Lab interests: Exploiting the double-edged sword of hypoxia for therapeutic benefit
There are many, many sub-projects from the themes below that can be individually tailored for postdoctoral fellows, graduate student, rotating students and summer students. We are always looking for talented and motivated individuals who want to help us improve outcomes for patients with pancreatic cancer.
1. Protecting the intestinal tract from radiation injury.
This affords several therapeutic opportunities, all of which are being studied in ongoing projects: 1) Increase the dose to solid tumors of the abdomen when necessary (ex: Pancreatic Cancer). 2) Reduce acute and chronic GI toxicity from conventional treatments and 3) provide a medical countermeasure in the event of nuclear strike
The inhibition of the EGLN proteins promote regeneration after potential grave physiological insults, such as lethal radiation, strokes, cardiovascular ischemia and wounds. We are interested in understanding and exploiting how this EGLN/HIF pathway promotes tissue regeneration and use it to improve outcomes for our patients. We explore the cellular and molecular mechanisms of cytoprotection and regeneration regulated by the EGLN family of prolyl hydroxylases in normal tissues, using genetically engineered mouse models and patient-derived enteroids.
- Fujimoto,T.N.; Colbert, L.E.; Molkentine, J.M.; Baseler, L; Deorukhkar A, Kingsley, C.V.; Tailor, R.C.; Sawakuchi, G.O.; Taniguchi, C.M. Cancer Research ACCEPTED 2019 BioRxiv 195610 [Preprint]. Available from: https://doi.org/10.1101/195610
- Taniguchi CM, Diep, AN, Miao YR, Wu C, Rankin EB, Atwood TA, Xing L, Giaccia AJ. Prolyl Hydroxylase Inhibition Mitigates and Protects Against Radiation-Induced Gastrointestinal Toxicity Through a HIF2-Dependent Mechanism” Science Translation Medicine, 2014 May 12; 6(236):236ra64 (Received Cover).
- Molkentine, JM; Fujimoto, TN; Horvath, T; Grossberg, AJ; Deorukhkar, A; Samuel, ELG; Chan, WK; Lorenzi, PL; Dantzer, R; Tour, JM; Mason, KA; Taniguchi, CM. Sci Rep. 2019 Feb 13;9(1):1949. https://www.nature.com/articles/s41598-018-37147-9
- Colbert, LE; Rebueno, N; Moningi, S; Beddar, S; Sawakuchi GO; Herman JH; Koong AC; Das, P; Holliday EB; Koay EJ; Taniguchi, CM. Adv Radiat Oncol. 2018 Oct 23;3(4):693-700. doi: 10.1016/j.adro.2018.07.008. eCollection 2018 Oct-Dec.
- de la Cruz Bonilla M, Stemler KM, Taniguchi CM*, Piwnica-Worms, H*. Stem cell enriched-epithelial spheroid cultures for rapidly assaying small intestinal radioprotectors and radiosensitizers in vitro. Scientific Reports. 2018 Oct 18;8(1):15410. doi: 10.1038/s41598-018-33747-7 *Co-Corresponding authors
2. Leveraging the unique biology of the mitochondria for novel therapy.
Did you know that mitochondria are not static organelles that look like little beans, but actually are fused together over long networks? Check out this video from Dylan Burnette at Vanderbilt that illustrates our point. The nucleus is stained with DAPI (blue) and the yellow are mitochondria. This is time-lapse video using confocal microscopy shows just how dynamic the mitochondria in a cell are. (Video courtesy of Dylan Burnette at Vanderbilt University (@MAG2ART)).
In every normal cell and cancer cell, the mitochondria break apart by a process called mitochondrial fission and also come together to form vast networks in a process called mitochondrial fusion. We will show in our upcoming and ongoing work that mitochondrial fusion is a druggable pathway that can stop tumor growth, regardless of tumor genetics.
We also have other projects related to lipid metabolism and hypoxia that we have published previously as well.
- Preprint: Yu, M; Huang, Y; Deorukhkar, A; Fujimoto, TN; Govindaraju, S; Molkentine, JM; Lin, D; Kang, Y; Koay, EJ; Fleming, JB; Gupta, S; Maitra A; Taniguchi, CM. BioRxiv 279745 [Preprint]. Available from: https://doi.org/10.1101/279745
- Taniguchi CM, Finger EC, Krieg, AJ, Wu, C, Diep AN, LaGory EL, Wei K, McGinnis LC, Yuan J, Kuo CJ, Giaccia AJ. “Cross-talk between Hypoxia and Insulin Signaling via PHD3 Regulates Hepatic Glucose and Lipid Metabolism and Ameliorates Diabetes.” Nature Medicine, 2013 19(10): 1325-1330.
- Wei K*, Piecewicz S*, McGinnis LM*, Taniguchi CM, Wiegand S, Chan CW, Mulligan KX, Kuo D, Yuan J, Mortin L, Lefai E, Simon MC, Maher JJ, McGuinness OP, Thurston G, Giaccia AJ, Kuo CJ. A Liver HIF-2 alpha/IRS2 pathway sensitizes insulin signaling and is modulated by VEGF inhibition. Nature Medicine, 2013 19(10): 1331-1337.
Both articles were featured in Science Signaling and Selected by F1000
3. How can we reverse the negative effects of hypoxia in the tumor microenvironment?
A common feature of some of the most aggressive tumors is that they are hypoxic, with a tissue concentration of less than 1% oxygen. Most normal tissue have an oxygen tension somewhere between 5-8%. Tumor gets hypoxic by growing bigger than the diffusion capacity of the nearest capillary or vessel (thought to be about 180 microns). Tumors and other cells in the microenvironment use biologically programmed responses to hypoxia to support tumor growth. We are trying to dissect the relative roles of hypoxia signaling in tumor and the cells of the microenvironment, such as the fibroblasts, macrophages and lymphocytes.
We have tissue samples from patients and a dual recombinase mouse model that drives our science. We use cutting edge technology like single cell sequencing and metabolomics to find the answer to this important question.
- Published Review: Huang Y., Lin,D. & Taniguchi, C.M. Sci. China Life Sci. (2017). Hypoxia in the Tumor Microenvironment: Friend or Foe? Published online first: October 13, 2017. https://doi.org/10.1007/s11427-017-9178-y
- Bernard, VB; Semaan, A; Huang, J; San Lucas, FA; Mulu, FC; Stephens, BM; Guerrero, PA; Huang, Y; Zhao, J; Kamyabi, N; Sen, S; Scheet PA; Taniguchi, CM; Kim, MP; Tzeng, CW; Katz MH; Singhi, AD; Maitra, A; Alvarez, HA. Clin Cancer Res. 2018 Nov 1. doi: 10.1158/1078-0432.CCR-18-1955. [Epub ahead of print]
- Bernard V, Kim DU, San Lucas FA, Castillo J, Allenson K, Mulu FC, Stephens BM, Huang J, Semaan A, Guerrero PA, Kamyabi N, Zhao J, Hurd MW, Koay EJ, Taniguchi CM, Herman JM, Javle M, Wolff R, Katz M, Varadhachary G, Maitra A, Alvarez HA. Gastroenterology. 2019 Jan;156(1):108-118.e4. doi: 10.1053/j.gastro.2018.09.022. Epub 2018 Sep 19.