Title
Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines
Author
Schlicker, A.
Beran, G.
Chresta, C.M.
McWalter, G.
Pritchard, A.
Weston, S.
Runswick, S.
Davenport, S.
Heathcote, K.
Alferez Castro, D.
Orphanides, G.
French, T.
Wessels, L.F.A.
Faculty
Electrical Engineering, Mathematics and Computer Science
Department
Intelligent Systems
Date
2012-12-31
Abstract
Background Colorectal cancer (CRC) is a heterogeneous and biologically poorly understood disease. To tailor CRC treatment, it is essential to first model this heterogeneity by defining subtypes of patients with homogeneous biological and clinical characteristics and second match these subtypes to cell lines for which extensive pharmacological data is available, thus linking targeted therapies to patients most likely to respond to treatment. Methods We applied a new unsupervised, iterative approach to stratify CRC tumor samples into subtypes based on genome-wide mRNA expression data. By applying this stratification to several CRC cell line panels and integrating pharmacological response data, we generated hypotheses regarding the targeted treatment of different subtypes. Results In agreement with earlier studies, the two dominant CRC subtypes are highly correlated with a gene expression signature of epithelial-mesenchymal-transition (EMT). Notably, further dividing these two subtypes using iNMF (iterative Non-negative Matrix Factorization) revealed five subtypes that exhibit activation of specific signaling pathways, and show significant differences in clinical and molecular characteristics. Importantly, we were able to validate the stratification on independent, published datasets comprising over 1600 samples. Application of this stratification to four CRC cell line panels comprising 74 different cell lines, showed that the tumor subtypes are well represented in available CRC cell line panels. Pharmacological response data for targeted inhibitors of SRC, WNT, GSK3b, aurora kinase, PI3 kinase, and mTOR, showed significant differences in sensitivity across cell lines assigned to different subtypes. Importantly, some of these differences in sensitivity were in concordance with high expression of the targets or activation of the corresponding pathways in primary tumor samples of the same subtype. Conclusions The stratification presented here is robust, captures important features of CRC, and offers valuable insight into functional differences between CRC subtypes. By matching the identified subtypes to cell line panels that have been pharmacologically characterized, it opens up new possibilities for the development and application of targeted therapies for defined CRC patient sub-populations.
Subject
colorectal cancer
tumor subtyping
cell lines
targeted therapy
To reference this document use:
http://resolver.tudelft.nl/uuid:538a9813-5214-4fb8-91a5-ec072868eb48
DOI
https://doi.org/10.1186/1755-8794-5-66
Publisher
BioMed Central
ISSN
1755-8794
Source
http://www.biomedcentral.com/1755-8794/5/66
Source
BMC Medical Genomics, 5, 2012
Part of collection
Institutional Repository
Document type
journal article
Rights
© 2012 The Author(s)
Licensee BioMed Central Ltd. - This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited