Professor Anna Philpott
Proneural transcription factors
Email: ap113@cam.ac.uk
Laboratory: Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre
Departmental Affiliation: Department of Oncology
Biography
Anna Philpott graduated from the University of Cambridge with a BA degree in Natural Sciences in 1988 and a PhD in Molecular Cell Biology in 1991. She held post-doctoral fellowships at Massachusetts General Hospital Cancer Centre in 1992, moving to the Department of Cell Biology at Harvard Medical School in 1993.
She returned to the University of Cambridge in 1998 to a Lectureship in the Department of Oncology, where she is currently Professor of Cancer and Developmental Biology and Head of the School of the Biological Sciences.
Funding
Cancer Research UK, Wellcome Trust
(A) Neurons generated by transcription factor-mediated forward programming. (B) Neurons stained purple in a developing Xenopus frog embryo. (C) Confetti coloured labelling of pancreatic ducts.
Research
We aim to characterise mechanisms that control the ability of cells to respond to cell fate challenges, as well as explore mechanisms that co-ordinate cell cycling with stem cell maintenance and differentiation during development, homeostasis and disease. In particular, we have uncovered a conserved regulatory mechanism where cdk-dependent phosphorylation of multiple proneural proteins promotes maintenance of progenitor/stem status, while dephosphorylation drives differentiation.
Our future aims are three-fold: we will explore how distinct fate-specifying transcription factors induce different responses at different developmental stages at the embryo, tissue and single cell level; we will further characterise the molecular mechanisms that link cell cycling and differentiation: We will also investigate perturbation of the balance between stem-ness/progenitor maintenance and differentiation that is a frequent hallmark of multiple cancers, focussing on molecular regulation of proliferation and differentiation in neuroblastoma, with the aim of developing new therapeutic strategies.
Group Members
Frances Connor, Lidiya Mykhaylechko, Toshiaki Shigeoka, Lydia Parkinson, Laura Woods, William Beckman, Roberta, Azzarelli, Rosalind Drummond
Plain English
Controlling the balance between division of cells and the process of differentiation, whereby cells stop dividing and adopt their specialised function, is critical both in development and in adult tissues that must maintain and repair themselves. Moreover, in many cancers and in particular cancers of children, this balance is disrupted. We are investigating the role of a class of proteins, the proneural factors, in controlling the fate choices cells make as well as their cell division and differentiation, and how their activity is controlled by chemical modification in response to their cellular environment. We are: - Studying how chemical modification of proneural proteins controls cell division versus differentiation in the nervous system, pancreas and gut. - Investigating how proneural proteins work to turn on different genes to either change their fate, promote cell division or arrest it, depending on the environment the cells are in. - Developing treatments for the childhood cancer neuroblastoma by changing the chemical modification of proneural proteins using new drugs. In the longer term, our understanding of the control of this crucial class of proteins, the proneurals, will help us to turn stem cells into useful tissues such as nerve and pancreas, as well as aid us in rational development of new therapies for cancers where proneural protein activity has been disrupted.
Key Publications
- The proneural transcription factor ASCL1 regulates cell proliferation and primes for differentiation in neuroblastoma. Parkinson LM, Gillen SL, Woods LM, Chaytor L, Marcos D, Ali FR, Carroll JS, Philpott A. Frontiers Cell Dev Biol. 2022 Oct 3;10:942579. doi: 10.3389/fcell.2022.942579. eCollection 2022.
- p57Kip2 imposes the reserve stem cell state of gastric chief cells. (2022). Ji-H. Lee, S .Kim S. Han J. Min B.Caldwell, A. Bamford, A. Rocha, H. Lee, J. Fink, S.Pilat-Carotta, J.Kim, M. Josserand, J.Park, S.Lee, R. Szep-Bakonyi , Y.Ahn, Y. Seok Ju, A. Philpott, B. D. Simons, D. E. Stange, E. Choi5, BK. Koo, and Jong Kyoung Kim. Cell Stem Cell 29, 826-839.
- ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation. (2022). Azzarelli R, McNally A, Dell'Amico C, Onorati M, Simons B, Philpott A.Sci Rep.;12(1):2341.
- Elevated ASCL1 activity creates de novo regulatory elements associated with neuronal differentiation. (2022). Woods LM, Ali FR, Gomez R, Chernukhin I, Marcos D, Parkinson LM, Tayoun ANA, Carroll JS, Philpott A. BMC Genomics. 23(1):255.
- Tracing oncogene-driven remodelling of the intestinal stem cell niche. M.K.Yum , S. Han , J. Fink, S.S. Wu, C. Dabrowska, T. Trendafilova, R. Mustata, L. Chatzeli, R. Azzarelli, I. Pshenichnaya, E.Lee, F. England, J.K. Kim, D.E. Stange, A. Philpott, J.H. Lee, B.K.Koo B.D Simons. Nature. 2021 Jun;594(7863):442-447. doi: 10.1038/s41586-021-03605-0. Epub 2021 Jun 2.PMID: 34079126
- Three-dimensional model of glioblastoma by co-culturing tumor stem cells with human brain organoids. 2021.R. Azzarelli, M. Ori , Philpott A, B. D.Simons .Biol Open. 2021 Feb 22;10(2):bio056416. doi: 10.1242/bio.056416.
- Tracing the cellular basis of islet specification in mouse pancreas. Sznurkowska MK, Hannezo E, Azzarelli R, Chatzeli L, Ikeda T, Yoshida S, Philpott A*, Simons BD*. (2020). Nat Commun. Oct 7;11(1):5037.
- Dephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma. (2020) Ali FR, Marcos D, Chernukhin I, Woods LM, Parkinson LM, Wylie LA, Papkovskaia TD, Davies JD, Carroll JS, Philpott A. Mol Cancer Res. 2020 Dec;18(12):1759-1766.
- Phospho-regulation of ATOH1 Is Required for Plasticity of Secretory Progenitors and Tissue Regeneration. Tomic G, Morrissey E, Kozar S, Ben-Moshe S, Hoyle A, Azzarelli R, Kemp R, Chilamakuri CSR, Itzkovitz S, *Philpott A, *Winton DJ. (2018). Cell Stem Cell. Sep 6;23(3):436-443 *Joint corresponding authors.
- The developmental ontogeny of neurological cancers: a cellular and molecular framework. Azzarelli R, Simons B, Philpott A. (2018). Development, 145,145(10).
- Defining lineage potential and fate behavior of precursors during pancreas development. Sznurkowska MK, Hannezo E, Rulands S, Nestorowa S, Hindley CJ, Azzarelli R, Nichols J, Göttgens B, Huch M, Philpott A*, Simons B*. (2018) Developmental Cell. Aug 6;46(3):360-375. * Joint corresponding authors.
- Neurogenin3 phosphorylation controls pancreatic endocrine differentiation and maintenance of β-cell function. Azzarelli R, Hurley C, Sznurkowska M, Gamper I, Ali F, McCracken L, Hindley C, McDuff F, Hardwick L, Jones2 K, Kemp R, Simons B, Huch M, Evan G, Winton D, Philpott A. (2017). Developmental Cell 41: 274-286.
- Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma. Wylie LA, Hardwick LJA, Papkovskaia TD, Thiele CJ, Philpott A (2015). Disease Model Mech. 8:429-41.
- The phosphorylation status of Ascl1 is a key determinant of neuronal differentiation and maturation in vivo and in vitro. Ali FR, Cheng K, Kirwan P, Metcalfe S, Livesey FJ, Barker RA, Philpott A (2014). Development. 141, 2216-24.