RESEARCH INTERESTS
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. Tumor site-specific research programs are described below:
Kidney Cancer
Although all solid tumors experience regions of hypoxia, the deregulation of the HIFs is most well studied in clear cell renal cell carcinoma (CCRCC). CCRCC is the most common and aggressive form of kidney cancer, and is highly resistant to chemotherapy and radiation. 90% of CCRCC cases are associated with the loss of the von Hippel-Lindau (pVHL) tumor suppressor protein. The hypoxia-inducible factors, HIF-1 and HIF-2, become constitutively activated due to pVHL loss, and play central roles in the initiation and progression of CCRCC. Although both HIFs are upregulated in early kidney lesions, it is believed that it is HIF-2α that drives progression of these lesions to CCRCC, whereas HIF-1α plays a tumor suppressor role, and is lost in advanced disease. The mechanism for this ‘HIF switch’ from HIF-1 to HIF-2 is unclear. However, our studies have shown that the Hypoxia Associated Factor (HAF), which selectively degrades HIF-1α and promotes HIF-2α activity, is a likely mediator of the HIF switch. The goal of our studies is to better understand the roles of the HIFs in CCRCC, and to identify new therapeutic targets and strategies, such as through the selectively targeting of HAF or HIF-2α.
Liver Cancer
Inflammatory fatty liver disease or non-alcoholic steatohepatitis (NASH) is the third leading cause of liver cancer (hepatocellular carcinoma, HCC) after viral Hepatitis (B or C) infection. NASH 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 the progression from NASH to HCC is critical for the identification of new treatments. To this end, my lab has generated mice that spontaneously develop HCC with hallmarks of NASH. These mice bear a genetic deletion of one copy of the HAF gene (known as SART1+/-). The SART1+/- mice show increased infiltration of pro-inflammatory HIF-1α positive cells into mouse livers prior to the development of HCC, similar to that seen in human HCC. Thus, the SART1+/- mouse will serve as a tool to identify the key components of the patients’ immune system that drive the progression from NASH to HCC.
RELATED LINKS
Education History
| Undergraduate |
University of Manchester |
BSc (Honors), Biochemistry with Biotechnology |
|---|---|---|
| Doctoral Training |
University of Manchester |
PhD, Molecular Pharmacology |
Selected Publications
Journal Article
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Acuña-Pilarte K, Reichert EC, Green YS, Halberg LM-T, McFarland SA, Mimche P, Golkowski M, Kamden SD, Maguire KM, Summers S, Maschek JA, Reelitz JW, Cox J, Evason KJ, Koh MY. HAF Prevents Hepatocyte Apoptosis and Hepatocellular Carcinoma through Transcriptional Regulation of the NF-κB pathway. Hepatology 2024 (in press).
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Wu Y, Chen S, Yang X, Sato K, Lal P, Wang Y, Shinkle AT, Wendl MC, Primeau TM, Zhao Y, Gould A, Sun H, Mudd JL, Hoog J, Mashl RJ, Wyczalkowski MA, Mo CK, Liu R, Herndon JM, Davies SR, Liu D, Ding X, Evrard YA, Welm BE, Lum D, Koh MY, Welm AL, Chuang JH, Moscow JA, Meric-Bernstam F, Govindan R, Li S, Hsieh J, Fields RC, Lim KH, Ma CX, Zhang H, Ding L, Chen F. Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma. Cancer Res. 2023;83(24):4161-78. doi: 10.1158/0008-5472.CAN-23-0604. PubMed PMID: 38098449; PMCID: PMC10722140.
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Green YS, Ferreira Dos Santos MC, Fuja DG, Reichert EC, Campos AR, Cowman SJ, Acuna Pilarte K, Kohan J, Tripp SR, Leibold EA, Sirohi D, Agarwal N, Liu X, Koh MY. ISCA2 inhibition decreases HIF and induces ferroptosis in clear cell renal carcinoma. Oncogene. 2022;41(42):4709-23. Epub 2022/09/14. doi: 10.1038/s41388-022-02460-1. PubMed PMID: 36097192; PMCID: PMC9568429.
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Revisiting the HIF switch in the tumor and its immune microenvironment. Cowman SJ, Koh MY. Trends Cancer. 2022 Jan;8(1):28-42. doi: 10.1016/j.trecan.2021.10.004. Epub 2021 Nov 4. PMID: 34743924 Free PMC article. Review.
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Cowman S, Fuja DG, Liu XD, Tidwell RSS, Kandula N, Sirohi D, Agarwal AM, Emerson LL, Tripp SR, Mohlman JS, Stonhill M, Garcia G, Conley CJ, Olalde AA, Sargis T, Ramirez-Torres A, Karam JA, Wood CG, Sircar K, Tamboli P, Boucher KM, Maughan BL, Spike BT, Ho TH, Agarwal N, Jonasch E, Koh MY. Macrophage HIF-1α is an independent prognostic indicator in kidney cancer. Clin Cancer Res. 2020 Jun 25:clincanres.3890.2019. doi: 10.1158/1078-0432.CCR-19-3890. Epub ahead of print. PMID: 32586940.
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Passing the baton: the HIF switch. Koh MY, Powis G. Trends Biochem Sci. 2012 Sep;37(9):364-72. doi: 10.1016/j.tibs.2012.06.004. Epub 2012 Jul 18. PMID: 22818162 Free PMC article. Review.
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The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Koh MY, Lemos R Jr, Liu X, Powis G. Cancer Res. 2011 Jun 1;71(11):4015-27. doi: 10.1158/0008-5472.CAN-10-4142. Epub 2011 Apr 21. PMID: 21512133 Free PMC article.
Book Chapter
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Koh MY, Spivak-Kroizman TR, Powis G. HIF-1alpha and Cancer Therapy. In: Recent Results Cancer Res. 180. Springer, 15-34, 2010