The migration of cancer cells away from the primary tumor mass and their subsequent metastasis to distant organs is regarded as a fatal step in cancer progression and is associated with the majority of cancer mortalities. Furthermore, individual cancer cells appear to be able to evade current pharmacologic intervention of invasion and metastasis by switching between mesenchymal and amoeboid modes of motility. The cellular mechanisms controlling this phenotypic plasticity are poorly understood. We have recently identified distinct functions for the closely related adhesion-associated scaffold proteins paxillin and Hic-5 in the regulation of tumor cell plasticity, invasion and metastasis. In this proposal, using established cancer cell lines, as well as cells isolated from primary tumors, we will apply state-of-the art real-time imaging techniques to track tumor cell morphology and migration as well as adhesion and cytoskeletal dynamics in 3D-extracellular matrix in vitro model systems. Xenograft studies in mice will be used to evaluate the relative impact of paxillin and Hic-5 signaling on tumor progression and metastasis in vivo. We will use RNA interference and mutant protein expression to dissect the respective roles for paxillin and Hic-5 in controlling the mode of tumor cell invasion and identify the pertinent functional domains and signaling pathways. We will use similar approaches to study a role for paxillin in the regulation of matrix metalloproteinase-2 (MMP-2) trafficking and secretion to control mesenchymal tumor invasion strategies. Hic-5 is upregulated during TGF-?-induced epithelial mesenchymal transition. The role of Hic-5 in TGF-?-dependent cell invasion, through the formation and function of matrix-degrading invadopodia, will also be examined. The proposed studies will provide insight into the underlying cellular mechanisms controlling tumor cell migration and invasion and the coordination of their phenotypic plasticity and may in the future suggest novel strategies for detection or treatment of metastatic cancers.

Public Health Relevance

Tumor cell invasion and metastasis to secondary sites is the single worst prognostic factor dictating patient long-term survival. The ability of tumor cells to switch between distinct modes of migration, called plasticity, is an important factor in the limited efficacy of invasion-directed therapeutics. The signaling mechanisms mediating cancer cell plasticity remain poorly understood. The proposed research will describe new roles for two closely related adhesion associated adaptor proteins, paxillin and Hic-5, in the regulation of cancer cell migration, plasticity and matrix-metalloproteinase function and thereby increase our understanding of cancer progression, malignancy and metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Snyderwine, Elizabeth G
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Upstate Medical University
Anatomy/Cell Biology
Schools of Medicine
United States
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Gulvady, Anushree C; Dubois, Fatemeh; Deakin, Nicholas O et al. (2018) Hic-5 expression is a major indicator of cancer cell morphology, migration, and plasticity in three-dimensional matrices. Mol Biol Cell 29:1704-1717
Goreczny, Gregory J; Forsythe, Ian J; Turner, Christopher E (2018) Hic-5 regulates fibrillar adhesion formation to control tumor extracellular matrix remodeling through interaction with tensin1. Oncogene 37:1699-1713
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Dubois, Fatemeh; Alpha, Kyle; Turner, Christopher E (2017) Paxillin regulates cell polarization and anterograde vesicle trafficking during cell migration. Mol Biol Cell 28:3815-3831
Rashid, Mamunur; Belmont, Judson; Carpenter, David et al. (2017) Neural-specific deletion of the focal adhesion adaptor protein paxillin slows migration speed and delays cortical layer formation. Development 144:4002-4014
Quattrochi, Brian; Gulvady, Anushree; Driscoll, David R et al. (2017) MicroRNAs of the mir-17~92 cluster regulate multiple aspects of pancreatic tumor development and progression. Oncotarget 8:35902-35918
Goreczny, G J; Ouderkirk-Pecone, J L; Olson, E C et al. (2017) Hic-5 remodeling of the stromal matrix promotes breast tumor progression. Oncogene 36:2693-2703
Ouderkirk-Pecone, Jessica L; Goreczny, Gregory J; Chase, Sharon E et al. (2016) Myosin 1e promotes breast cancer malignancy by enhancing tumor cell proliferation and stimulating tumor cell de-differentiation. Oncotarget 7:46419-46432
Goreczny, Gregory J; Wormer, Duncan B; Turner, Christopher E (2015) A Simplified System for Evaluating Cell Mechanosensing and Durotaxis In Vitro. J Vis Exp :e52949
Deakin, Nicholas O; Turner, Christopher E (2014) Paxillin inhibits HDAC6 to regulate microtubule acetylation, Golgi structure, and polarized migration. J Cell Biol 206:395-413

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