The projects featured below are the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC)’s current funding recipients.
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.
Metabolic crosstalk between melanoma and its microenvironment
There have been astounding advances in the treatment of metastatic melanoma with both targeted therapy and immunotherapy, but unfortunately more than half of people with metastatic melanoma still die of the disease. Therefore, it is important to understand the mechanisms of melanoma metastasis. This wide-ranging effort will explore the role of cellular stress and immune responses on metastasis in melanoma. Researchers also will investigate how the melanoma microenvironment induces metabolic alterations within melanoma cells that directly facilitate cellular invasion and metastasis.
This is the first GMTEC award to include multiple projects. In addition, the research team has applied to the National Institutes of Health for a P01 grant related to this work.
Project 1: Molecular mechanisms, immune responses, and cancer cell metabolism
Santosha Vardhana and Craig Thompson
This project will explore the metabolic consequences of redox regulation and its effect on T cell function within the tumor. It aims to look at the connection between metabolic adaptation in the setting of chronic inflammation and the promotion of immune evasion and metastasis in melanoma. The researchers will examine the role of altered metabolism in promoting immune dysfunction in melanoma. They also seek to determine the contribution of exogenous fatty acids to altered melanoma-specific immune responses.
Project 2: Characterize the role of lipid uptake–induced ER stress in metastasis of melanoma
This project will examine the ability of melanoma cells to metabolize fat as an energy source despite BRAF inhibition. One tool in this research is transgenic zebrafish, which will be used to characterize the role of fat cells in the progression of melanoma. These models will also be used to assess the mechanism of lipid-mediated ER stress in melanoma invasion and study the effects that lipids have on immune cells within the tumor microenvironment. The project will also look at whether blocking SLC27A fatty acid transporter proteins has therapeutic potential, and may ultimately lead to clinical trials evaluating this approach.
Project 3: Enhancing immune-mediated control of melanoma metastasis by modulating glycolytic stress
This project will examine the LDH/lactate axis and the effect of lactate on immune suppression in melanoma. It aims to study the connection between lactate production and the anti-melanoma immune response. It will also investigate whether blocking lactate production can improve T cell responses against melanoma.