Quantitative phosphoproteomic analysis reveals reciprocal activation of receptor tyrosine kinases between cancer epithelial cells and stromal fibroblasts.

Abstract

BACKGROUND:

Cancer-associated fibroblasts (CAFs) are one of the most important components of tumor stroma and play a key role in modulating tumor growth. However, a mechanistic understanding of how CAFs communicate with tumor cells to promote their proliferation and invasion is far from complete. A major reason for this is that most current techniques and model systems do not capture the complexity of signal transduction that occurs between CAFs and tumor cells.

METHODS:

In this study, we employed a stable isotope labeling with amino acids in cell culture (SILAC) strategy to label invasive breast cancer cells, MDA-MB-231, and breast cancer patient-derived CAF this has already been defined above cells. We used an antibody-based phosphotyrosine peptide enrichment method coupled to LC-MS/MS to catalog and quantify tyrosine phosphorylation-mediated signal transduction events induced by the bidirectional communication between patient-derived CAFs and tumor cells.

RESULTS:

We discovered that distinct signaling events were activated in CAFs and in tumor epithelial cells during the crosstalk between these two cell types. We identified reciprocal activation of a number of receptor tyrosine kinases including EGFR, FGFR1 and EPHA2 induced by this bidirectional communication.

CONCLUSIONS:

Our study not only provides insights into the mechanisms of the interaction between CAFs and tumor cells, but the model system described here could be used as a prototype for analysis of intercellular communication in many different tumor microenvironments.

• Authors: Xinyan Wu, Muhammad Saddiq Zahari, Santosh Renuse, Nandini A Sahasrabuddhe, Raghothama Chaerkady, Min-Sik Kim, Mary Jo Fackler, Martha Stampfer, Edward Gabrielson, Saraswati Sukumar, Akhilesh Pandey
• Journal: Clinical proteomics (Clin Proteomics) Vol. 15 Pg. 21 ( 2018) ISSN: 1542-6416 [Print] England
• PMID: 29946230 (Publication Type: Journal Article)