The focus of the Cheng laboratory is to elucidate the molecular mechanisms underlying cell death with the hope that the knowledge derived from our research can be translated into mechanism-based therapeutic strategies that effectively trigger cancer cell death and enhance anti-cancer immune memory. We employ molecular cell biology, biochemistry, quantitative proteomics, genome-wide genetic screens, high-throughput chemical screens, state-of-the-art single-cell omics, and genetically engineered mouse models to dissect cell death pathways both in vitro and in vivo. We are particularly interested in the impact of different types of cell death (apoptosis, BAX/BAK-dependent immunogenic cell death, pyroptosis, necroptosis, ferroptosis, etc.) on tumor-immune crosstalk and immunotherapy. The overarching goal of our research is to develop novel cell death mechanism-based anti-cancer therapy that not only eliminates cancer cells but also generates anti-tumor immunity and enhances immunotherapy.
The research of the Cheng laboratory has helped delineate the mammalian core apoptotic pathway governed by the BCL-2 family proteins at the mitochondrion. Specifically, we have elucidated how BAX and BAK are activated to form the apoptotic machinery, presented “sequestration model” by which anti-apoptotic BCL-2 family members inhibit apoptosis, identified gatekeepers of apoptosis, mapped apoptotic signaling networks, and modeled apoptosis in mice. Our studies concluded an “interconnected hierarchical model”, which not only offers a common ground deciphering the complex interplays among the BCL-2 subfamilies but also provides a molecular blueprint concerning the clinical application of BH3-mimetics, such as venetoclax (ABT-199, a BCL-2 selective inhibitor) and navitoclax (ABT-263, a dual inhibitor of BCL-2 and BCL-XL) in killing cancer cells. Our recent work has established a predictive paradigm for determining cancer addiction to anti-apoptotic BCL-2 family members, which may help guide future practice of precision cancer medicine targeting the BCL-2 family.
Our current efforts are aimed at delineating aberrant survival/death signaling pathways in cancer, studying epigenetic regulation of cell death and epigenetic mechanisms of resistance to targeted therapy, interrogating the impact of cell death on tumor-immune crosstalk and immunotherapy, and identifying therapeutic strategies that trigger potent immunogenic cell death in cancer. For the past few years, our research efforts have expanded to studying the epigenetic regulators that are commonly deleted/mutated in kidney cancer such as SETD2. On this front, we are investigating whether and how loss of these novel tumor suppressors that modulate the epigenetic landscape of cancer genomes may control survival/death to promote tumorigenesis and engender therapeutic vulnerabilities.