The overall goals of our research programs are to understand the fundamental principles of cell signaling in the regulation of basic cellular functions in normal cell and developmental processes and to determine how the disruption of normal signaling pathways lead to diseases such as cancer. Current studies investigate the mechanisms of autophagy and kinase signaling in cancer development and progression as well as other biological processes.
One area of our research focuses on the role and mechanisms of focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase that is important in mediating signaling by integrins as well as some growth factor receptors, in the regulation of diverse disease and biological processes. Since the 1980s, tyrosine phosphorylation has been known as a key mechanism of cellular signaling. However, this is mostly associated with signaling by receptors for growth factors and cytokines which often encode a kinase in their cytoplasmic domain. With relatively short cytoplasmic domains, integrins were not considered to be capable of transmitting biochemical signaling across the plasma membrane to induce protein tyrosine phosphorylation like the growth factor receptors. Our work in the early 1990s demonstrated for the first time that integrin-mediated cell adhesion induced tyrosine phosphorylation of a 120 kDa protein (pp120). Shortly after this publication, we identified pp120 as a novel tyrosine kinase FAK that is controlled by both cell adhesion and oncogenic transformation. These studies helped to open up a new research field on signal transduction by integrins in the early-mid 1990s.
By the late 1990s, FAK has been firmly established as a key component of integrin signaling and its role in the regulation of cell migration and other cellular functions have been shown by numerous papers. Yet, the role and mechanism of FAK in cancer and other physiological and disease processes are not well understood beyond studies using cell lines in vitro or those that correlate changes of FAK expression and/or activation in various systems (e.g. increased expression in breast cancer). This was in part due to lack of suitable in vivo models for these studies (e.g. total FAK knockout in mouse leads to embryonic lethality). Therefore, we create the floxed FAK mouse for Cre-loxP conditional knockout approach to delineate the role and mechanisms of FAK and its signaling pathways in vivo. Using this and other sophisticated mouse models with conditional FAK mutant knockin, we have made important contributions to demonstrate critical functions of FAK signaling in tumor development, metastasis, cancer stem cells, and angiogenesis. We have also made major contributions in the discovery and characterization of other signaling molecules and pathways in the regulation of cell migration, survival and proliferation by intergrin signaling through FAK. Current projects in the laboratory include examination of the kinase and scaffolding functions of FAK in breast cancer stem cells, cancer metastasis, angiogenesis, and tumor microenvironments using many unique mouse models developed in the lab in combination with cutting-edge molecular and cell biological approaches.
A second area of research aims to determine the role and mechanisms of autophagy in cancer and other biological processes. Autophagy is a highly conserved cellular process for degradation of bulk cytoplasmic materials for maintenance of cellular homeostasis and in response to starvation. While it was originally described many decades ago, autophagy has emerged as one of the most exciting research fields in the last decade with the identification of a set of autophagy genes first in yeast and subsequently in mammalian cells that are essential for the process. While initially not involved in autophagy research, our lab identified FIP200 (FAK-family Interacting Protein of 200 kDa) in the early 2000s, which was subsequently shown to be a component of the ULK1/Atg13/FIP200 complex essential for the induction of autophagy in a collaboration with researchers in Japan. We have created the floxed FIP200 mice and used various Cre transgenic mice to delineate the role and mechanisms of FIP200-mediated autophagy in different biological and disease processes in vivo.
Autophagy was initially thought to play a tumor suppressive role primarily based on the identification of a tumor suppressor gene beclin1 as an essential component of autophagy and subsequent studies both in mouse models and human cancers. While there were some studies suggesting also a positive role for autophagy in cancer growth in cultured cells, our studies showing that conditional knockout of FIP200 decreased mammary tumor development, growth, and metastasis driven by PyMT oncoprotein provided the first evidence for a pro-tumorigenesis role for autophagy in animals with intact immune systems. In addition, we also developed an in vivo system to induce deletion of FIP200 in established tumors and showed that acute inhibition of autophagy by FIP200 deletion reduced growth of established tumor, providing support for targeting autophagy in cancer therapy in a better model (i.e. blocking autophagy in established tumors). These studies made important contributions to our current understanding that autophagy promote tumor growth and progression and could serve as a therapeutic target.
In addition to our studies of autophagy in breast cancer, our lab was among the first to suggest a role for autophagy in the regulation of tissue stem cells (i.e. in a hematopoietic stem cells system). More recently, we published the first paper that demonstrated a role of autophagy and underlying mechanisms in the regulation of neural stem cells (NSCs). As many stem cells are long lived and persist throughout the life of an organism, the quality control mechanisms such as autophagy to maintain cellular homeostasis would be even more crucial for these cells. However, in contrast to the body of data derived from studies of somatic cells and disease models, surprisingly little have been published on autophagy in stem cells. Our publications on this topic helped to stimulate the general interests in the exciting intersection of autophagy and stem cell biology, both are rapidly developing fields that have seen tremendous growth in recent years. Using sophisticated mouse genetics and other approaches, current projects in the laboratory are directed at dissecting the mechanisms of autophagy and its cross-talk with intracellular signaling in diverse systems including breast cancer, vascular tumors, neural stem cells and brain tumor.
A third area of research in the laboratory studies the role and mechanisms of hyper-activation of mTORC1 signaling in vascular and other tumors. Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase associated with different protein partners to form two independently regulated hetero-oligomeric complexes, the rapamycin-sensitive and rapamycin-insensitive mTOR complex (mTORC) 1 and 2, respectively. mTORC1 signaling has been shown to coordinate numerous cellular processes, and its dysfunction is implicated in many diseases including vascular tumors and malformations. In a recent study, we showed that constitutive activation of mTORC1 upon inducible endothelial cell-specific deletion of Tsc1 led to the development and progression of lymphangiosarcoma in mice, which recapitulate salient features of the human disease with poor prognosis. These studies also revealed the critical role of VEGF autocrine signaling triggered by mTORC1 through HIF1α and c-Myc in lymphangiosarcoma development and progression. In another line of study, we have found that, although mTORC1 is a well-known negative regulator for autophagy under nutrient-replete condition, autophagy remains high and is required for the maintenance of hyper-activation of mTORC1 in Tsc1-deficient NSCs that leads to brain tumor development. These studies suggest a novel cross-talk mechanism between mTORC1 signaling and autophagy. Current projects in the lab aim to further dissect the signaling pathways involved in vascular and brain tumors as well as the development of potential novel therapies based on the new mechanistic insights. Lastly, in addition to the studies outlined above focusing on autophagy, FAK and mTORC1 signaling pathways, we are very interested in understanding the potential cross-talk between autophagy and intracellular signaling mediated by these kinases.