title: Cross-species proteomics reveals specific modulation of signaling in cancer and stromal cells by phosphoinositide 3-kinase (PI3K) inhibitors.
abstract: The tumor microenvironment plays key roles in cancer biology, but its impact on the regulation of signaling pathway activity in cancer cells has not been systemically investigated. We designed an analytical strategy that allows differential analysis of signaling between cancer and stromal cells present in tumor xenografts. We used this approach to investigate how in vivo growth conditions and PI3K inhibitors regulate pathway activities in both cancer and stromal cell populations. We found that, despite inducing more modest changes in protein expression, in vivo growing conditions extensively rewired protein kinase networks in cancer cells. As a result, different sets of phosphorylation sites were modulated by PI3K inhibitors in cancer cells growing in tumors relative to when these cells were in culture. The p110δ PI3K-selective compound CAL-101 (Idelalisib) did not inhibit markers of PI3K activity in cancer or stromal cells; however, unexpectedly, it induced phosphorylation on SQ motifs in both subpopulations of tumor cells in vivo but not in vitro. Thus, the interaction between cancer cells and the stroma modulated the ability of PI3K inhibitors to induce the activation of apoptosis in solid tumors. Our study provides proof-of-principle of a proteomics workflow for measuring signaling specifically in cancer and stromal cells and for investigating how cancer biochemistry is modulated in vivo.
authors.affiliation: From the ‡Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Barts School of Medicine and Dentistry, UK;
authors.forename: Vinothini
authors.initials: V
authors.lastname: Rajeeve
authors.affiliation: §Activiomics Ltd, Charterhouse Square, London, UK.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Vendrell
authors.affiliation: From the ‡Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Barts School of Medicine and Dentistry, UK;
authors.forename: Edmund
authors.initials: E
authors.lastname: Wilkes
authors.affiliation: §Activiomics Ltd, Charterhouse Square, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Torbett
authors.affiliation: From the ‡Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Barts School of Medicine and Dentistry, UK; p.cutillas@qmul.ac.uk.
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Cutillas
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D040901:Proteomics; D011687:Purines / Q000008:administration & dosage; D052999:Quinazolinones / Q000008:administration & dosage; D015398:Signal Transduction / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; C552946:idelalisib