Stem Cell Signaling, Growth Control, and Cancer Metastasis
TGFβ signaling in embryonic stem cells.
Two signal-driven SMAD complexes cooperate to activate master differentiation genes. (Adapted from Nature Reviews 2012)
There are more than 30 cytokines of the TGFβ family in the human genome, including the TGFβs, the nodals, the activins, the bone morphogenetic proteins (BMPs), the myostatins, and others. These factors control many aspects of cell behavior, from early embryonic development to the regeneration and homeostasis of adult tissues.
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, increasingly clarifying its multifunctional nature and medical relevance. However, an old mystery has endured: How does the context determine the cellular response to TGFβ? A major objective of our current research is to solve this question, which is key to understanding the biology of TGFβ and the many ways in which this pathway may malfunction.
Stem cells and tumor suppression
Working in embryonic stem cells, we recently discovered that TGFβ receptors stimulate SMAD transcription factors to form a complex with the histone-binding protein TRIM33. Signal-driven SMAD-TRIM33 binds to repressive histone marks on master differentiation genes, relaxing their poised chromatin to enable companion SMAD complexes to trigger transcription. The lab is currently defining the specific mechanisms and regulatory implications of this process in both embryonic and adult stem cells.
Disseminated cancer cell in the brain.
A metastatic cell (geen) hugs a brain capillary for survival (red) in the brain parenchyma (blue nuclei). (Image, M. Valiente).
TGFβ is a powerful tumor suppressor signal. Premalignant cells that have acquired driver oncogenic mutations become sensitive to TGFβ-induced death. We are interested in identifying the mechanisms that reprogram premalignant cells for TGFβ-induced death. When cancer cells avert these tumor suppressor mechanisms, tumors can progress toward metastasis.
Metastasis genes and functions
Metastasis is the cause of 90 percent of deaths from cancer. We are identifying 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 protein-encoding genes, microRNAs, and signaling pathways that mediate metastasis in breast cancer, lung adenocarcinoma, and renal cell carcinoma to sites including the bone, lung, and brain. Our interest is currently directed to two of the most ominous forms of metastasis: brain metastasis and latent metastasis.
Linking metastasis and chemotherapy resistance.
Metastatic breast cancer cells produce CXCL chemokines, which recruit myeloid cells that produce S100 factors for cancer cell survival. Chemotherapy triggers TNFa production in the tumor stroma, which further stimulates the CXCL-S100 loop to diminish the effectiveness of the therapy. (adapted from Acharyya et al Cell 2012)
Brain metastasis is highly lethal. Its incidence is several-fold higher than that of all other brain tumor types combined, and growing. We have created new 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, disseminated tumor cells hold promise for the prevention of relapse after removal of a primary tumor. Adjuvant chemotherapy is already achieving this goal in the clinic, albeit inefficiently and with many side effects. We are developing new models of latent metastasis to further investigate the survival mechanisms of the latent state.
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 survival and stem cell functions. Mechanisms that link metastasis and resistance to chemotherapy are also emerging. Our goal is to turn this knowledge into better ways of preventing and treating metastasis.