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Mei Y. Koh

Assistant Professor of Pharmacology and Toxicology

Solid Tumor Hypoxia, Kidney Cancer, Liver Cancer, HIF-1 and HIF-2, Ferroptosis

Koh

 

Molecular Biology Program

Biological Chemistry Program

Education

B.Sc. University of Manchester

Ph.D. University of Manchester

Links

Faculty Page

PubMed Literature Search

mei.koh@utah.edu

 

Research

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.

References (Selected Publications)

  1. 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.
  2. Cowman SJ, Koh MY. Revisiting the HIF Switch in the Tumor and its Immune Microenvironment. Trends in Cancer. 2022 Jan; 8 (1): 28-42. Pubmed PMID: 34743924. PMCID: PMC8702465
  3. Koh MY, Sayegh N, Agarwal N. Seeing the forest for the trees-single-cell atlases link CD8(+) T cells and macrophages to disease progression and treatment response in kidney cancer. Cancer Cell. 2021;39(5):594-6. Epub 2021/04/17. doi: 10.1016/j.ccell.2021.03.008. PubMed PMID: 33861995.
  4. Cowman SJ, 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 K, Maughan B, Spike BT, Ho TH, Agarwal N,Jonasch E, Koh MY. Macrophage HIF-1alpha Is an Independent Prognostic Indicator in Kidney Cancer. Clin Cancer Res. 2020. doi: 10.1158/1078-0432.CCR-19-3890. PubMed PMID: 32586940. PMCID: PMC7968518.
  5. Tchoghandjian A, Koh MY, Taieb D, Ganaha S, Powis G, Bialecki E, Graziani N, Figarella-Branger D, Metellus P.Hypoxia-associated factor expression in low-grade and anaplastic gliomas: a marker of poor outcome.  2016 Mar 14. doi: 10.18632/oncotarget.8046. [Epub ahead of print] PubMed PMID: 26989023.
  6. Koh MY, Gagea M, Sargis T, Lemos R, Grandjean G, Charbono A, Bekiaris V, Sedy J, Kiriakova G, Liu X, Roberts LR, Ware C, Powis G. A new HIF-1α/RANTES driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF. 2016 May;63(5):1576-91. Epub 2016 Mar 7. PubMed PMID: 26799785; PubMed Central PMCID: PMC4840057.
  7. Koh MY, Nguyen V, Lemos R, Darnay BG, Kiriakova G, Abdelmelek M, Ho TH, Karam J, Monzon FA, Jonasch E and Powis G. Hypoxia-induced SUMOylation of E3 ligase HAF determines specific activation of HIF-2 in clear cell renal cell carcinoma. Cancer Research 75(2) 316-329 1/2015. e-Pub 11/2014. PMC4297521.
  8. Koh MY, Lemos R, Liu X, Powis G. The hypoxia associated factor (HAF) switches cells from HIF-1{alpha} to HIF-2{alpha} dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res 71(11):4015-27, 6/2011. e-Pub 4/2011. PMCID: PMC3268651.
  9. Koh MY, Spivak-Kroizman TR, Powis G. Inhibiting the hypoxia response for cancer therapy - the new kid on the block. Clin Cancer Res 15(19):5945-6, 10/2009. e-Pub 9/2009. PMCID: PMC2760048.
  10. Koh MY, Darnay BG, Powis G. Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation. Mol Cell Biol 28(23):7081-95. e-Pub 10/2008. PMCID: PMC2593390.
  11. Baker AF, Koh MY, Williams RR, James B, Wang H, Tate WR, Gallegos A, Von Hoff DD, Han H, Powis G. Identification of thioredoxin-interacting protein 1 as a hypoxia-inducible factor 1alpha-induced gene in pancreatic cancer. Pancreas 36(2):178-86, 3/2008.
  12. Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, Powis G. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol Cancer Ther 7(1):90-100, 1/2008.
  13. Welsh SJ, Koh MY, Powis G. The hypoxic inducible stress response as a target for cancer drug discovery. Semin Oncol 33(4):486-97, 8/2006.
  14. Griffiths GJ, Koh MY, Brunton VG, Cawthorne C, Reeves NA, Greaves M, Tilby MJ, Pearson DG, Ottley CJ, Workman P, Frame MC, Dive C. Expression of kinase-defective mutants of c-Src in human metastatic colon cancer cells decreases Bcl-xL and increases oxaliplatin- and Fas-induced apoptosis. J Biol Chem 279(44):46113-21, 10/2004. e-Pub 8/2004.

Invited Articles

  1. Koh MY, Powis G. Passing the baton: the HIF switch. Trends Biochem Sci. e-Pub 7/2012. PMCID: PMC3433036.
  2. Koh MY, Powis G. HAF: the new player in oxygen-independent HIF 1alpha degradation. Cell Cycle 8(9):1359-66, 5/2009. PMCID: PMC2700049.
  3. Koh MY, Spivak-Kroizman TR, Powis G. HIF-1 regulation: not so easy come, easy go. Trends Biochem Sci     33(11):526-34, 11/2008. e-Pub 9/2008

Book Chapters

  1. Koh MY, Spivak-Kroizman TR, Powis G. HIF-1alpha and Cancer Therapy. In: Recent Results Cancer Res. 180. Springer, 15-34, 2010
Last Updated: 8/9/24