Chengyu Liang, M.D., Ph.D.

Starting at the center of the cell, we study how cells sense and repair DNA damage, including double strand breaks, mismatches, and UV-induced lesions; and how failures in these processes leave enduring “footprints” on the genome. Particularly, we understand why genetically similar cells exposed to comparable environmental stress can accumulate vastly different mutational burdens.

Using melanoma as a paradigm, we investigate how intrinsic DNA repair capacity shapes UV-associated mutational signatures, tumor evolution, and immune recognition. By defining how genomic damage is repaired, tolerated, or allowed to persist, we aim to identify new biomarkers of cancer risk and predictors of therapeutic response.

Cells can undergo profound and reversible changes in identity and behavior without acquiring new genetic mutations. We investigate how transcriptional and epigenetic reprogramming enables cellular plasticity in response to stress, oncogenic signaling, and therapeutic pressure.

Our work explores how these adaptive states are established and stabilized, and how plasticity contributes to tumor progression, immune evasion, and therapy resistance. Understanding these mechanisms may reveal strategies to constrain maladaptive cell states or restore more therapy-sensitive programs.

Once genes are expressed, cellular behavior is shaped not only by transcription alone but by post-translational regulatory logic. We study protein modifications, including ubiquitination, phosphorylation, and citrullination, as dynamic molecular codes that determine when signals are propagated, reshaped, spatially confined, or terminated.

We are interested to understand how these modification systems intersect with vesicular trafficking and membrane organization to impose specificity, timing, and directionality on signaling pathways. By elucidating how signals are edited, buffered, or extinguished at membrane interfaces, we aim to uncover general principles that preserve signaling homeostasis and prevent pathological activation in cancer and inflammatory disease.

We study autophagy and membrane trafficking as core cellular surveillance systems that govern how information, nutrients, and stress signals are processed within the cell. Rather than viewing autophagy as a terminal degradative pathway, our work established it as an active, integrative regulatory network that coordinates signaling, metabolism, and cellular adaptation.

A central contribution of our laboratory was the identification of UVRAG (UV-radiation Resistance-Associated Gene) as a multifunctional autophagic tumor suppressor and the demonstration that it functions far beyond canonical autophagy. We were the first to show that UVRAG synchronizes autophagic, endocytic, secretory, and melanogenic pathways, directly linking membrane trafficking to cellular stress responses and metabolic control. These studies redefine autophagy regulators as systems-level organizers that integrate membrane dynamics with signaling and disease control.

Beyond individual molecules, we view organelles as active signaling platforms where metabolic, immune, and oncogenic signals converge. Our work focuses on how the dynamic state and quality control of organelles shape cell fate decisions, host defense, and disease progression. We study the centrosome as a key organizer of mitosis and cellular architecture; although centrosome amplification is a hallmark of cancer and correlates with tumor aggressiveness, how cancer cells tolerate or exploit supernumerary centrosomes remains poorly understood.

In parallel, we investigate mitochondria as hubs of innate immune signaling, defining how changes in mitochondrial architecture regulate antiviral defense and how pathogens exploit organelle dynamics to suppress immune responses. These efforts highlight organelle remodeling as a fundamental and targetable layer of immune and cancer biology.

We have made early and continuing contributions to understanding how cellular and viral Bcl-2 family proteins regulate cell survival, organelle function, and immune evasion in oncogenic viral infections. Our work helped establish that Bcl-2 proteins control not only apoptosis, but also autophagy, organelle dynamics, and innate immune signaling, thereby shaping both tumor progression and viral persistence.

Using Kaposi’s sarcoma–associated herpesvirus (KSHV) as a model, we revealed how virally encoded Bcl-2 proteins hijack host cellular machinery to reprogram mitochondria, suppress antiviral immunity, and promote viral replication. These studies uncover the virus-organelle interface as a fundamental mechanism of immune evasion and highlight it as a promising target for antiviral and cancer therapy.