The development and maintenance of multicellular organisms requires tight control over the proliferation, differentiation, organization, and death of their constituent cells. Intricate molecular signaling networks control these processes. My lab is focusing on how cells receive and interpret these signals and how the disruption of these processes leads to cancer and other diseases.
We are approaching these questions through the rich venue provided by the transforming growth factor-β (TGFβ) pathway. The TGFβ family of cytokines is among the most prominent and versatile. With more than 30 members in the human genome, including the TGFβs, the nodals, the activins, the bone morphogenetic proteins, the myostatins, and others, these factors control many aspects of cell behavior from early embryo development to the regeneration and homeostasis of adult tissues.
Work in my lab elucidated the key steps of this pathway by identifying the TGFβ receptors and defining the identity, mechanism of action, and structural basis of each step in the pathway. The TGFβ receptors are serine/threonine protein kinases, and the SMAD transcription factors are their substrates. Receptor-activated SMADs (RSMADs) form complexes with SMAD4 and different DNA binding cofactors. RSMADs undergo cycles of peak activation, deactivation, and destruction through CDK8/9 and GSK3 kinase-operated switches that drive interactions with transcription cofactors and with SMAD ubiquitin ligases, respectively.
SMAD complexes target large sets of genes to stimulate or inhibit their transcription. These genes include p27Kip1, p57Kip2, and other inhibitors of cyclin-dependent kinases that the lab codiscovered in order to explain how TGFβ inhibits cell division. Other TGFβ targets include cell microenvironment modifiers such as cytokines and extracellular matrix components, whose runaway activation by hyperactive TGFβ causes inflammation and fibrosis. TGFβ is also a key enforcer of constraint in the immune system, and alterations in this role lead to immune disorders.
The basic elements of the TGFβ pathway came to light more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: How does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions and is a major objective of our current research.
In embryonic stem cells, we recently discovered that RSMADs form a complex with the histone-binding protein TRIM33. Signal-driven RSMAD-TRIM33 binds to repressive histone marks on master differentiation genes, relaxing their poised chromatin to enable companion RSMAD-SMAD4 complexes to trigger transcription. The lab is currently defining the specific mechanism and regulatory implications of this process, both in embryonic and in adult stem cells.
TGFβ is a powerful tumor suppressor signal. Premalignant cells that have acquired driver oncogenic mutations become exposed to TGFβ-induced apoptosis. The lab is interested in identifying the mechanism that sets premalignant cells for TGFβ-induced death. The hypothesis that this mechanism is tied to oncogene-driven reprogramming of progenitor cells is under investigation.
Tumor progression requires a loss of TGFβ suppressive effects. In gastrointestinal and pancreatic carcinomas, inactivating mutations in TGFβ receptors and SMADs allow cancer cells to avert TGFβ signaling altogether. With this accomplished, the cancer cells can benefit from protumorigenic effects of TGFβ on the tumor stroma. In the case of breast and lung carcinomas, and melanomas, the cancer cells go one step further. These tumors select for cancer cells that have disabled downstream TGFβ tumor suppressive responses but are free to employ their remaining TGFβ responses for dissemination and outgrowth in distant organs. That is, in aggressive tumors TGFβ becomes a mediator of metastasis.
Metastasis is the cause of 90 percent of deaths from cancer. In response to this challenge, we set out to identify clinically relevant genes that mediate cancer cell infiltration into distant organs, survival of the disseminated tumor cells (DTCs) in host tissues, and the eventual outgrowth of DTCs as lethal metastases. We use in vivo selection and molecular profiling of human metastatic cells, functional testing of candidate genes in mouse models, and bioinformatics analysis of clinical data sets. With these protocols, we have identified many protein-encoding genes, microRNAs, and signaling pathways that mediate metastasis to specific organs in experimental models and are associated with relapse to these organs in patients.
This work has revealed mechanisms of metastasis in breast cancer, lung adenocarcinoma, and renal cell carcinoma to sites including bone, lung, and brain. Our interest is currently directed to two of the most ominous forms of metastasis: brain metastasis and latent metastasis. Brain metastasis is highly lethal. Its incidence is several-fold higher than that of all other brain tumor types combined and is growing. We have created experimental models to investigate brain metastasis and are using these models and human tissue samples to identify stromal and cancer cell mediators of brain metastasis.
Identifying and targeting the mechanisms that support the survival of latent DTCs holds promise of more effectively preventing relapse in patients after removal of their primary tumor. Adjuvant chemotherapy is already achieving this goal in the clinic, albeit inefficiently and with many side effects. Very recently, we identified molecules that amplify the survival response of DTCs to limiting levels of host stroma signals. Amplifiers of PI3K, NOTCH, WNT, and TGFβ signaling are emerging as critical supporters of DTC stemness and survival. Mechanisms that link metastasis and resistance to chemotherapy are also emerging. We are developing new models of latent metastasis in order to further investigate the survival mechanisms of the latent state. Our goal is to turn this knowledge into better ways to prevent and treat metastasis.
Grants from the National Institutes of Health and the Department of Defense provide support for some of these projects.
As of June 3, 2013
