Complexity of metastasis-associated SDF-1 ligand signaling in breast cancer stem cells

Tumor metastasis is the main cause of cancer’s lethality. Much research has been dedicated to understand the signaling networks underlying tumor metastasis, with the ultimate goal of identifying signaling nodes or pathways whose inhibition will prevent metastasis. Although previous studies have identified the interaction of the chemokine ligand stromal cell-derived factor-1 (SDF-1) and the G protein-coupled receptor chemokine (C-X-C motif) receptor 4 (CXCR4) as essential for breast cancer metastasis (1), the signaling pathways downstream of SDF-1/CXCR4 have not been well established. In PNAS, Yi et al. use quantitative, liquid chromatography tandem mass spectrometry (LC-MS/MS) to greatly expand our knowledge of the protein phosphorylation networks downstream of SDF-1/CXCR4 in breast cancer stem cells (2). Yi et al. (2) begin by enriching for a subpopulation of CXCR4-expressing cells with an elevated ability to initiate tumors in vivo, that is, breast cancer stem cells, which are required for tumor recurrence and metastasis (3). Following induction with the chemokine SDF-1, they measured protein phosphorylation by LC-MS/MS. To verify that changes in phosphorylation were caused by the specific interactions of SDF-1/CXCR4, the authors compared cells with and without transient knockdown of CXCR4. Among the proteins with significantly changing phosphorylation sites (13% of the total observed), over 20% were related to cell adhesion, migration, and cytoskeleton, highlighting and further confirming the role of SDF-1/CXCR4 signaling in biophysical processes related to metastasis. The significance of Yi et al.’s (2) work in breast cancer stem cells derives from the hope that identification of the signaling pathways downstream of SDF-1/CXCR4 will suggest pathways or nodes that can be therapeutically targeted. To date, the most successful class of druggable targets are kinases, and Yi et al. identify 50 kinases with significantly changing phosphorylation sites, including 44 kinases not …