Our laboratory research has focused in the field of cancer cell signaling with specific emphasis on understanding the role of post-translational protein modifications (PTMs) during oncogenesis. Our laboratory is primarily involved in identifying ubiquitination machineries that maintain various oncoprotein stabilities including epidermal growth factor receptor (EGFR), mutant KRAS and mutant TP53, where we are studying PTMs importance in the progression of various upper aerodigestive cancers. We employ such knowledge to develop novel therapeutic strategies.
We also focus on understanding and identifying molecular and/or cellular mechanisms responsible for the development of radiation-induced lung toxicities (RILT). We utilize such mechanistic information to develop lung radioprotectors. Being a part of the Cancer Biology (CB) core group at the University of Michigan Rogel Cancer Center, our lab has expertise in the field of protein degradation. In collaboration with other Rogel Cancer Center members we are unraveling the complex process of oncogenesis.
We are also a part of the Program of Biological Sciences (PIBS), Dr. Ray is an Adjunct faculty in the Department of Nuclear Engineering and Radiological Sciences (NERS) and also Director of the Cancer Research Summer Internship Program (CaRISP) for undergraduates.
RNF128 Regulation of TP53 in Barrett’s Progression
This project is in collaboration with David G Beer, PhD, Co-Director, Cancer Genetics (CG) program, UMCCC. In this project we are deciphering the role of a RING type ubiquitin ligase (E3) in the maintenance of mutant TP53 protein stability, a key molecular interaction that promotes Barrett’s progression to esophageal adenocarcinoma (EAC). In this project we are utilizing various genetic, cell biology and biochemical studies to understand unique function of RNF128 in the regulation of mutant TP53 stability, the most critical oncogenic driver involved in EAC. Recently we have obtained a R01 funding from NCI to study this interesting linkage in clinical samples.
Lung radioprotection by inhibition of TNF-α signaling
The efficacy of radiation therapy for upper thoracic cancers is limited by radiation-induced lung toxicity (RILT). Amifostine, a radical scavenger, is the only FDA-approved radioprotector, however, does not protect the lung and has substantial toxicity. Thus, there is an absolute need to develop a lung radioprotector and to improve our understanding on the molecular regulators involved in RILT. Among different mediators, release of inflammatory cytokines has been well documented. Among them, early release of tumor necrosis factor-alpha (TNFa) is reported to play a critical role in the initiation of inflammatory responses. In the past we have performed studies with various genetically modified mouse models (GEMMs) that establish the therapeutic potency of anti-TNFa agents as a possible lung radioprotectors. A collaborative study is underway establishing the role of Tristetraprolin (TTP)-TNFa axis in radiation pneumonitis.
Targeting ubiquitination machinery to destabilize EGFR and mutant KRAS stability.
Accumulation of oncogene-specific activating mutation undoubtedly plays a key role not only in cancer initiation and progression, but in many occasions further promote drug resistance. Mutation, which alters the primary amino acid sequence in an oncogene, changes its function and protein-protein interaction abilities mediated via altered protein folding and stability. In our laboratory we focus on studying the activating mutations of two critical oncogenes: epidermal growth factor receptor (EGFR) and mutant KRAS. Recently, we have obtained data that a HECT type ubiquitin ligase (E3), SMad Ubiquitination Regulatory Factor 2 (SMURF2) enhances protein stability of EGFR and mutant KRAS. In contrast, loss or catalytic inactivation of SMURF2 causes rapid oncoprotein degradation to kill such oncogene-addicted cancer cells. Our long-term objective is to develop a novel therapeutic strategy to degrade EGFR/mutant KRAS proteins to enhance tumor specific chemo- and radio-sensitization via SMURF2 targeting. Our approach has two novel aspects: (a) Basic aspect: that deals with improving our current molecular understanding how SMURF2 cooperates with EGFR/mutant KRAS to promote oncogenesis. Towards that we are employing a genetic approaches using conditional knockout and transgenic mouse models to establish the role of SMURF2-EGFR-KRAS signaling axis in lung and pancreatic cancer; and (b) Translational aspect: where we are exploring the therapeutic potential of novel small molecules to degrade EGFR/mutant KRAS proteins via disruption of specific protein-protein interactions.
Defining a novel biological role for CYP24A1 in promoting cell growth in cancer.
This is a collaborative project with Drs. Nithya Ramnath (a medical oncologist at the UMCCC) and Al Rehemtulla (Associate Director, UMCCC). CYP24A1, an inner mitochondrial protein belongs to the cytochrome p450 family of phase II metabolizing enzymes and is the rate limiting catabolic enzyme for Vitamin D3. Our published and preliminary data however, demonstrate that increased CYP24A1 behaves as a proto-oncogene and increases cancer cell proliferation and invasion. The goal of this project is to identify molecular regulators (particularly the ubiquitin ligases) that may be interacting with CYP24A1, which may be critical in promoting cell growth. This will provide novel thoughts pertaining to the cytochrome P450 biology and its importance in lung cancer to improve patients’ survival.
NIH R01-CA215596-01: RNF128 Regulation of TP53 in Barrett's Progression. 2017-2022. Principal Investigators: David Beer and Dipankar Ray
- Ray P, Nancarrow DJ, Ferrer-Torres D, Wang Z, San Martinho M, Hinton T, Wu JH, Wu A, Turgeon DK, Hammer MA, Dame MK, Lawrence TS, O'Brien PJ, Spence JR, Beer DG, Ray D. UBCH5 Family Members Differentially Impact Stabilization of Mutant p53 via RNF128 Iso1 During Barrett's Progression to Esophageal Adenocarcinoma. Cell Mol Gastroenterol Hepatol. 2021 Aug 17;13(1):129-149. doi: 10.1016/j.jcmgh.2021.08.003. [Epub ahead of print] PubMed PMID: 34416429; PubMed Central PMCID: PMC8593620
- Lagisetty KH, McEwen DP, Nancarrow DJ, Schiebel JG, Ferrer-Torres D, Ray D, Frankel TL, Lin J, Chang AC, Kresty LA, Beer DG. Immune determinants of Barrett's progression to esophageal adenocarcinoma. JCI Insight. 2021 Jan 11;6(1). doi: 10.1172/jci.insight.143888. PubMed PMID: 33290281; PubMed Central PMCID: PMC7821593.
- Cousins MM, Morris E, Maurino C, Devasia TP, Karnak D, Ray D, Parikh ND, Owen D, Ten Haken RK, Schipper MJ, Lawrence TS, Cuneo KC. TNFR1 and the TNFα axis as a targetable mediator of liver injury from stereotactic body radiation therapy. Transl Oncol. 2021 Jan;14(1):100950. doi: 10.1016/j.tranon.2020.100950. Epub 2020 Dec 13. PubMed PMID: 33395747; PubMed Central PMCID: PMC7744766.
- Martinho MS, Nancarrow DJ, Lawrence TS, Beer DG, Ray D. Chaperones and Ubiquitin Ligases Balance Mutant p53 Protein Stability in Esophageal and Other Digestive Cancers. Cell Mol Gastroenterol Hepatol. 2021;11(2):449-464. doi: 10.1016/j.jcmgh.2020.10.012. Epub 2020 Oct 31. Review. PubMed PMID: 33130332; PubMed Central PMCID: PMC7788241.
- Ray P, Raghunathan K, Ahsan A, Allam US, Shukla S, Basrur V, Veatch S, Lawrence TS, Nyati MK, Ray D. Ubiquitin ligase SMURF2 enhances epidermal growth factor receptor stability and tyrosine-kinase inhibitor resistance. J Biol Chem. 2020 Sep 4;295(36):12661-12673. doi: 10.1074/jbc.RA120.013519. Epub 2020 Jul 15. PubMed PMID: 32669362; PubMed Central PMCID: PMC7476725.
- Huang W, Ray P, Ji W, Wang Z, Nancarrow D, Chen G, Galbán S, Lawrence TS, Beer DG, Rehemtulla A, Ramnath N, Ray D. The cytochrome P450 enzyme CYP24A1 increases proliferation of mutant KRAS-dependent lung adenocarcinoma independent of its catalytic activity. J Biol Chem. 2020 May 1;295(18):5906-5917. doi: 10.1074/jbc.RA119.011869. Epub 2020 Mar 12. PubMed PMID: 32165494; PubMed Central PMCID: PMC7196648.
- Nyati S, Gregg BS, Xu J, Young G, Kimmel L, Nyati MK, Ray D, Speers C, Rehemtulla A. TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling. Neoplasia. 2020 Apr;22(4):163-178. doi: 10.1016/j.neo.2020.02.001. Epub 2020 Mar 3. PubMed PMID: 32143140; PubMed Central PMCID: PMC7057164.
- Ray D, Ray P, Ferrer-Torres D, Wang Z, Nancarrow D, Yoon HW, San Martinho M, Hinton T, Owens S, Thomas D, Jiang H, Lawrence TS, Lin J, Lagisetty K, Chang AC, Beer DG. Isoforms of RNF128 Regulate the Stability of Mutant P53 in Barrett's Esophageal Cells. Gastroenterology. 2020 Feb;158(3):583-597.e1. doi: 10.1053/j.gastro.2019.10.040. Epub 2019 Nov 9. PubMed PMID: 31715145; PubMed Central PMCID: PMC7429981.
- Ferrer-Torres D, Nancarrow DJ, Steinberg H, Wang Z, Kuick R, Weh KM, Mills RE, Ray D, Ray P, Lin J, Chang AC, Reddy RM, Orringer MB, Canto MI, Shaheen NJ, Kresty LA, Chak A, Wang TD, Rubenstein JH, Beer DG. Constitutively Higher Level of GSTT2 in Esophageal Tissues From African Americans Protects Cells Against DNA Damage. Gastroenterology. 2019 Apr;156(5):1404-1415. doi: 10.1053/j.gastro.2018.12.004. Epub 2018 Dec 19. PubMed PMID: 30578782; PubMed Central PMCID: PMC6441633.
- Luo Y, McShan D, Ray D, Matuszak M, Jolly S, Lawrence T, Ming Kong F, Ten Haken R, El Naqa I. Development of a Fully Cross-Validated Bayesian Network Approach for Local Control Prediction in Lung Cancer. IEEE Trans Radiat Plasma Med Sci. 2019 Mar;3(2):232-241. doi: 10.1109/TRPMS.2018.2832609. Epub 2018 May 2. PubMed PMID: 30854500; PubMed Central PMCID: PMC6404542.
Please contact Dipankar Ray, PhD if you are interested in working with his lab.