Cell Adhesion, Migration and Metastasis

This newly-formed subgroup represents a strong group of cancer cell biologists that work toward understanding how cells attach to substrates and each other, and how these attachments are altered as a cell initiates migration and invasion. Many of these important processes are also utilized during tumor angiogenesis.

Investigator: Panagiotis Anastasiadis, Ph.D.

The Anastasiadis Laboratory studies molecular and cellular mechanisms that are involved in metastasis. The primary focus is to elucidate the mechanisms whereby cadherins and other adhesion molecules, acting through catenin family members, regulate cellular motility and invasion. A central player in these events is p120 catenin, a cadherin binding partner which is thought to turn adhesion 'on' or 'off' depending on its phosphorylation status.

Dr. Anastasiadis' team has shown that association of p120 with epithelial E-cadherin promotes adhesion, whereas association with mesenchymal cadherins promotes increased motility and invasiveness, through the regulation of Rho family GTPases (The Journal of Cell Biology 174(7):1087-96, 2006). Current work focuses on the role of the p120-cadherin complex on the growth and metastatic potential of human tumors, including breast, pancreatic, renal, and brain tumors. The investigators hope to translate this better understanding of cell motility and invasiveness into targeted therapeutic treatments that block invasiveness and metastasis in cancer patients.

Investigator: Daniel Billadeau, Ph.D.

Dr. Billadeau's research team focuses on the identification of signaling pathways and proteins that modulate the cytoskeleton, and thus can influence cell migration, cell adhesion, proliferation, survival and activation. In particular, they have focused their attention on the role of Rho family GTPases, their downstream activators (WASp, WAVE2) and upstream guanine nucleotide exchange factors (GEFs) on the regulation of the actin cytoskeleton. They have found that the WAVE2 complex is a major regulator of inside-out signaling leading to the activation of integrins in T lymphocytes (Current Biology. 16:24-34, 2006; Molecular and Cellular Biology. 27(17):5986-6000, 2007). They have identified a novel Cdc42 GEF, ASEF2, which is regulated through an intramolecular interaction and is involved in the migration of pancreatic cancer cells (Molecular and Cellular Biology. 27(4):1380-1393, 2007). Additional studies are aimed at identifying small molecule inhibitors of the Rac family of GTP-binding proteins, as these proteins are involved in cancer cell proliferation, survival and motility.

More recently, they have been investigating the role of the formin family of actin nucleating proteins in the regulation of the T cell cytoskeleton. These studies have resulted in the identification of two formin family members in the regulation of centrosome polarity during T cell-APC interaction (Immunity. 26(2):177-190). Moreover, they have identified a third family member as a key regulator of cell-cell adhesion through its effects on the E-cadherin complex. Altogether, their molecular and cellular studies are providing new information on the role of signaling proteins and pathways in the regulation of cytoskeletal dynamics in lymphocytes and cancer cells.

Investigator: Karen Hedin, Ph.D.

Dr. Hedin's research is focused on developing a better molecular understanding of chemokine receptor signal transduction in immune and cancer cell types, and on improving general understanding of how the chemokine system regulates immunity and tumor behavior.

Chemokines are a family of peptide hormones that regulate cellular adhesion, migration proliferation, and survival. Accumulating evidence indicates critical regulatory roles for chemokines during the development of hyperplasias and metastatic tumors. In fact, chemokines promote tumor metastasis, growth, survival, and angiogenesis. Currently, however, the limited molecular understanding of the expression patterns and effects of chemokines on immune and cancer cells severely inhibits the development of drugs and approaches that exploit the powerful regulatory links between the chemokine system and cancer.

A major area of research in Dr. Hedin's laboratory relevant to the Cell Adhesion, Migration and Metastasis sub-theme in the Cell Biology Program is characterizing the signal transduction pathways used by the CXCR4 chemokine receptor to control T lymphocyte immune activation, survival, and migratory behavior. Her recent studies show that CXCR4 potently stimulates the Ras-ERK signaling pathway via complexing with other cell-surface receptors that contain immunoreceptor tyrosine activation motifs (ITAMs) (Immunity 25:213-24, 2006). These novel results open up new mechanisms that can be exploited to prevent CXCR4 from promoting cancer development and cancer cell proliferation.

Investigator: Nicole Murray, Ph.D.

In the Murray Laboratory, investigators hypothesize that PKCι plays an important role in cell migration and wound healing. PKCι expression may protect against colon cancer by mediating wound healing in the untransformed colonic epithelium and conversely, PKCι may promote colon cancer invasion and metastasis by mediating cell migration in transformed colon cells.

K-ras is frequently mutated in colon cancer, and is thought to play a critical role in colon cancer development. Dr. Murray's team is using mouse models to characterize oncogenic K-ras-mediated signaling in the untransformed colonic epithelium and to investigate the role of oncogenic K-ras in early colon carcinogenesis. They are also using mouse models to determine the requirement for PKCι in K-ras-mediated signaling and carcinogenic effects in the colonic epithelium.

The researchers have also initiated a new study to evaluate the role of PKCι in pancreatic cancer. They plan to investigate the effect of genetic and pharmacological inhibition of PKCι signaling on the transformed phenotype of pancreatic cancer cells. Thus far they have demonstrated that PKCII plays a requisite role in early colon cancer. The team hypothesizes that PKCII I is a target for colon cancer chemoprevention. Using a mouse carcinogen model of colon cancer, they are testing the hypothesis that the PKC-selective inhibitor, enzastaurin, will protect against colon carcinogenesis.

Investigator: Vijay Shah, M.D.

In the Shah Laboratory, the research team focuses on angiogenic signaling pathways in cancer. They have discovered a number of novel mechanisms by which the multifunctional cytokine, nitric oxide regulates endothelial cell (EC) migration and vascular tube formation, which are important steps in the process of tumor angiogenesis. This includes a new role for nitric oxide in the regulation of receptor internalization pathways relevant to angiogenic signaling such as the VEGF receptor, KDR.

Another new pathway of endothelial cell migration that has been a focus of their work relates to the nuclear receptor, FXR. For example, recent studies have elucidated a mechanism whereby FXR activation in EC promotes EC migration through a mechanism dependent on the multifunctional protease, MMP-9.

In addition to their work in EC, a second major line of cancer related work relates to pericytes, an important cell that resides within the tumor microenvironment. Their recent studies have identified novel cross-talk between nitric oxide and platelet derived growth factor (PDGF) signaling pathways that converge at the level of the small GTPase, Rac1. By using a variety of cell biological and complementary in vivo approaches the laboratory is situated to define the role of endothelial cell-pericyte crosstalk in the tumor vasculature.