Functional validation of cancer dependencies in colorectal cancer patients
Francesca Ciccarelli (Crick/King’s), Mark George (Guy’s and St Thomas’ NHS Trust) and Baljit
Gill-Barman (Guy’s and St Thomas’ NHS Trust)
Apply to: King's
Summary:
Tumour genetic heterogeneity is an obstacle to the effectiveness of cancer therapy because
virtually each cancer is mutated in its own way. This requires personalised interventions that
(1) identify cancer altered processes and (2) target them in the affected patients. Key for the
success of the personalised medicine agenda is a multidisciplinary approach that combines the
analysis of cancer genomic alterations with the identification of the relevant genes or
pathways that can be targeted in therapy.
The Ciccarelli group has developed a method to identify cancer dependencies that result from
the acquisition of somatic loss-of-function mutations [1]. Our method starts from the analysis
of cancer mutations, copy number alterations and expression data and identifies inactive or
defective genes specific of each cancer sample [2]. We then identify the putative functional
compensators of these inactive genes based on sequence identity, biochemical pathways, and
interaction network data. Predicted dependencies are finally validated in cancer cell lines using
RNAi, genome editing, and/or small molecules [1]. Although largely used in research, cancer
cell lines are far from recapitulating tumour complexity because each tumour possibly yields a
distinct pattern of dependencies and vulnerabilities depending on its genetic makeup.
This project aims to establish ex vivo cell cultures derived from colorectal cancer patients that
can be used to confirm cancer synthetic dependencies and to identify genes to be further
investigated as targets for precision treatment.
Archived tissues of colorectal cancers from Guy's and St Thomas' Hospital will be accessed
through the centralised cancer biobank, which is part of the Division of
Cancer Studies at King’s College London. Second supervisors of the project are the clinical lead
(Mark George) and the consultant histopathologist (Baljit Gill-Barman) for colorectal cancer at
Guy's and St Thomas'. They will support the fellow with the clinical expertise for obtaining
primary colorectal tissues. Patient genomic data will derive from the 100,000 Genomes Project
and will be analysed in each patient individually with the method developed in the Ciccarelli
lab [1].
Predicted dependencies will be then verified through perturbation of relevant genes in cells
derived from these patients.
Role of the fellow in the first year of the project: The fellow will be responsible of (1)
establishing the protocol for tissue cryopreservation; (2) deriving ex-vivo cell cultures from
cancer and normal colorectal tissues; and (3) set up a proof-of principle to test synthetic
dependency in patient-derived cells through gene and/or protein perturbation.
The fellow will work in a multidisciplinary team of computational and experimental scientists,
in tight collaboration with pathologists and clinicians at Guy’s and St Thomas’ and basic
scientists at the Francis Crick Institute. Previous experience in tissue culture and molecular
biology would be advantageous.
References:
1. D'Antonio, M., et al. (2013) Recessive cancer genes engage in negative genetic
interactions with their functional paralogs. Cell Rep. 5, 1519-1526
2. D'Antonio, M. and Ciccarelli, F.D. (2013) Integrated analysis of recurrent properties of
cancer genes to identify novel drivers Genome Biol 14, R52
3. Cereda M, Mourikis TP and Ciccarelli FD Genetic redundancy, functional compensation
and cancer vulnerability (under revision)
1. Rambaldi D, Giorgi FM, Capuani F, Ciliberto A, Ciccarelli FD Low duplicability and
network fragility of cancer genes 2008 Trends Genet 24:427-30