RESEARCH
Starting in October 2024, our laboratory at the University of Massachusetts Chan Medical School will be dedicated to improving cancer treatment through innovative approaches. We focus on understanding how changes in metabolism and epigenetics contribute to cancer development and immune system evasion. Using techniques such as mouse models, cellular immunology, functional genomics, and single-cell profiling, we aim to uncover mechanisms that allow cancers to escape immune detection and develop new therapeutic strategies. Our goal is to translate these insights into novel, more effective, and personalized cancer therapies.
Please contact Meng-Ju about any of the projects below:
Restoring Immune Surveillance in Cancer
Our recent work established that mutations in isocitrate dehydrogenase 1 (mIDH1) are critical drivers of immune evasion in intrahepatic cholangiocarcinoma (ICC). We have found that mIDH1 inhibition can restore immune surveillance by reactivating transposable elements (TEs) and inducing cGAS-STING signaling. We are exploring new mechanisms and combination therapies to enhance these pathways in tumorigenesis and improve the response to mIDH1 inhibitors in vivo.
Viral Mimicry and Immune Activation
Our research has shown that inhibition of mutations like mIDH1 leads to the re-expression of silenced TEs, triggering a "viral mimicry" response that enhances immune activation. These re-expressed TEs generate viral antigens presented on the tumor cell surface, improving immune recognition and recruitment. We are investigating the specific TEs involved and their impact on immune cell recruitment and activation. Additionally, we are exploring other methods to induce the viral mimicry response, such as using DNA methyltransferase (DNMT) inhibitors, to enhance immune activation further. Our goal is to harness these mechanisms to develop combination therapies that improve the efficacy of these inhibitors by boosting antigen presentation and immune response.
Metabolic Crosstalk in Tumor-Immune Interactions
Mutations in metabolic enzymes, such as IDH1, result in significant metabolic alterations that affect tumor-immune interactions. Our recent studies show that these mutations impair immune cell function via metabolic crosstalk. Single-cell RNA sequencing reveals that T cell effector function and myeloid cell populations, including macrophages and neutrophils, are altered by these mutations and rescued by their inhibition. These effects are partly due to the uptake of tumor-derived oncometabolites by immune cells and metabolic competition, where tumor-driven metabolic processes, such as glycolysis and the consumption of other critical nutrients, limit the availability required for immune cell function. Additionally, fibroblasts within the tumor microenvironment may also be affected, further contributing to immune evasion. Our research aims to identify metabolic pathways and intermediates contributing to immune evasion and tumor progression. By targeting these metabolic pathways, we hope to disrupt the tumor's immune evasion strategies and improve therapeutic outcomes. We will test the hypothesis that these processes collectively underlie the extreme T-cell excluded phenotype of these tumors.
Epigenetic Control of Immune Evasion
We have discovered that tumors with metabolic mutations, such as mIDH1, exhibit defective responses to immune signals due to epigenetic modifications. Our studies show that inhibition of these mutations promotes the demethylation of critical immune response genes. We will further explore the role of key epigenetic regulators by in vivo CRISPR screening in modulating the immune microenvironment and develop therapeutic strategies targeting these pathways.
Exploring Mechanisms of Resistance to Inhibition
Resistance to inhibitors of metabolic mutations remains a significant challenge. Our lab is investigating the mechanisms of primary and adaptive resistance using transcriptomic and immunological profiling, as well as in vivo CRISPR screens. Understanding these resistance pathways will inform the development of strategies to overcome resistance and enhance long-term treatment efficacy.
Novel Therapeutic Targets in Cancers with Altered Metabolic or Epigenetic States
Through our research, we aim to identify novel therapeutic targets involved in the immune evasion and tumorigenesis of cancers with altered metabolic or epigenetic states. This includes exploring the roles of innate immune pathways, TE reactivation, and various metabolic alterations. By targeting these pathways, we aim to develop innovative treatments that improve immune responses and reduce tumor growth.
New Subtype-Specific Mouse Models of Liver Cancers
It has recently become apparent that liver cancers, including cholangiocarcinoma, consist of various subtypes that significantly impact disease phenotypes and patient outcomes. One such subtype, characterized by specific metabolic mutations, shows distinct biological and clinical behaviors. We aim to build next-generation genetically engineered mouse models of cholangiocarcinoma and other liver cancers that are subtype-specific to more faithfully mimic the patient’s disease. These models will enable us to study the unique molecular circuits and therapeutic vulnerabilities of each subtype, ultimately guiding the development of more effective, personalized treatments.