. Given that the CAM is a 2-3 layer of tissue it is ideal for intra-vital imaging and angiogenesis studies.
The versatility and advantages of the Chick Embryo CAM system were recently used to explore the mechanisms of hypoxia induced dormancy and chemotherapy resistance of disseminated tumor cells: Fluegen G, Avivar-Valderas A, Wang Y, Padgen M, Williams JK, Nobre AR, Calvo V, Cheun JF, Bravo Cordero J, Entenberg D, Castracane J , Verkhusha V, Keely PJ, Condeelis J and Aguirre-Ghiso, JA. Phenotypic heterogeneity of disseminated tumor cells is preset by primary tumor hypoxic microenvironments. Nature Cell Biology (2017) doi:10.1038/ncb3465.
Multiple studies from our lab have employed the avian system for modeling metastasis and dormancy. To highlight a few:
James K. Williams, David Entenberg, Yarong Wang, Alvaro Avivar-Valderas, Michael Padgena, Ashley Clark, Julio A. Aguirre-Ghiso, James Castracane, John S. Condeelis.Validation of a device for the active manipulation of the tumor microenvironment during intravital imaging. Intravital (2016);5(2). pii: e1182271. PMID: 27790386
Sosa MS, Parikh F, Maia AG, Estrada Y, Bosch A, Bragado P, Ekpin E, George A, Zheng Y, Lam HM, Morrissey C, Chung CY, Farias EF, Bernstein E, Aguirre-Ghiso JA. NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes. Nat Commun. 2015 Jan 30;6:6170. doi: 10.1038/ncomms7170. PubMed PMID:25636082; PubMed Central PMCID: PMC4313575
Bragado P., Estrada Y., Parikh F., Krause S., Capobianco C., Farina H.G., Schewe D.M., and Julio A. Aguirre-Ghiso JA. TGFβ2 dictates disseminated tumour cell fate in target organs through TGFβ-RIII and p38α/β signalling. Nat. Cell. Bio.(2013). Nov;15(11):1351-61. doi: 10.1038/ncb2861. Epub 2013 Oct 27. PMID: 24161934.
Ulrike Begley, Maria Soledad Sosa, Alvaro Avivar-Valderas, Ashish Patil, Lauren Endres, Yeriel Estrada, Clement T.Y. Chan, Dan Su, Peter C. Dedon, Julio A. Aguirre-Ghiso and Thomas Begley. A human tRNA methyltransferase 9-like protein prevents tumor growth by regulating LIN9 and the hypoxic response. EMBO Mol Med (2013) Feb 4. doi: 10.1002/emmm.201201161
Paloma Bragado, Yeriel Estrada, Maria Soledad Sosa, Alvaro Avivar-Valderas, David Cannan, Eric Genden, Marita Teng, Aparna C. Ranganathan, Huei-Chi Wen, Avnish Kapoor, Emily Bernstein and Julio A. Aguirre-Ghiso. Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties. PLoS One. (2012) ;7(1):e29974. PMCID: PMC3262798
Alejandro P. Adam, Ajish George, Paloma Bragado, Bibiana V. Iglesias, Denis Schewe, Aparna Ranganathan, Antonis Kourtidis, Douglas S. Conklin and Julio A. Aguirre-Ghiso. Computational identification of a p38SAPK regulated transcription factor network required for tumor cell quiescence. Cancer Res. (2009) Jul 15;69(14):5664-72. Epub 2009 Jul 7.
Denis M. Schewe and Julio A. Aguirre-Ghiso. ATF6α-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc Natl Acad Sci U S A. (2008) Jul 29;105(30):10519-24.
David Liu, Julio A. Aguirre-Ghiso, Yeriel Estrada and Liliana Ossowski. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell (2002); 1: 445-457
Julio Aguirre-Ghiso. Inhibition of FAK signaling activated by urokinase receptor induces human carcinoma dormancy in vivo. Oncogene (2002) 21(16): 2513-24.