nutritional microenvironment in tumor development and drug response, metabolism and epigenetics, protein phosphatase regulation in diabetes and obesity
• Research Scholar Award, American Cancer Society
• Pew Scholar, Pew Foundation
• Innovative Research Grant Award, Stand Up to Cancer
• V Scholar, V Foundation for Cancer Research
• Sidney Kimmel Scholar, Sidney Kimmel Foundation for Cancer Research
• Research Career Development Award, Stop Cancer Foundation
• Special Fellow, the Leukemia and Lymphoma Society
• Postdoctoral Fellowship in Cancer Research, AACR
1. Nutritional microenvironment in tumor development and drug response.
Tumor cells often display fundamental changes in metabolism and increase their uptake of nutrients to meet the increased bioenergetic demands of proliferation. During tumor growth, increased uptake and rapid accumulation of cells can exceed the supply of the essential nutrients, such as glucose and glutamine. Similar to hypoxic conditions, we found glutamine is deprived in many solid tumors in contrast to the abundance of glutamine in plasma. Our lab explores the mechanisms describing how nutritional microenvironment affects tumor development and drug response. We study this question from various aspects, including signal transduction pathways, epigenetic modifications, and metabolic alterations.
2. Regulation of protein phosphatase 2A complexes in metabolic diseases.
Reversible protein phosphorylation is the major regulatory mechanism used by cells to respond to environmental and nutritional stress. Aberrant regulation of this activity leads to dysregulated cellular behavior and disease phenotypes, including many forms of cancer, diabetes and obesity. Although we know much about how protein kinases function in specific signaling governed by phosphorylation, whether protein phosphatases are also regulated and actively function in the processes that counteract kinases in disease related signaling pathways has not been established. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that plays a role in regulating many signaling pathways. Unlike kinases, serine/threonine phosphatases are promiscuously active, and their specificity is governed largely by associated proteins. Our laboratory is interested in characterizing specific PP2A complexes in nutritional signaling related to cancer, diabetes, and obesity.
Hanse EA, Pan M, Liu W, Yang Y, Ishak Gabra MB, Tran TQ, Lowman XH, Ruiz B, Wang QA, Kong M. The B56a subunit of PP2A is necessary for mesenchymal stem cell commitment to adipocyte. EMBO Rep. 2021 Jul 7:e51910. doi: 10.15252/embr.202051910. PMID: 34232566
Ishak Gabra MB, Yang Y, Li H, Senapati P, Hanse EA, Lowman XH, Tran TQ, Zhang L, Doan LT, Xu X, Schones DE, Fruman DA, Kong M. Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth. Nat Commun. 2020 Jul 3; 11(1):3326. doi: 10.1038/s41467-020-17181-w. PMID: 32620791
Tran TQ, Hanse EA, Habowski AN, Li H, Ishak Gabra MB, Yang Y, Lowman XH, Ooi AM, Liao SY, Edwards RA, Waterman ML, Kong M. a-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer. Nature Cancer. 2020 1(3):345-58. doi: 10.1038/s43018-020-0035-5. PMID: 32832918
Davis RT, Blake K, Ma D, Ishak Gabra MB, Hernandez GA, Phung AT, Yang Y, Maurer D, Lefebvre A, Alshetaiwi H, Xiao Z, Liu J, Locasale JW, Digman MA, Mjolsness E, Kong M, Werb Z and Lawson DA. Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing. Nat Cell Biol. 2020 Mar;22(3):310-320. doi: 10.1038/s41556-020-0477-0. Epub 2020 Mar 6. PMID: 32144411
Lowman XH, Hanse EA, Yang Y, Ishak Gabra MB, Tran TQ, Li H, Kong M. p53 Promotes Cancer Cell Adaptation to Glutamine Deprivation by Upregulating Slc7a3 to Increase Arginine Uptake. Cell Rep. 2019 Mar 12; 26(11):3051-3060.e4. PMID: 30865893.
Yang Y, Ishak Gabra MB, Hanse EA, Lowman XH, Tran TQ, Li H, Milman N, Liu J, Reid MA, Locasale JW, Gil Z, Kong M. MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1. Nat Commun. 2019 Feb 18;10(1):809.
Bian C, Zhang C, Luo T, Vyas A, Chen SH, Liu C, Kassab MA, Yang Y, Kong M, Yu X. NADP+ is an endogenous PARP inhibitor in DNA damage response and tumor suppression. Nat Commun. 2019 Feb 11;10(1):693
Ishak Gabra MB, Yang Y, Lowman XH, Reid MA, Tran TQ, Kong M. IKKß activates p53 to promote cancer cell adaptation to glutamine deprivation. Oncogenesis. 2018 Nov 26;7(11):93.
Tran TQ, Ishak Gabra MB, Lowman XH, Yang Y, Reid MA, Pan M, O'Connor TR, Kong M. (2017). Glutamine deficiency induced DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes. PLoS Biol. Nov 6;15(11):e2002810. doi: 10.1371/journal.pbio.2002810. 2017 Nov. PMID: 29107960
Pan M., Reid M.A., Lowman X.H., Kulkarni R.P., Tran T.Q., Liu X., Yang Y., Hernandez-Davies J.E., Rosales K.K., Li H., Hugo W., Song C., Xu X., Schones D.E., Ann D.K., Gradinaru V., Lo R.S., Locasale J.W., Kong M. (2016). Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol. Oct;18(10):1090-101. PMID: 276179322.
Reid M.A., Lowman X.H., Pan M., Tran T.Q., Warmoes M.O., Ishak Gabra M.B., Yang Y., Locasale J.W., Kong M. (2016). IKKß promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3. Genes & Development. Aug 15;30(16):1837-51. PMID: 27585591; PMCID: PMC5024682
Tran T.Q., Lowman X.H., Reid M.A., Mendez-Dorantes C., Pan M., Yang Y., Kong M. (2016). Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction. Oncogene. Oct 10. PMID: 27721412
Rosales K.R., Reid M.A., Yang Y., Tran T.Q., Wang W.I., Lowman X., Pan M. and Kong M. (2015). TIPRL inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response. PLoS One. 2015 Dec 30.
Fong M.Y., Zhou W., Liu L., Alontaga A.Y., Chandra M., Ashby J., Chow A., O'Connor S.T., Li S., Chin A.R., Somlo G., Palomares M., Li Z., Tremblay J.R., Tsuyada A., Sun G., Reid M.A., Wu X., Swiderski P., Ren X., Shi Y., Kong M., Zhong W., Chen Y., Wang S.E. (2015). Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nature Cell Biology. Jan 26. doi: 10.1038/ncb3094.
Hernandez-Davies JE, Tran TQ, Reid MA, Rosales KR, Lowman XH, Pan M, Moriceau G, Yang Y, Wu J, Lo RS, Kong M. (2015). Vemurafenib resistance reprograms melanoma cells towards glutamine dependence. J Transl Med. Jul 3;13(1):210. doi: 10.1186/s12967-015-0581-2. PMID: 26139106
Reid M.A., Wang W.I., Rosales K.R., Welliver M.X., Pan M., and Kong M. (2013). The B55? subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Molecular Cell. 50(2):200-211.
Jiang L., Stanevich V., Satyshur K.A., Kong M., Watkins G.R., Wadzinski B.E., Sengupta R., and Xing Y. (2013). Structural basis of protein phosphatase 2A stable latency. Nat Commun. Apr 16;4:1699. doi: 10.1038/ncomms2663
Lin T.C., Chen Y.R., Kensicki E., Li A.Y., Kong M., Li Y., Mohney R.P., Shen H.M., Stiles B., Mizushima N., Lin L.I., & Ann D.K. (2012). Autophagy: Resetting glutamine-dependent metabolism and oxygen consumption. Autophagy. 8(10): 1477-1493
Gruber J., Yong J., Zatechka D.S., Sabin L., Zhang Z., Lum J.J., Kong M., Zong W.X., Lau C.K., Cherry S., Ihle J., Dreyfuss G., and Thompson C.B. (2009). Ars2 links the nuclear cap binding complex to RNA interference and cell proliferation. Cell 138:328-39
Kong M., Ditsworth D., Lindsten T., and Thompson C.B. (2009). ?4 is an essential regulator of PP2A phosphatase activity. Molecular Cell. 36:51-60
Kong M., Bui .TV., Ditsworth D., Gruber J.J., Goncharov D., Krymskaya V.P., Lindsten T., and Thompson C.B. (2007). The PP2A-associated protein alpha4 plays a critical role in the regulation of cell spreading and migration. J. Biol. Chem. 282, 29712-20
Lum J.J., Bauer D.E., Kong M., Harris M.H., Li C., Lindsten T., Thompson C.B. (2005). Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237-48
Kong M., Fox C.J., Mu J., Solt L., Xu A., Cinalli R.M., Birnbaum M.J., Lindsten T., Thompson C.B. (2004). The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science 306, 695-8
Cellular and Molecular Biosciences