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.
Highlights
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; §Activiomics Ltd, Charterhouse Square, London, UK
Mouse tumor xenografts are often used as biological models in preclinical studies as this in vivo growth condition is thought have higher biological relevance than in vitro models in which cells are grown on plastic
The extent to which the biochemistry and signaling differ between cells growing in culture relative to the same cells growing in a tumor xenograft have not been investigated systematically
Summary
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; §Activiomics Ltd, Charterhouse Square, London, UK. Transformed epithelial cells recruit different types of somatic cells to the tumor microenvironment where they influence varying aspects of cancer biology. The tumor microenvironment determines the ability of cancer cells to survive in specific organs and their ability to proliferate and metastasize [7,8,9]. It is important to investigate specific effects of compounds in clinical development on stromal cells in addition to those exerted toward malignant cancer cells [12]. We investigated the effects that the pharmacological inhibitors of PI3K, namely GDC-0941 or CAL-101, would have on the phosphoproteomes of stromal cells relative to cancer cells in solid tumors.
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