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Metabolic Regulation of Cell Survival and Death in Cancer

The Gan Laboratory has a long-standing interest in understanding how cancer cells sense and adapt to metabolic stress and how metabolic vulnerabilities can be exploited for cancer therapy. Our research lies at the intersection of cancer metabolism, regulated cell death and therapeutic response, with a particular focus on understanding how nutrients, redox metabolism and metal homeostasis determine whether cancer cells survive or die.

Our current research centers on three interconnected forms of metabolically regulated cell death: ferroptosis, disulfidptosis and cuproptosis. Although these forms of cell death are driven by distinct metabolic stresses, together they provide complementary systems for understanding how cancer cells maintain metabolic fitness and how disruption of these adaptations can expose therapeutic vulnerabilities. We seek to define the fundamental mechanisms governing these cell-death processes and translate these discoveries into strategies to overcome resistance to cancer therapies.

1. Ferroptosis: iron-dependent cell death driven by lipid peroxidation

Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation. Our laboratory has made a series of discoveries establishing important connections between ferroptosis, cellular metabolism, tumor suppression and cancer therapy (; ; ; ; ; ). Our studies have identified mechanisms by which tumor suppressor pathways, nutrient and energy availability, lipid metabolism and mitochondrial metabolism regulate ferroptosis, and have helped establish ferroptosis as an important mechanism of tumor suppression and therapeutic response.

A major focus of our current research is to understand the metabolic and signaling networks that determine ferroptosis sensitivity and resistance in cancer. We are particularly interested in identifying ferroptosis defense mechanisms and metabolic liabilities that can be therapeutically targeted. We also investigate how ferroptosis interacts with conventional and targeted cancer therapies, including radiotherapy (; ; ) with the goal of developing strategies that exploit ferroptosis to overcome therapeutic resistance.

2. Disulfidptosis: cell death induced by disulfide stress

Our studies of cystine metabolism revealed an unexpected metabolic vulnerability in cancer cells with high expression of the cystine transporter SLC7A11. Although increased cystine uptake protects cancer cells from ferroptosis, it also creates a strong dependency on NADPH-generating metabolic pathways. Under conditions such as glucose starvation, excessive cystine uptake can cause rapid NADPH depletion, abnormal accumulation of disulfides and profound disulfide stress ().

Building on these findings, our laboratory discovered and named disulfidptosis, a distinct form of cell death triggered by excessive disulfide stress (; ). We found that disulfide stress causes aberrant disulfide bonding in actin cytoskeleton proteins, leading to cytoskeletal collapse and cell death. This work uncovered a previously unrecognized connection between nutrient dependency, redox homeostasis, the actin cytoskeleton and cell death ().

Our ongoing research seeks to define the molecular and metabolic mechanisms that regulate disulfidptosis, understand how cancer cells adapt to disulfide stress and identify strategies to exploit this vulnerability therapeutically. In particular, we are interested in translating disulfidptosis into new approaches for targeting SLC7A11-high cancers and other metabolically vulnerable tumors.

3. Cuproptosis: copper-dependent cell death

Cuproptosis is a recently identified form of regulated cell death caused by copper accumulation and its interaction with lipoylated mitochondrial proteins. The laboratory investigates how copper metabolism and cuproptosis influence cancer progression and therapeutic response, extending our broader interest in how metabolic and metal homeostasis govern cancer cell survival.

The lab's recent work has uncovered an important role for cuproptosis in cancer therapy resistance. We have identified mechanisms through which cancer cells suppress cuproptosis to survive radiotherapy and demonstrated that targeting these mechanisms can restore cuproptosis and overcome radioresistance (). More recently, our studies have revealed crosstalk between cuproptosis and antitumor immunity, providing a framework for understanding and potentially overcoming resistance to cancer immunotherapy ().

Our ongoing research seeks to understand how copper homeostasis, mitochondrial metabolism and cellular stress responses regulate cuproptosis and to develop strategies for therapeutically manipulating copper-dependent cell death in cancer.

From Metabolic Vulnerabilities to Cancer Therapy

Across these research areas, a common theme of our work is that the metabolic adaptations that enable cancer cells to survive can simultaneously create metabolic liabilities (). We seek to understand these trade-offs and exploit them therapeutically. By integrating mechanistic studies of ferroptosis, disulfidptosis and cuproptosis with cancer models and translational research, our ultimate goal is to develop new strategies to induce cancer cell death, overcome therapeutic resistance and improve cancer treatment.