Cancer cells employ complex and multifarious molecular mechanisms to overcome innate barriers that normally prevent runaway proliferation. To address this complexity directly, we have pioneered the application of genome-wide siRNA screening to identify those gene products whose depletion has the most significant impact on paclitaxel sensitivity in Non-Small Cell Lung Cancer cells (NSCLC). This effort uncovered a collection of diverse candidates many of whom appear to be the products of anomalous gene expression programs and only impact mitosis in tumor cells. Using a stringent objective statistical algorithm and experimental validation, we have identified 3 novel and functionally diverse genes, whose role in mitosis has not previously been characterized. Because many of these genes display elevated expression patterns in tumors, we hypothesize that they may be tumor-cell specific dependencies for cell cycle progression. The purpose of this proposal is the mechanistic elaboration of the function of these genes with respect to their impact on mitosis and tumor growth in vivo. The long-term objective of this work is to deconstruct the components that are uniquely required for tumor cell mitosis. Ultimately, an understanding of how these proteins support mitosis will open new avenues for therapeutic intervention.
With respect to public health, these studies will identify the dependencies that are required only in tumor cells for mitotic progression. Therefore, we will uncover novel intervention points for therapy as well as new potential combinations of existing chemotherapeutics. Importantly, the genes we are evaluating here were identified from a genome-wide analysis to identify those components with the most significant impact on tumor cell mitosis. Thus, these studies will identify the sensitive pressure points in tumor for anti-cancer therapy. Ultimately, an understanding of how these proteins support mitosis will open new avenues for therapeutic intervention.
|Maine, Erin A; Westcott, Jill M; Prechtl, Amanda M et al. (2016) The cancer-testis antigens SPANX-A/C/D and CTAG2 promote breast cancer invasion. Oncotarget 7:14708-26|
|Maxfield, Kimberly E; Taus, Patrick J; Corcoran, Kathleen et al. (2015) Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer. Nat Commun 6:8840|
|Sinnott, Rebecca; Winters, Leah; Larson, Brittany et al. (2014) Mechanisms promoting escape from mitotic stress-induced tumor cell death. Cancer Res 74:3857-69|
|Li, Zhijun; Pei, Xin-Hai; Yan, Jun et al. (2014) CUL9 mediates the functions of the 3M complex and ubiquitylates survivin to maintain genome integrity. Mol Cell 54:805-19|
|Whitehurst, Angelique W (2014) Cause and consequence of cancer/testis antigen activation in cancer. Annu Rev Pharmacol Toxicol 54:251-72|
|Yan, Jun; Yan, Feng; Li, Zhijun et al. (2014) The 3M complex maintains microtubule and genome integrity. Mol Cell 54:791-804|
|Wang, Edina C; Sinnott, Rebecca; Werner, Michael E et al. (2014) Differential cell responses to nanoparticle docetaxel and small molecule docetaxel at a sub-therapeutic dose range. Nanomedicine 10:321-8|
|Cappell, Kathryn M; Sinnott, Rebecca; Taus, Patrick et al. (2012) Multiple cancer testis antigens function to support tumor cell mitotic fidelity. Mol Cell Biol 32:4131-40|
|Whitehurst, Angelique W; Xie, Yang; Purinton, Scott C et al. (2010) Tumor antigen acrosin binding protein normalizes mitotic spindle function to promote cancer cell proliferation. Cancer Res 70:7652-61|
|Cappell, Kathryn M; Larson, Brittany; Sciaky, Noah et al. (2010) Symplekin specifies mitotic fidelity by supporting microtubule dynamics. Mol Cell Biol 30:5135-44|