Our studies on the biology of survivin, and its contribution to tumor progression in humans, have reached important milestones during the last cycle of CA78810. We now know that the anti-apoptotic function of survivin involves a pool of the molecule compartmentalized in mitochondria, and released in the cytosol in response to cell death stimuli. We also know that mitochondria-derived survivin forms a complex with a related protein, XIAP, and it is this interaction that cooperatively inhibits apoptosis, and enhances tumor growth, in vivo. In unraveling this pathway, we found that a survivin-XIAP complex is not only competent to counteract cell death, but also activates a broad gene expression program in tumor cells, with upregulation of a distinct class of adhesion molecules, especially fibronectin. This has profound implications, as survivin-expressing cells become highly invasive, in vitro, and exhibit aggressive metastatic dissemination in xenograft and transgenic models, in vivo. Therefore, a unifying hypothesis that survivin functions as a novel metastasis gene, in vivo, via de novo upregulation of gene expression can be formulated, and will constitute the focus of the next cycle of CA788810. Experiments in the first specific aim will dissect the phenotypic requirements of tumor cell invasion mediated by survivin, with respect to modulation of epithelial-mesenchymal transition, matrix metalloproteinase expression, and activation of a pivotal regulator of this pathway, the Src kinase. The second specific aim will attain a comprehensive characterization of how a survivin-XIAP complex influences molecular mechanisms of gene expression. These studies will focus on the cellular and signaling requirements of fibronectin gene regulation, and elucidate their involvement in tumor cell invasion. Lastly, in the third specific aim, we will test the relevance of this pathway in metastasis models, in vivo. This will be accomplished by systematically targeting the assembly of a survivin-XIAP complex, its requirements for gene expression, and its downstream signaling effectors in xenograft studies, and in a transgenic mouse model of localized and disseminated breast cancer. Overall, these studies will unravel the molecular underpinnings of a novel pathway of tumor cell invasion at the crossroads between intracellular signaling by apoptosis regulators and modulation of adhesion molecule gene expression. The results may help in the design of novel molecularly- directed therapies that interfere with metastatic disease, an incurable and invariably fatal occurrence of cancer progression in humans.

Public Health Relevance

The dissemination of tumor cells to distant organs, or metastasis, is a deadly occurrence in cancer progression, but its underlying mechanisms are still largely obscure. The present proposal will dissect a novel pathway of metastasis, involving interplay between regulators of cell survival and cell adhesion. The results may open new prospects for the treatment of metastatic cancer, which is currently incurable.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078810-16
Application #
8448012
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
1998-07-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
16
Fiscal Year
2013
Total Cost
$287,949
Indirect Cost
$120,537
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Lu, Huimin; Wang, Tao; Li, Jing et al. (2016) αvβ6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor. Cancer Res 76:5163-74
Chae, Young Chan; Vaira, Valentina; Caino, M Cecilia et al. (2016) Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming. Cancer Cell 30:257-72
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Chae, Young Chan; Angelin, Alessia; Lisanti, Sofia et al. (2015) Corrigendum: Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun 6:7605
Forno, Irene; Ferrero, Stefano; Russo, Maria Veronica et al. (2015) Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression. PLoS One 10:e0130060
Rivadeneira, Dayana B; Caino, M Cecilia; Seo, Jae Ho et al. (2015) Survivin promotes oxidative phosphorylation, subcellular mitochondrial repositioning, and tumor cell invasion. Sci Signal 8:ra80
Trerotola, Marco; Ganguly, Kirat K; Fazli, Ladan et al. (2015) Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts. Oncotarget 6:14318-28
Caino, M Cecilia; Altieri, Dario C (2015) Disabling mitochondrial reprogramming in cancer. Pharmacol Res 102:42-5

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