Pennsylvania Cancer and Regenerative Medicine Research Center

Status

Dr. Gabriele Di Sante is currently an Assistant Professor at the Baruch S. Blumberg Institute, Pennsylvania Biotechnology center, Doylestown, PA. Previously a Postdoctoral Research Fellow at Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Cancer Biology, Philadelphia, PA. 

background

 My expertise in mitophagy, autophagy and transgenics is well matched with the proposed grant entitled “Dachshund cell fate determination factor in prostate cancer onset and progression“. In prostate cancer I published a key study on prostate intraepithelial neoplasia (PIN) and the role of SIRT1 in this process. Furthermore I contributed key studies to the recent paper on Dach1 in the prostate. My biomedical research in the field of Cancer Biology at Thomas Jefferson University focuses on the role of autophagy and chromosomal instability, and transcriptional co-regulators. My work on new techniques for studying autophagy are relevant to the current proposal. My studies have successfully been published in peer-reviewed journals, including “Oncotarget”, “Molecular Endocrinology” and “Cancer Research”. The American Italian Cancer Foundation has also awarded my cancer research studies with a training grant. In summary, I have a demonstrated track record of productive research projects in an area of high relevance as Breast Cancer. 

Contributions to Science

Dach1 and Cancer. Dr. Pestell was the first to show that Dach1 restrains tumor growth, that the abundance of Dach1 is reduced in human cancers and that Dach1 restrains stem cells through reprogramming an Oct/Nanog/EKLF pathway. He was the first to show Dach1 binds to non canonical TF binding sites (c-Jun, Smad) and bind DNA directly to promote gene expression modules. He showed Dach1 is phosphorylated and acetylated and controls breast cancer epithelial cell growth and migration in vitro and in vivo. My work showed that acetylation of DACH1 determines binding to p53 and specific signaling to restrain p53-mediated stem cell functions.

1. Chen K, Wu K, Jiao X, Wang L, Ju X, Wang M, Di Sante G, Xu S, Wang Q, Li K, Sun X, Xu C, Li Z, Casimiro MC, Ertel A, Addya S, McCue PA, Lisanti MP, Wang C, Davis RJ, Mardon G, Pestell RG. The Endogenous Cell-Fate Factor Dachshund Restrains Prostate Epithelial Cell Migration via Repression of Cytokine Secretion via a CXCL Signaling Module. Cancer Res. 2015 May 15;75(10):1992-2004. PMCID: PMC4433595.

2. Chen K, Wu K, Gormley M, Ertel A, Wang J, Zhang W, Zhou J, Di Sante G, Li Z, Rui H, Quong AA, McMahon SB, Deng H, Lisanti MP, Wang C, Pestell RG. Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer. Oncotarget. 2013 Jun;4(6):923-35. PMCID: PMC3757249.

Autophagy and mitophagy assays. I demonstrated a key role for SIRT1 in regulating autophagy in vivo and prostate intraepithelial cell neoplasia. I developed a technique, which will be used in the proposed R35 studies, to follow mitophagy via Parkin recruitment.

1. Di Sante G, Casimiro MC, Pestell T and Pestell RG .Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation As a Marker For Cellular Mitophagy. Journal of Visualized Experiments. 2015 (in Press). PMCID: Identifier absent.

2. Di Sante G, Pestell TG, Casimiro MC, Bisetto S, Powell MJ, Lisanti MP, Cordon-Cardo C, Castillo-Martin M, Bonal DM, Debattisti V, Chen K, Wang L, He X, McBurney MW, Pestell RG. Loss of sirt1 promotes prostatic intraepithelial neoplasia, reduces mitophagy, and delays park2 translocation to mitochondria. Am J Pathol. 2015 Jan;185(1):266-79. doi: 10.1016/j.ajpath.2014.09.014. PMCID: PMC4278247.

3. Di Sante G, Wang L, Wang C, Jiao X, Casimiro MC, Chen K, Pestell TG, Yaman I, Di Rocco A, Sun X, Horio Y, Powell MJ, He X, McBurney MW, Pestell RG. Sirt1 deficient mice have hypogonadotropic hypogonadism due to defective GnRH neuronal migration. Mol Endocrinol. 2014 Dec 29:me20141228. [Epub ahead of print]. PMCID: PMC4318884.

Non canonical functions of Cyclin D1. The laboratory in which I work, of Dr. Pestell has made seminal discoveries in the understanding of cell-cycle control in cancer. Thet were first to show that: 1) cyclins are direct transcriptional targets of oncogenic and tumor suppressor signals; 2) cyclin D1 expression is rate-limiting for oncogene-induced breast tumor and colon growth in vivo; 3) cyclin D1 binds DNA to regulate gene expression and chromosomal instability; 4) cyclins interact with nuclear receptors and tumor suppressors; 5) cyclins regulate mitochondrial metabolism, cellular migration, the non-coding genome and its biogenesis. My studies showed that cyclin D1 is recruited by androgens into chromatin and determines DHT-mediated DNA repair. I showed a key role for cyclin D1 in promoting chromosomal instability, and an essential role for cyclin D1 in ERa-mediated signaling.

1. Casimiro MC*, Di Sante G*, Ju X, Li Z, Chen K, Crosariol M, Yaman I, Gormley M, Meng H, Lisanti MP, and PestellRG. Casimiro, M.C., Ju, X., Gormley, M., Meng, H., Jiao, X., Katiyar, S., Crosariol, M., Chen, K., Wang, M., Quong, A.A., Lisanti MP, Ertel A, Pestell RG. Cyclin D1 promotes androgen-dependent DNA damage repair in prostate cancer cells. Cancer Research, 2015, Nov 18 *: Equal contribution. PMCID: PMC4715975.

2. Casimiro MC, Di Sante G, Crosariol M, Loro E, Dampier W, Ertel A, Yu Z, Saria EA, Papanikolaou A, Li Z, Wang C, Addya S, Lisanti MP, Fortina P, Cardiff RD, Tozeren A, Knudsen ES, Arnold A, Pestell RG. Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis. 6(11): 8525- 38, Oncotarget, 2015. PMCID: PMC4496164.

3. Yu Z, Xu Z, Di Sante G, Wright J, Wang M, Li Y, Zhao Q, Ren T, Ju X, Gutman E, Wang G, Addya S, Li T, Xiang Z, Wang C, Yang X, Yang X, Pestell RG. miR-17/20 sensitization of breast cancer cells to chemotherapy-induced apoptosis requires Akt1. 5(4): 1083-90, Oncotarget, 2014. PMC4011585.

4. Casimiro MC, Wang C, Li Z, Di Sante G, Willmart NE, Addya S, Chen L, Liu Y, Lisanti MP, Pestell RG. Cyclin D1 Determines Estrogen Signaling in the Mammary Gland in Vivo. Molecular Endocrinology, 2013. PMCID: Identifier absent .