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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wistar Institute
United States
Zip Code
Lu, Huimin; Bowler, Nicholas; Harshyne, Larry A et al. (2018) Exosomal ?v?6 integrin is required for monocyte M2 polarization in prostate cancer. Matrix Biol 70:20-35
Caino, M Cecilia; Seo, Jae Ho; Wang, Yuan et al. (2017) Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer. J Clin Invest 127:3755-3769
Altieri, Dario C (2017) Mitochondria on the move: emerging paradigms of organelle trafficking in tumour plasticity and metastasis. Br J Cancer 117:301-305
Bryant, Kelly G; Chae, Young Chan; Martinez, Rogelio L et al. (2017) A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy. Oncotarget 8:112184-112198
Behera, Reeti; Kaur, Amanpreet; Webster, Marie R et al. (2017) Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho. Clin Cancer Res 23:3181-3190
Ishida, Chiaki Tsuge; Shu, Chang; Halatsch, Marc-Eric et al. (2017) Mitochondrial matrix chaperone and c-myc inhibition causes enhanced lethality in glioblastoma. Oncotarget 8:37140-37153
Altieri, Dario C (2017) AML Therapy: Wake Up the Guardian and Cut Loose the Executioners. Cancer Cell 32:719-720
Karpel-Massler, Georg; Ishida, Chiaki Tsuge; Bianchetti, Elena et al. (2017) Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses. Cancer Res 77:3513-3526
Dheekollu, Jayaraju; Malecka, Kimberly; Wiedmer, Andreas et al. (2017) Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency. Oncotarget 8:7248-7264
Lu, Huimin; Wang, Tao; Li, Jing et al. (2016) ?v?6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor. Cancer Res 76:5163-74

Showing the most recent 10 out of 140 publications