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Phil Jones

PJ Photo 2016

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

Biography | Pubmed

 

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.

The Jones group studies how normal cell behaviour is altered by mutation in the earliest stages of cancer development, before the formation of a visible tumour.  We focus on squamous tissues, the skin epidermis and the lining of the oesophagus, using transgenic models, novel sequencing approaches, live imaging and single cell analysis to uncover the processes that shape the evolution of a single mutated cell into a tumour and define the points at which therapeutic intervention may prevent cancers forming.

 

Our current projects include:

 

Cell dynamics in normal tissues

Our group pioneered the use of large-scale genetic lineage tracing to quantify cell behaviour in vivo.  This approach reveals that a single population of progenitor cells maintains normal cell turnover of the epidermis and oesophageal epithelium.  Progenitor cell division either generates two progenitor daughters, two non-dividing differentiated cells or one progenitor and one differentiating cell.  The outcome of a given division is unpredictable, but in homeostasis the probabilities of producing two progenitor and two differentiating daughters are the same, so that on average, equal numbers of progenitors and differentiating cells are produced across whole population of progenitors.  Following injury, nearby progenitors switch from 'maintenance mode' to ‘wound mode’ in which they produce an excess of progenitor daughters until the tissue is repaired, when they revert to maintenance mode once more.  This behavioural plasticity allows all dividing cells to participate in tissue repair, making tissues resilient to injury.

 

Mutant cell dynamics

The ability of progenitors to produce excess progenitor daughters for wound repair represents a potential vulnerability.  Even a small increase in the odds of producing progenitors over differentiated cells will result in a tumour.  Mutations may bias progenitor cell fate towards proliferation.  We have shown that p53 and Notch inhibiting mutations, both of which are common in squamous cancers, imbalance cell fate in this way, generating large mutant clones.  We have developed a sequencing based approach to show similar in human tissues, finding around a third of cells in normal sun exposed facial skin carry cancer driver gene mutations.  Remarkably, normal tissues restrain the expansion of mutant clones, so very few of them progress to form tumours.  One focus of our current research is to understand the mechanism of this restraint.  We are also investigating mutant clones in other human tissues.

PJFig112016small
Mutant clones in normal human eyelid skin. The size of the circle indicates the size of the mutant clone, the colour the mutated gene. About a third of cells carry cancer driver mutations.

 

The molecular basis of progenitor cell fate decisions

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.
PJFig22016
Clusters of Oesophageal cells each deriving from a single cell induced to express either a red, green, blue or yellow fluorescent protein. The number and location of cells in each cluster can be used to infer the behaviour of the labelled cell and its daughters.
 

 

 

Contact:

Click  to contact Dr Phil Jones by email.

 

Selected Publications:

A single dividing cell population with imbalanced fate drives oesophageal tumour growth. Frede J, Greulich P, Nagy T, Simons BD, Jones PH. Nat Cell Biol. 2016 18: 967-78.

Human keratinocytes have two interconvertible modes of proliferation. Roshan A, Murai K, Fowler J, Simons BD, Nikolaidou-Neokosmidou V, Jones PH. Nat Cell Biol (2016) 18:145-56.  

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) 47:1402-7.

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.

Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. Alcolea MP, Greulich P, Wabik A, Frede J, Simons BD, Jones PH.  Nat Cell Biol. 2014 16:615-22.

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 

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.

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