Koh Research Lab
Koh Research Lab
AREA OF RESEARCH:
Kidney Cancer Liver Cancer
Tumor Hypoxia
Tumor Cell Signaling
Koh Lab Research Overview
All solid tumors and their metastases suffer from regions of oxygen deprivation, also known as hypoxia. This occurs as a result of the diffusion limitation of oxygen, and to the highly proliferative nature of cancer cells. Hypoxic tumors are intrinsically resistant to radiation and chemotherapy, and patients with these tumors are likely to have a poorer prognosis.
My lab aims to determine how tumor hypoxia, and the hypoxia-inducible factors, HIF-1 and HIF-2, drive outcomes that promote cancer progression and resistance to therapy.
These outcomes include ‘reprogramming’ of cancer cells to favor increased growth (such as through increased iron uptake), reversion to a multipotent stem-like (and more aggressive) phenotype, and increased metastasis. The hypoxic tumor microenvironment also alters the patient’s immune cells that are in proximity to the tumor, suppressing their ability to eliminate cancer cells. The overall goal of my lab is to identify new therapeutic strategies for cancer by targeting components of the tumor and the tumor microenvironment that drive cancer progression.
Major Research
Ferroptosis induction for the treatment of solid tumors
Ferroptosis is a novel form of regulated cell death characterized by iron-dependent lipid oxidation that disrupts cellular organelles and membranes, resulting in membrane rupture and cell death. Ferroptosis is a promising treatment strategy for cancer since cancer cells that acquire resistance to apoptosis typically show increased sensitivity to ferroptosis. Moreover, cancer cells intrinsically possess higher levels of oxidative stress, unsaturated lipids and/or iron compared to normal tissue, which renders them more sensitive to ferroptosis compared to normal tissue.
We have identified novel molecules that can induce ferroptosis through the targeting of Iron Sulfur Cluster Assembly 2 (ISCA2), a protein involved in iron utilization. Inhibition of ISCA2 generates a phenotype of iron deprivation within the cell, which mediates the dual effect of increased iron uptake, which promotes ferroptosis, and inhibition of HIF, which blocks tumor growth. We have found that kidney cancer, melanoma and ovarian cancer are the most sensitive tumor types to ferroptosis. Anti-tumor efficacy assays using small molecule inhibitors of ISCA2 are currently underway to assess the effectiveness of these inhibitors in blocking tumor growth and their ability to synergize with currently approved therapies. We are also characterizing the role of ISCA2 and the Fe-S pathway in tumor progression.
The Three Determinants of Ferroptosis Sensitivity.
Ferroptosis inducers modulate the functionality of these major pathways to increase sensitivity to ferroptosis. A) Polyunsaturated fatty acid containing phospholipids (PUFA-PLs) are susceptible to oxidation and promote sensitivity to ferroptosis. B) The xC transporter facilitates the uptake of cystine, which is converted to glutathione (GSH) and GPX4, antioxidant proteins that protect against ferroptosis. C) Transferrin-bound iron is taken up by the cell through the transferrin receptor (TFRC). This is released in the lysosome which may release redox active iron (Fe2+) that promotes ferroptosis.
Characterizing the role of HAF in Liver Cancer
Metabolic dysfunction-associated fatty liver disease (MAFLD) together with its inflammatory component, metabolic dysfunction-associated steatohepatitis (MASH) is the third leading cause of liver cancer (hepatocellular carcinoma, HCC) after viral Hepatitis (B or C) infection. MASH is the major cause of the increasing incidence of HCC in the USA associated with the obesity epidemic. Since HCC is a disease associated with chronic inflammation of the liver, the identification of the key inflammatory mediators associated with>To this end, my lab has generated mice that spontaneously develop HCC with hallmarks of MASH. These mice bear a heterozygous deletion of the HAF gene within hepatocytes (known as hepSART1+/-, hepS+/- mice).These hepS+/- mice spontaneously develop steatosis (fatty liver) which leads to HCC at age 12 months. We have found that hepatocytes from hepS+/- mice have defective NF-κB signaling, and activation of a variety of pro-inflammatory pathways including p38 and JNK. We are currently investigating the impact of HAF deregulation during progression to HCC to identify novel diagnostic and therapeutic strategies.
The Three Determinants of Ferroptosis Sensitivity.
Ferroptosis inducers modulate the functionality of these major pathways to increase sensitivity to ferroptosis. A) Polyunsaturated fatty acid containing phospholipids (PUFA-PLs) are susceptible to oxidation and promote sensitivity to ferroptosis. B) The xC transporter facilitates the uptake of cystine, which is converted to glutathione (GSH) and GPX4, antioxidant proteins that protect against ferroptosis. C) Transferrin-bound iron is taken up by the cell through the transferrin receptor (TFRC). This is released in the lysosome which may release redox active iron (Fe2+) that promotes ferroptosis.
Characterizing the role of HAF in Liver Cancer
Metabolic dysfunction-associated fatty liver disease (MAFLD) together with its inflammatory component, metabolic dysfunction-associated steatohepatitis (MASH) is the third leading cause of liver cancer (hepatocellular carcinoma, HCC) after viral Hepatitis (B or C) infection. MASH is the major cause of the increasing incidence of HCC in the USA associated with the obesity epidemic. Since HCC is a disease associated with chronic inflammation of the liver, the identification of the key inflammatory mediators associated with>To this end, my lab has generated mice that spontaneously develop HCC with hallmarks of MASH. These mice bear a heterozygous deletion of the HAF gene within hepatocytes (known as hepSART1+/-, hepS+/- mice).These hepS+/- mice spontaneously develop steatosis (fatty liver) which leads to HCC at age 12 months. We have found that hepatocytes from hepS+/- mice have defective NF-κB signaling, and activation of a variety of pro-inflammatory pathways including p38 and JNK. We are currently investigating the impact of HAF deregulation during progression to HCC to identify novel diagnostic and therapeutic strategies.
Progression from health liver to hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. MAFLD: metabolic dysfunction associated fatty liver disease; MASH: metabolic dysfunction associated steatohepatitis