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Phil Jones

ph jones

Dr Phil Jones (Joint faculty member with the Sanger Institute)

Biography | Pubmed

 

The Jones Group uses transgenic models, advanced imaging, novel sequencing approaches and quantitative methods to define the critical evolutionary steps that lead to non-melanoma skin and oesophageal cancer, and test the ability of targeted therapies to reduce the risk of cancer development

Cancer arises after extensive exposure to agents that mutate DNA. For example, one such agent is the ultraviolet light in sunshine on skin cells, while tobacco-derived chemicals cause mutations in the oesophagus of smokers. However, these tissues can continue to look and function normally despite accumulating a large proportion of cells that are carrying mutations that promote cancer formation. Understanding the processes that restrain mutant cells from developing into tumours, and how they are breached when cancers do form will guide the development of strategies to reduce the chance of cancer development in individuals who have acquired a high level of mutations.

 

Our current projects include:

-Mapping mutations in normal human tissues

We have developed a new method to use ultradeep sequencing to detect mutant clones in normal tissues. Our research has revealed that normal sun-exposed skin is a patchwork of thousands of competing clones, with a quarter or more of skin cells carrying cancer-causing mutations. We are extending this analysis to oesophageal epithelium in smokers.

-Modelling clonal evolution in pre-cancer

We have used large-scale in vivo lineage tracing to quantify the behaviour of stem cells in transgenic mouse epidermis and oesophagus, and shown how oncogenic mutation alters cell dynamics. We are now examining the effects of mutation and carcinogen exposure on clonal evolution in an approach that combines deep sequencing and lineage tracing.

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Lineage tracing reveals how progenitors maintain oesophageal epithelium (basal layer is shown, blue progenitor cell, red differentiating cell)

 

-The molecular basis of stem cell fate decisions

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3D imaging of a 3 cell clone derived from individual epidermal progenitor cell genetically labelled 3 weeks previously, blue DNA stain, yellow EYFP.
 
We have found that the balanced fate of human epidermal stem cells is replicated in vitro. This allows us to apply live cell imaging and single cell analysis methods to identify regulators of normal and mutant cell behaviour, to identify potential therapeutic targets for manipulating stem cell behaviour.
 

 

- Biophysical models of pre-cancer

We draw on gene expression, mutation, cell dynamics, cell shape and 3D imaging data to develop new integrative models to reveal the key processes which restrain the expansion of clones carrying cancer-driver mutations.

 

Contact:

Click here to contact Dr Phil Jones by email.

 

Selected Publications:

Human keratinocytes have two interconvertible modes of proliferation. Roshan A, Murai K, Fowler J, Simons BD, Nikolaidou-Neokosmidou V, Jones PH. Nat Cell Biol (2015) Dec 7. doi: 10.1038/ncb3282. [Epub ahead of print].

Clock-like mutational processes in human somatic cells. Alexandrov LB, Jones PH, Wedge DC, Sale JE, Campbell PJ, Nik-Zainal S, Stratton MR. Nat Genet (2015) Dec;47(12):1402-7. doi: 10.1038/ng.3441. Epub 2015 Nov 9.

Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.  Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge DC, Fullam A, Alexandrov LB, Tubio JM, Stebbings L, Menzies A, Widaa Stratton MR, Jones PH*, Campbell PJ*. * Co-corresponding authors. Science (2015) 348:880-886.

Switching roles: the functional plasticity of adult tissue stem cells. Wabik A, Jones PH.  EMBO Journal (2015) 34:1164-1179.

Cell competition: winning out by losing Notch. Alcolea MP, Jones PH. Cell Cycle (2015) 14:9-17.

A Single Progenitor Population Switches Behavior to Maintain and Repair Esophageal Epithelium.  Doupe DP, Alcolea MP, Roshan A, Zhang G, Klein AM, Simons BD, Jones PH. Science, 2012 Jul 19, DOI: 10.1126/science.1218835 ***Full text PDF link***

Stem cell fate in proliferating tissues: equal odds in a game of chance. Jones PH. Dev Cell. 2010 Oct 19;19(4):489-90.

The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. Doupé DP, Klein AM, Simons BD, Jones PH. Dev Cell. 2010 Feb 16;18(2):317-23.

Stochastic fate of p53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia. Klein AM, Brash DE, Jones PH, Simons BD. Proc Natl Acad Sci USA. 2010 Jan 5;107(1):270-5. 

A single type of progenitor cell maintains normal epidermis. Clayton E, Doupé DP, Klein AM, Winton DJ, Simons BD, Jones PH. Nature. 2007 Mar 8;446(7132):185-9.

Differentiation imbalance in single Oesophageal progenitor cells causes clonal immortalization and field change. Maria P. Alcolea,1 Philip Greulich,2 Agnieszka Wabik,1 Julia Frede,1 Benjamin D. Simons,2,3,4 and Philip H. Jones.