Prof. Anna Mandinova (MD, PhD)
Assistant Professor, Harvard Medical School / Associate Member of the Broad Institute of Harvard/MIT
Prof Anna Mandinova received her MD in 1995 at the University of Sofia, Bulgaria before moving to Switzerland to complete a PhD specialization in Cell Biology at the University of Basel.
In 2004, Prof Mandinova was recruited for a post doctoral position in the dermatology department of Harvard University, whereafter she established her career as an assistant professor. Since 2008 she has run a reasearch laboratory focusing on the molecular mechanisms of squamous cell skin cancer and the genetic determinents of “stemness” in epidermal tissue.
Our laboratory uses genetic and chemical biology approaches in models of epidermal growth and differentiation to dissect molecular pathways involved in stem cell decisions and tumor development in the skin. We have recently identified a novel-signaling pathway in keratinocytes involving inhibition of the RhoE gene downstream of Notch1, which plays a key role in squamous cell carcinoma development
In the course of these experiments we became more interested in uncovering novel mechanisms controlling epidermal stem cell fate in health and disease. Stem and progenitor cell function can be regulated by both transcriptional and post-transcriptional control of key genes. Several prominent transcription and epigenetic factors have been identified to govern these processes and maintain stem cell function. At the same time it is now recognized that the cellular abundance of proteins is predominantly controlled at the level of translation with RNA binding proteins taking a leading role in this process. We were therefore very excited to identify a novel epidermal stem cell regulator, the RNA binding protein, YB-1, which modulates key steps of protein translation in a sequence specific manner. We found that loss of YB-1 expression in keratinocytes results in failure of epidermal stem cell function; decrease of the proliferative potential of epidermal progenitors in vitro and alterations in all of the epidermal lineages in vivo.
High resolution RNA-sequencing analysis of the actively translating polysomal portion of the keratinocyte mRNAs indicates that YB-1 modulates the translation of various targets among which a subset of potent senescence-associated cytokines is significantly enriched. As a consequence YB-1 depleted epidermal cells exhibit a senescent phenotype.
These findings are particularly important because it is now recognized that while epidermal stem cells consist of quiescent and actively cycling populations and their activation is characterized by increased metabolism and high proliferative rates, key determinants of their “stemness” is prevention of commitment to differentiation as well as of undergoing senescence associated with their intense proliferative state.
We are now focusing our efforts to uncover the molecular mechanisms of YB-1 driven epidermal stem cell function and more broadly to understand how RNA-binding proteins control specific steps of translation to modulate stem cell fate decisions.
- Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolfschoten I, Devgan V, Lieb J, Raffoul W, Hohl D, Neel V, Garlick J, Chiorino G, Dotto GP. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases; Genes Dev. 2007 Mar 1;21(5):562-77; PMID: 17344417; PMCID: PMC1820898
- Mandinova A,*, Karine Lefort*, Alice Tommasi di Vignano, Wesley Stonely, Paola Ostano, Giovanna Chiorino, Haruhi Iwaki, Jotaro Nakanishi and G. Paolo Dotto; FoxO3a is a key transcriptional target of canonical Notch signaling in the keratinocyte UVB-response. EMBO J. 2008 Apr 23;27(8):1243-54; PMID: 18388864; PMCID: PMC2367396
- Kolev V*, Mandinova A*, Guinea-Viniegra J, Hu B, Lefort K, Lambertini C, Neel V, Dummer R, Wagner EF, Dotto GP.EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer. Nat Cell Biol. 2008 Aug;10(8):902-11 (equal first author); PMID: 18604200; PMCID: PMC2747621
- Stanton BZ, Peng LF, Maloof N, Nakai K, Wang X, Duffner JL, Taveras KM, Hyman JM, Lee SW, Koehler AN, Chen JK, Fox JL, Mandinova A, Schreiber SL. A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol. 2009 Mar;5(3):154-6. Epub 2009 Jan 18. PMID: 19151731; PMCID: PMC2770933
- Mandinova A, Kolev V, Neel V, Hu B, Stonely W, Lieb J, Wu X, Colli C, Han R, Pazin M, Ostano P, Dummer R, Brissette JL, Dotto GP. A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans. J Clin Invest. 2009 Oct;119(10):3127-37. PMID: 19729838; PMCID: PMC2752067
- Lee KK, Todorova K, Mandinova A. Maximizing early detection of esophageal squamous cell carcinoma via SILAC-proteomics. Cancer Biol Ther. 2010 Oct 15;10(8):811-3. Epub 2010 Oct 15. PMID:20953140; PMCID:PMC3093917
- Mandinova A, Lee SW. The p53 pathway as a target in cancer therapeutics: obstacles and promise. Sci Transl Med. 2011 Jan 5;3(64):64rv1. PMID: 21209413; PMCID: PMC3763710
- Raj, L., Ide, T., Schenone, M., Li, X., Wei, G., Tolliday, N.J., Golub, T.R., Carr, S.C., Foley, M., Mandinova, A., Schreiber, S.L., and Lee, S.W. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475: 231-234, 2011. PMID: 21753854; PMCID: PMC3316487 (co-corresponding author).
- Kawasumi M, Lemos B, Bradner JE, Thibodeau R, Kim YS, Schmidt M, Higgins E, Koo SW, Angle-Zahn A, Chen A, Levine D, Nguyen L, Heffernan TP, Longo I, Mandinova A, Lu YP, Conney AH, Nghiem P. Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase. Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13716-21. Epub 2011 Aug 15. PMID:21844338; PMCID:PMC3158235
- Brown-Endres L, Schoenfeld D, Tian F, Kim HG, Namba T, Muñoz-Fontela C, Mandinova A, Aaronson SA, Lee SW. Expression of the p53 target CDIP correlates with sensitivity to TNFα-induced apoptosis in cancer cells. Cancer Res. 2012 May 1;72(9):2373-82. PMID:22549949; PMCID:PMC3349239
- Gurkar, A.U., Chu, K., Raj, L., Kim, Y.-B., Dunn, S.E., Mandinova, A., and Lee, S.W. Identification of ROCK1 kinase as a critical regulator of Beclin1 mediated autophagy during metabolic stress. Nature Communication, 4: 2189, 2013. PMID: 23877263
- Namba, T., Tian, F, Chu, K., So-Young Hwang, S.-Y., Yoon, K.W., Hiraki, M., Mandinova, A., and Lee, S.W. CDIP-BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under ER stress. Cell Reports 5: 331-339, 2013. PMID: 24139803
- Kim HG, Tan L, Weisberg EL, Liu F, Canning P, Choi HG, Ezell SA, Wu H, Zhao Z, Wang J, Mandinova A, Griffin JD, Bullock AN, Liu Q, Lee SW, Gray NS. Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor. ACS Chem Biol. 2013 Oct 18;8(10):2145-50. doi: 10.1021/cb400430t. Epub 2013 Aug 13. PMID:23899692
- Zhu Z, Todorova K, Lee KK, Wang J, Kwon E, Kehayov I, Kim HG, Kolev V, Dotto GP, Lee SW, Mandinova A. Small GTPase RhoE/Rnd3 is a critical regulator of Notch1 signaling. Cancer Res. 2014 Feb 13. [Epub ahead of print]; PMID:24525741
- Yoon, K.W., Byun, S., Hwang, S.-Y., Kwon, E., Chu, K., Hiraki, M., Weins, A., Hakroush, S., Cebulla, A., Greka, A., Mundel, P., Sykes, D.B., David E Fisher, D.E., Mandinova, A. & Lee, S.W. Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. In press, Science, 2015 (Research Article).