The Molecular Basis of Cell Adhesion in Normal and Pathological Situations

Our laboratory is interested in understanding the mechanisms underlying metastasis, the spread of tumor cells throughout the body. We are particularly involved in studying the role of the extracellular matrix, a fibrillar meshwork of proteins that surrounds both normal and tumor cells and plays many important roles in tumor progression. We are also interested in changes in the metastatic cells themselves and in the contributions of normal cells such as platelets, leukocytes and blood vessels, both in metastasis and in other body functions.

Most cells adhere to their neighbors and to the extracellular matrix, a fibrillar meshwork surrounding or underlying most cells in the body. Cell adhesion plays important roles in the normal functions of cells, contributing to cellular organization and structure, proliferation and survival and gene expression. During embryological development, cell adhesion is important for the correct movements of cells modeling the embryo. In the adult, appropriate cell adhesion is necessary for numerous physiological processes and can be deranged in many diseases, including thrombosis, inflammation, and cancer.

The Hynes laboratory seeks to understand the proteins involved in cell adhesion and the ways in which these proteins control adhesion and migration of cells in both normal and pathological processes. Cell adhesion is mediated by several families of proteins, called adhesion receptors, specialized for adhesion between adjacent cells or between cells and the extracellular matrix. Adhesion receptors do much more for cells than merely sticking them down in the correct locations, although that in itself is important. They also form physical linkages between the extracellular environment and the internal structures of cells and thus control cell shape and motility.

Adhesion receptors also act as two-way transducers of signals both into and out of cells. Therefore, cells can control whether or not their adhesion receptors are functional; this is important to ensure appropriate cell adhesion. For example, when a blood vessel is damaged, blood platelets must adhere to staunch bleeding—this process is called hemostasis. They must not, however, adhere at the wrong time or place—that produces thrombosis. Similarly, leukocytes must adhere in appropriate places to fight infections; if they adhere at the wrong place or time, the result is inflammation. Alterations in cell adhesion also play important roles in the control of cell behavior during invasion and metastasis of malignant cancer cells. Thus, control of adhesion receptors is a matter of life and death. In their role as signal transducers into cells, adhesion receptors control cell proliferation, cell survival, and the expression of specific genes.

The goal of research in the Hynes laboratory is to understand these processes both at the molecular level and also in the context of intact, living organisms. So we study cell adhesion both by the methods of molecular cell biology and by using mouse models genetically modified in their cell adhesion functions. We have generated several mouse models of human diseases affecting cell adhesion, including animals with defects in the functions of their blood platelets that serve as valuable models for the study of hemostasis and thrombosis and others that affect the adhesion of white blood cells (leukocytes) that are useful models for studies of inflammation. Our work, together with that of many other laboratories, has contributed to the development of drugs that are used to combat thrombosis, inflammation and autoimmunity.

Our current work focuses on cancer, a disease in which cell adhesion plays many important roles. We are particularly interested in the mechanisms that control the metastatic spread of cancer cells throughout the body. Metastasis is responsible for 90% of all cancer deaths and is much less well understood than the development of primary tumors. If one thinks of primary tumor development as loss of growth control, one can think of metastasis as loss of positional control and that is a far more complex and insidious process. Changes in cell adhesion contribute to the initial migration and invasion of malignant tumor cells, the first steps leading to metastasis. Cell adhesion and cell-cell interactions also play vital roles in many later steps in metastasis, including the entry of cancer cells into the blood and their survival in the bloodstream and their arrest and establishment at distant sites in the body. What changes contribute to these events? By understanding them, could one do something to improve treatments for metastasis? Our laboratory is investigating changes both in the tumor cells themselves and in their surrounding microenvironment, which includes other normal cells and the extracellular matrix. We have shown, for example, that blood platelets, although beneficial in preventing bleeding, are able to enhance the metastasis of tumor cells by binding and signaling to them and enhancing their migration, invasion and metastatic spread. We are currently working to understand in more detail how this platelet-tumor cell interaction works and how it also involves other normal cells such as leukocytes. Such studies may lead to new ways to intervene in metastatic spread.

Another major focus is on understanding the multiple functions of the extracellular matrix during cancer progression. The matrix changes extensively during tumor progression and metastasis and our laboratory is playing a leading role in analyzing these changes using proteomic methods. We have shown that many of the changes we detect in the matrix are causal in promoting metastasis and tumor survival and in promoting the development of new blood vessels that help tumors to grow and survive - so-called tumor angiogenesis. In both these roles, proteins of the extracellular matrix affect the behavior of the cells that interact with them through adhesion receptors, including integrins and others, and these classes of proteins are another focus of research in the Hynes laboratory. We have detected changes in several of these adhesion receptors and their intracellular mediators that also contribute to regulation of metastasis. Integrin-matrix interactions are essential for building blood vessels both during normal development and in tumors, both primaries and metastases. There is interest in understanding this complex process with the hope that it may be possible to inhibit tumor angiogenesis. Extracellular matrix also constitutes an important part of the microenvironment or niche of tumor cells themselves, providing signals for growth and survival of tumor cells and also contributing to the development of resistance to radio- and chemo-therapy. This resistance is one of the most challenging aspects of cancer therapy.

Grants from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the Ludwig Foundation provided partial support for some of this research.