Metastatic tumor cells are distinguished by their ability to invade the basement membrane of epithelial barriers and migrate to distant sites. Recent studies from this program demonstrate that host macrophages are critical for the motility and invasion of tumor cells, due to a paracrine loop involving the mutual signaling and chemotaxis between macrophages and tumor cells. PI3K is a critical regulator of cell motility, and distinct PI3K isoforms are required for regulation of actin-based motility in tumor cells versus macrophages. We propose to use isoform-specific inhibitors of Class IA PISKs as well as genetic approaches to examine the requirement for PI3K-mediated motility of both tumor cells and macrophages during invasion and metastasis. By selectively inhibiting the motility of tumor cells versus macrophages, we will test whether the enhanced tumor cell chemotaxis observed in the presence of macrophages requires pre-exposure to macrophage-derived cytokines, versus the presence of continuous macrophage signaling during coordinated migration of the two cell types. We will also examine the metastatic behavior of tumor cells expressing activating mutations of PI3K that are commonly found in human breast cancer. The unique assays developed by this program will allow a detailed analysis of how oncogenic p110ct mutants affect the tumor cell-macrophage paracrine loop. Finally, studies from this program have shown that genes coding for proteins that modulate the myosin-ll regulatory pathway are up-regulated in invasive tumor cells and that the amoeboid motility of tumor cells in a 3D matrix is mediated by the myosin-ll regulatory pathway. Given these findings, and our observations that PI3K regulates myosin-ll-based contractility in tumor cells, we will examine the PI3K isoform-dependence of myosin-ll phosphorylation, the identification of intermediary signaling pathways in tumor cells and macrophages, and the subsequent effects on motility and invasion. These studies will complete our analysis of the motility cycle as it relates to the invasion signature, and lead to new insights into the role of macrophage-tumor cell paracrine signaling during metastasis.
| Gizzi, Anthony S; Grove, Tyler L; Arnold, Jamie J et al. (2018) A naturally occurring antiviral ribonucleotide encoded by the human genome. Nature 558:610-614 |
| Karagiannis, George S; Condeelis, John S; Oktay, Maja H (2018) Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clin Exp Metastasis 35:269-284 |
| Yang, Ming; McKay, Daniel; Pollard, Jeffrey W et al. (2018) Diverse Functions of Macrophages in Different Tumor Microenvironments. Cancer Res 78:5492-5503 |
| Cabrera, Ramon M; Mao, Serena P H; Surve, Chinmay R et al. (2018) A novel neuregulin - jagged1 paracrine loop in breast cancer transendothelial migration. Breast Cancer Res 20:24 |
| Meirson, Tomer; Genna, Alessandro; Lukic, Nikola et al. (2018) Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors. Oncotarget 9:22158-22183 |
| Dulyaninova, Natalya G; Ruiz, Penelope D; Gamble, Matthew J et al. (2018) S100A4 regulates macrophage invasion by distinct myosin-dependent and myosin-independent mechanisms. Mol Biol Cell 29:632-642 |
| Liu, Xia; Taftaf, Rokana; Kawaguchi, Madoka et al. (2018) Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models. Cancer Discov : |
| Nobre, Ana Rita; Entenberg, David; Wang, Yarong et al. (2018) The Different Routes to Metastasis via Hypoxia-Regulated Programs. Trends Cell Biol 28:941-956 |
| Donnelly, Sara K; Miskolci, Veronika; Garrastegui, Alice M et al. (2018) Characterization of Genetically Encoded FRET Biosensors for Rho-Family GTPases. Methods Mol Biol 1821:87-106 |
| Entenberg, David; Voiculescu, Sonia; Guo, Peng et al. (2018) A permanent window for the murine lung enables high-resolution imaging of cancer metastasis. Nat Methods 15:73-80 |
Showing the most recent 10 out of 234 publications
