title: Subcellular protein expression models for microsatellite instability in colorectal adenocarcinoma tissue images.
abstract: BACKGROUND
  New bioimaging techniques capable of visualising the co-location of numerous proteins within individual cells have been proposed to study tumour heterogeneity of neighbouring cells within the same tissue specimen. These techniques have highlighted the need to better understand the interplay between proteins in terms of their colocalisation.
  
  
  RESULTS
  We recently proposed a cellular-level model of the healthy and cancerous colonic crypt microenvironments. Here, we extend the model to include detailed models of protein expression to generate synthetic multiplex fluorescence data. As a first step, we present models for various cell organelles learned from real immunofluorescence data from the Human Protein Atlas. Comparison between the distribution of various features obtained from the real and synthetic organelles has shown very good agreement. This has included both features that have been used as part of the model input and ones that have not been explicitly considered. We then develop models for six proteins which are important colorectal cancer biomarkers and are associated with microsatellite instability, namely MLH1, PMS2, MSH2, MSH6, P53 and PTEN. The protein models include their complex expression patterns and which cell phenotypes express them. The models have been validated by comparing distributions of real and synthesised parameters and by application of frameworks for analysing multiplex immunofluorescence image data.
  
  
  CONCLUSIONS
  The six proteins have been chosen as a case study to illustrate how the model can be used to generate synthetic multiplex immunofluorescence data. Further proteins could be included within the model in a similar manner to enable the study of a larger set of proteins of interest and their interactions. To the best of our knowledge, this is the first model for expression of multiple proteins in anatomically intact tissue, rather than within cells in culture.
authors: Department of Systems Biology, University of Warwick, Coventry, CV4 7AL, UK. violet.kovacheva@icr.ac.uk.|Department of Computer Science, University of Warwick, Coventry, CV4 7AL, UK. violet.kovacheva@icr.ac.uk.|Centre for Molecular Pathology, Institute of Cancer Research, London, SM2 5NG, UK. violet.kovacheva@icr.ac.uk.|Centre for Evolution and Cancer, Institute of Cancer Research, London, SM2 5NG, UK. violet.kovacheva@icr.ac.uk.|Division of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG, UK. violet.kovacheva@icr.ac.uk.
authors: Violeta N
authors: http://orcid.org/0000-0001-5335-2403
authors: VN
authors: Kovacheva
authors: Department of Computer Science, University of Warwick, Coventry, CV4 7AL, UK.|Department of Computer Science and Engineering, Qatar University, Doha, Qatar.|Department of Pathology, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
authors: Nasir M
authors: NM
authors: Rajpoot
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D013347:Subcellular Fractions
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins
keywords: Colorectal tissue architecture; Multiplex fluorescence imaging; Protein expression modelling; Subcellular protein expression