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A light micrograph of migrating pancreatic tumor cells stained for actin filaments and a small GTPase activating protein Vav1
Cancers of the liver and pancreas spread to distant organs in the body by migration through blood vessel walls. This process causes death in most people with liver and pancreatic cancer. The Cytoskeletal Membrane Dynamics Lab is investigating how specific proteins interact to regulate cytoskeletal and membrane dynamics during tumor cell migration that lead to metastasis.
These publications describe the Cytoskeletal Membrane Dynamics Lab's work in tumor cell migration and invasion:
Distinct forms of matrix degradation by tumor cells (DanG) and cancer-associated fibroblasts (PSC) (figure 1).
Cao H, Eppinga RD, Razidlo GL, Krueger EW, Chen J, Qiang L, McNiven MA. Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process. Oncogene. 2016;35:1099.
The non-invadopodial degradation by CAFs in the tumor microenvironment could possess a substantial capacity to amplify the invasive properties of the tumor cells. Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia.
Azathioprine inhibits invasive matrix degradation through Vav1 (figure 2).
Razidlo GL, Magnine C, Sletten AC, Hurley RM, Almada LL, Fernandez-Zapico ME, Ji B, McNiven MA. Targeting pancreatic cancer metastasis by inhibition of Vav1, a driver of tumor cell invasion. Cancer Research. 2015; 75:2907.
Metastasis is the primary cause of cancer death, but therapies that specifically inhibit metastatic invasion are not in use clinically. Here we describe a novel repurposing of the anti-inflammatory drug azathioprine as a metastasis suppressor in pancreatic cancer. Azathioprine inhibits Vav1-dependent invasion and migration by tumor cells, and reduces metastasis in mouse models of pancreatic cancer.
Vav1-dependent invadopodia in pancreatic cancer cells degrade the extracellular matrix (supplemental figure 2).
Razidlo GL, Schroeder B, Chen J, Billadeau DD, McNiven MA. Vav1 as a central regulator of invadopodia assembly. Current Biology. 2014;24:86.
Invadopodia are actin-based structures used by tumor cells to degrade and remodel the extracellular matrix. The exchange factor Vav1, which is aberrantly turned on in many pancreatic cancers, increases the invasiveness of pancreatic cancer cells by upregulating the formation of invadopodia. Strikingly, active Vav1 was dominant to other established signaling pathways in invadopodial biology, and can potently control the ability of tumor cells to degrade the matrix through activation of the GTPase Cdc42.
A Dyn2-based stabilization of Vav1 promotes activation of Rac1, lamellipod protrusion and invasive cellular migration and provides insight into how this specific Vav is ectopically expressed in pancreatic tumors (supplemental figure 2)
Razidlo GL, Wang Y, Chen J, Krueger EW, Billadeau DD, McNiven MA. Dynamin 2 potentiates invasive migration of pancreatic tumor cells through stabilization of the Rac1 GEF Vav1. Developmental Cell. 2013;24:573.
The large GTPase dynamin 2 can interact with the actin cytoskeleton directly and indirectly, and regulates actin dynamics to control the formation of pro-migratory lamellipodia. Dyn2 interacts with Vav1, an activator of the small GTPase Rac1, to regulate Rac activation, actin dynamics and cell migration. The interaction with Dyn2 stabilizes the Vav1 protein, as disruption of this binding leads to lysosomal degradation of Vav1. These findings link Dyn2 to regulation of the actin cytoskeleton, and describe a novel mechanism for modulating Vav1/Rac signaling.
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