Current Projects

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The projects featured below are the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC)’s current funding recipients.

2019

Ming Li (Classic Individual)
Reprogram Tumor-Associated Macrophages to Heal the Tumor Wound

Tumors develop by invoking a supportive stroma similar to that of a non-healing wound characterized by aberrant angiogenesis and chronic immune cell infiltration. To define how such a tumor-promoting microenvironment is induced and whether it can be reprogrammed to suppress tumor progression will not only unravel disease mechanisms but also provide new strategies for cancer therapy. Tumor-associated macrophages (TAMs) constitute the dominant myeloid cell population in most solid tumors. In a transgenic breast cancer model, we have recently found that the tumor parenchyma-localized TAMs exhibit low activity of mTORC1, a pivotal regulator of cell metabolism by integrating growth factor and nutrient signals. Growth factors promote mTORC1 signaling by inactivating the TSC complex that functions as a GTPase-activating protein (GAP) for the lysosome-localized mTORC1 activator Rheb, while nutrients act through the Rag family of small GTPases to promote lysosomal translocation of mTORC1. Macrophage-specific ablation of the TSC complex component Tsc1 enhances mTORC1 signaling in TAMs, which causes tumor cell death and attenuates cancer progression. Notably, the tumor cell death response does not appear to be mediated by direct leukocyte-mediated killing, as T cells and macrophages are excluded from the tumor parenchyma.

Instead, Tsc1-deficient TAMs are reprogrammed to exhibit a perivascular distribution pattern, which fortifies vasculature organization and inhibits vessel leakage resulting in hypoxia and tumor cell death. Based on these observations, we hypothesize that enhanced mTORC1 signaling reprograms TAMs to acquire an innate wound-healing function via the inhibition of tumor-associated angiogenesis. In this proposal, we will define the exact mechanisms by which Tsc1-deficient TAMs remodels the tumor stroma and halts cancer progression. We will also determine whether the nutrient mTORC1 signaling pathway can be modulated to impact TAM differentiation and function. These studies will generate insights into metabolic control of TAMs in the context of spontaneous tumorigenesis, which will guide the development of effective cancer immunotherapies.

2018

Minkui Luo (Classic Individual)
CARM1 Inhibition Alters the Epigenetic Plasticity of Metastatic Breast Cancer Cells

Numerous biological events need to be orchestrated genetically and epigenetically for cancer cell to metastasize into remote organs. Significant efforts have been made to identify the epigenetic cues that module metastatic outgrowth. CARM1 is an important epigenetic modulator to which metastatic breast cancer cells are “addicted”. Depletion of CARM1’s methyltransferase activity or R-to-K mutation of target methylation site(s) abolishes the metastatic capability of breast cancer cells. We postulate that CARM1 perturbation is effective because of the adaptive epigenetic plasticity of treated breast cancer cells. Our Aim 1, will be evaluation of this model on breast cancer cells harboring wild-type and catalytically dead CARM1 in combination with wild-type and the R-to-K-mutated substrate(s). In Aim 2, we will evaluate the outcomes of pharmacological inhibition of CARM1 in these contexts with single-cell resolution and will identify biomarkers that can be used for potential evaluation of pharmacological dynamics and prediction of clinical outcomes. 

Scott Lowe (Classic Individual)
The epigenetic control of tumor ecosystem dynamics during PDAC progression

Pancreatic cancer is a deadly disease characterized by its heterogeneous cellular composition and a dense fibro-inflammatory stroma that contributes to tumor progression and drug resistance. This project will combine single cell technologies, state-of-the art computational analyses and unique mouse models of pancreatic cancer enabling perturbation of gene function at different disease stages, to examine the dynamic nature and regulation of intratumoral heterogeneity in pancreatic cancer, from its inception through metastasis. The project will also look at whether interfering with tumor-altered epigenetic states can normalize the tumor ecosystem of early and metastatic stage pancreatic cancer lesions and elicit therapeutic responses.