Abstract C50: CXCL12-triggered amoeboid cell motility is mediated through a RhoA-directed signaling hub

Abstract

Abstract Morphological plasticity is a common feature of cancer cells in response to environmental cues. Mesenchymal cancer cells, dependent on proteolysis for motility, can switch to a protease-independent amoeboid morphology and evade anti-invasion therapeutics that target matrix metalloproteases. The highly conserved formin family of proteins play a role in cell motility and play a critical role in mediating cancer cell invasion and metastasis. The cellular actin dynamics driving cell motility are highly regulated by mammalian diaphanous-related formin 2 (mDia2). mDia2 assembles non-branched actin filaments and maintains the cortical F-actin cytoskeleton. Our lab previously demonstrated a direct interaction between mDia2 and its inhibitor diaphanous-interacting protein (DIP), which subsequently acts as a trigger for mesenchymal/amoeboid interconvertability in breast cancer cells by disrupting F-actin polymerization and bundling. This interaction plays an essential role in the disruption of the cell cortex leading to a membrane blebbing phenotype, a hallmark of amoeboid cell motility (ACM). We recently reported that the chemokine CXCL12 stimulates DIP:mDia2 complex assembly. It is well established that CXCL12 and its receptor CXCR4 are involved in cancer metastasis, including breast cancer metastasis to lung and lymph node. Sites of distant metastasis are also often shown to express high levels of CXCL12. We, therefore, hypothesize that CXCL12 secreted from the tumor microenvironment may be a physiological trigger of amoeboid cell motility and invasion via the mDia2:DIP axis. Our current objective is to interrogate the requirement for CXCL12-driven, mDia2-dependent non-apoptotic membrane blebbing. Here we show in MDA-MB-231 human breast cancer cells that CXCL12 activates the GTPase RhoA, a known binding partner and activator of mDia2. Upon activation of mDia2, its inhibitor DIP can bind, disrupting F-actin polymerization within the cell cortex, leading to blebbing. Collectively, these data indicate a potential unexplored link between CXCL12/RhoA/mDia signaling and ACM in breast cancer cells. Understanding the molecular basis of ACM will lend novel insight into mechanisms controlling breast cancer progression and may translate into development of therapeutics controlling invasion/metastatic dissemination. Citation Format: Meghan M. Wyse, Andrea L. Nestor-Kalinoski, Kathryn M. Eisenmann. CXCL12-triggered amoeboid cell motility is mediated through a RhoA-directed signaling hub. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C50.