Platelet PI3Kß regulates breast cancer metastasis.

Platelets promote tumor metastasis by several mechanisms. Platelet-tumor cell interactions induce the release of platelet cytokines, chemokines, and other factors that promote tumor cell epithelial-mesenchymal transition and invasion, granulocyte recruitment to circulating tumor cells (CTCs), and adhesion of CTCs to the endothelium, assisting in their extravasation at metastatic sites. Previous studies have shown that platelet activation in the context of thrombus formation requires the Class IA PI 3-kinase PI3Kß. We now define a role for platelet PI3Kß in breast cancer metastasis. Platelet PI3Kß is essential for platelet-stimulated tumor cell invasion through Matrigel. Consistent with this finding, in vitro platelet-tumor cell binding and tumor cell-stimulated platelet activation are reduced in platelets isolated from PI3Kß mutant mice. RNAseq and proteomic analysis of human breast epithelial cells co-cultured with platelets revealed that platelet PI3Kß regulates the expression of EMT and metastasis-associated genes in these cells. The EMT and metastasis-associated proteins PAI-1 and IL-8 were specifically downregulated in co-cultures with PI3Kß mutant platelets. PI3Kß mutant platelets are impaired in their ability to stimulate YAP and Smad2 signaling in tumor cells, two pathways regulating PAI-1 expression. Finally, we show that mice expressing mutant PI3Kß show reduced spontaneous metastasis, and platelets isolated from these mice are less able to stimulate experimental metastasis in WT mice. Taken together, these data support a role for platelet PI3Kß in promoting breast cancer metastasis and highlight platelet PI3Kß as a potential therapeutic target. Significance: We demonstrate that platelet PI3Kß regulates metastasis, broadening the potential use of PI3Kß-selective inhibitors as novel agents to treat metastasis.

Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract.

S100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4 (-/-) knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4 (-/-) mice revealed a robust increase in the expression of multiple photoreceptor- and Müller glia-specific genes, as well as the olfactory sensory neuron-specific gene, S100A5. This aberrant transcriptional profile is characterized by corresponding increases in the levels of proteins encoded by the aberrantly upregulated genes. Ingenuity pathway network and curated pathway analyses of differentially expressed genes in S100A4 (-/-) lenses identified Crx and Nrl transcription factors as the most significant upstream regulators, and revealed that many of the upregulated genes possess promoters containing a high-density of CpG islands bearing trimethylation marks at histone H3K27 and/or H3K4, respectively. In support of this finding, we further documented that S100A4 (-/-) knockout lenses have altered levels of trimethylated H3K27 and H3K4. Taken together, our findings suggest that S100A4 suppresses the expression of retinal genes during lens differentiation plausibly via a mechanism involving changes in histone methylation.