Godlewski Lab

The focus of Godlewski research group is the development of novel non-coding RNA (ncRNA) – based therapeutic approaches for the treatment of the most common and most deadly brain tumor in adults – glioblastoma multiforme.

Dr. Godlewski earned his PhD degree in biology in 2002 from the University of Warsaw, Poland. He conducted his post-doctoral training in molecular cell biology at the Texas A&M University Health Science Center and cancer cell biology at The Ohio State University Medical Center (OSUMC). In 2010 he became a Research Assistant Professor in the Department of Neurosurgery at OSUMC and in 2012 he joined the Department of Neurosurgery as Assistant Professor of Neurosurgery at Brigham and Women’s Hospital/Harvard Medical School (BWH/HMS).


People:
Present:
Arun K Rooj
Yuji Takeda
Mohamed M Farhath
Magdalena Skubal

Former:
Khairul I Ansari
Daisuke Ogawa
Pierpaolo Peruzzi
Yan Wang

Positions available:
Postdoctoral Researcher

Contact:
Email: jgodlewski@partners.org
Phone: 617-525-5060

Research

NcRNAs as therapeutic agents: NcRNAs such as microRNAs are unique therapeutic agents as they have very broad spectrum of targets. Many known tumor suppressor microRNAs coordinately subdue multiple pro-oncogenic effectors in numerous signaling pathways that are aberrantly activated in cancer cells. Glioblastoma is a heterogeneous a disease involving alterations in multiple pathways, and thus requires intervention at many levels. This makes microRNAs promising candidates for novel therapeutic agents. Additionally many of these microRNAs are highly expressed in non-malignant brain and thus are not cytotoxic to normal cells; their small size and high resistance to nuclease degradation are also highly beneficial for the development of novel therapeutic avenues for the successful treatment of glioblastoma.

Projects

  1. Targeting glioblastoma stem-like cells (casus microRNA-128): As glioblastoma stem-like cells (GSCs) are thought to be cells-of-origin in gliomagenesis and are especially resistant to conventional therapy, they constitute a primary object of targeted therapies. To maintain their “stemness”, GSCs are cultured as neurospheres (pictured). GSCs are extremely tumorigenic and aggressive. The microRNA-128 that is abundantly expressed in normal brain is only weakly expressed in GSCs. Using a genetic mouse model of glioblastoma our group demonstrated that loss of miR-128 expression in an early event in the course of gliomagenesis. When re-introduced to GSCs microRNA-128 significantly inhibits their growth, improves survival of tumor-bearing mice, and sensitizes GSCs to irradiation. It acts through simultaneous targeting of two epigenetic regulator complexes, Polycomb Repressive Complexes 1 and 2, thereby preventing their partially redundant functions. The mechanism of action of microRNA-128 underlines the unique properties of ncRNA-based therapeutic agents.
  2. Targeting glioblastoma invasiveness and therapy resistance (casus microRNA-451): Two major obstacles in successful eradication of glioblastoma are invasiveness i.e. inherent capability of small sub-population of glioblastoma cells to invade surrounding brain tissue, which prevents successful resection; and resistance to conventional radio- and chemo- therapy. Combination of these two traits makes recurrence virtually inevitable. MicroRNA-451, whose expression is linked to microenvironmental stimuli, is capable, through suppression of multiple components of LKB1/AMPK signaling axis, of simultaneous inhibition of invasion (pictured) and sensitization to irradiation and chemotherapy.
  3. Exosome-mediated delivery of tumor-suppressor ncRNAs: Exosomes are nanometer-sized vesicles shed by many cells. They contain numerous classes of DNA, RNA, proteins and lipids. Exosomes can be taken up by neighboring or distant cells (pictured) allowing inter-cellular communication via release and uptake of bio-active molecules. Exosomes released by cancer cells often contain multiple pro-oncogenic molecules which however are largely absent in exosomes shed by neural stem cells (NSCs). Engineered NSCs that stably overexpress tumor-suppressor microRNAs release exosomes that are loaded with large quantities of such microRNAs. These cells, that are fast-growing and easy to maintain, are characterized by tumor-tropism, and are not tumorigenic themselves, thus when implanted into brains of tumor-bearing mice release copious amounts of tumor-suppressor microRNAs into their surroundings which result in significant impediment of tumor growth. Exosome-encapsulated microRNAs are stable at 37 degrees, protected from nuclease degradation and operating at physiologically relevant level are effective in the simultaneous suppression of multiple oncogenes.

Publications

http://www.ncbi.nlm.nih.gov/sites/myncbi/1RQzhzlk9u2A7/bibliography/48009449/public/?sort=date&direction=descending

Selected publications from the last 10 years:

1. The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches. Mineo M, Ricklefs F, Rooj AK, Lyons SM, Ivanov P, Ansari KI, Nakano I, Chiocca EA, Godlewski J, Bronisz A. Cell Reports. 2016; 15(11):2500-9.

2. The role of octamer binding transcription factors in glioblastoma multiforme. Rooj AK, Bronisz A, Godlewski J. Biochimica et Biophysica Acta. 2016; 1859(6):805-11.

3. Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity. Ricklefs F, Mineo M, Rooj AK, Nakano I, Charest A, Weissleder R, Breakefield XO, Chiocca EA, Godlewski J, Bronisz A. Cancer Research. 2016; 76(10):2876-81.

4. MicroRNA and extracellular vesicles in glioblastoma: small but powerful. Rooj AK, Mineo M, Godlewski J. Brain Tumor Pathology. 2016; 33(2):77-88.

5. Extracellular Vesicles and MicroRNAs: Their Role in Tumorigenicity and Therapy for Brain Tumors. Bronisz A, Godlewski J, Chiocca EA. Cellular and Molecular Neurobiology. 2016; 36(3):361-76.

6. Therapeutic potential of targeting microRNA-10b in established intracranial glioblastoma: first steps toward the clinic. Teplyuk NM, Uhlmann EJ, Gabriely G, Volfovsky N, Wang Y, Teng J, Karmali P, Marcusson E, Peter M, Mohan A, Kraytsberg Y, Cialic R, Chiocca EA, Godlewski J, Tannous B, Krichevsky AM. EMBO Molecular Medicine. 2016; 8(3):268-87.

7. Response to energy depletion: miR-451/AMPK loop. Bronisz A, Chiocca EA, Godlewski J. Oncotarget. 2015; 6(20):17851-2.

8. Glucose-based regulation of miR-451/AMPK signaling depends on the OCT1 transcription factor. Ansari KI, Ogawa D, Rooj AK, Lawler SE, Krichevsky AM, Johnson MD, Chiocca EA, Bronisz A, Godlewski J. Cell Reports. 2015; 11(6):902-9.

9. Belonging to a network--microRNAs, extracellular vesicles, and the glioblastoma microenvironment. Godlewski J, Krichevsky AM, Johnson MD, Chiocca EA, Bronisz A. Neuro-Oncology. 2015; 17(5):652-62.

10. Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Bronisz A, Wang Y, Nowicki MO, Peruzzi P, Ansari KI, Ogawa D, Balaj L, De Rienzo G, Mineo M, Nakano I, Ostrowski MC, Hochberg F, Weissleder R, Lawler SE, Chiocca EA, Godlewski J. Cancer Research. 2014; 74(3):738-50.

11. MicroRNA-128 coordinately targets Polycomb Repressor Complexes in glioma stem cells. Peruzzi P, Bronisz A, Nowicki MO, Wang Y, Ogawa D, Price R, Nakano I, Kwon CH, Hayes J, Lawler SE, Ostrowski MC, Chiocca EA, Godlewski J. Neuro-Oncology. 2013; 15(9):1212-24.

12. Oncogenic effects of miR-10b in glioblastoma stem cells. Guessous F, Alvarado-Velez M, Marcinkiewicz L, Zhang Y, Kim J, Heister S, Kefas B, Godlewski J, Schiff D, Purow B, Abounader R. Journal of Neuro-Oncology. 2013; 112(2):153-63.

13. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Bronisz A, Godlewski J, Wallace JA, Merchant AS, Nowicki MO, Mathsyaraja H, Srinivasan R, Trimboli AJ, Martin CK, Li F, Yu L, Fernandez SA, Pécot T, Rosol TJ, Cory S, Hallett M, Park M, Piper MG, Marsh CB, Yee LD, Jimenez RE, Nuovo G, Lawler SE, Chiocca EA, Leone G, Ostrowski MC. Nature Cell Biology. 2011; 14(2):159-67.

14. Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity. Guerau-de-Arellano M, Smith KM, Godlewski J, Liu Y, Winger R, Lawler SE, Whitacre CC, Racke MK, Lovett-Racke AE. Brain. 2011; 134(Pt 12):3578-89.

15. Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments. Williams SP, Nowicki MO, Liu F, Press R, Godlewski J, Abdel-Rasoul M, Kaur B, Fernandez SA, Chiocca EA, Lawler SE. Cancer Research. 2011; 71(16):5374-80.

16. MicroRNA-451: A conditional switch controlling glioma cell proliferation and migration. Godlewski J, Bronisz A, Nowicki MO, Chiocca EA, Lawler S. Cell Cycle. 2010; 9(14):2742-8.

17. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Godlewski J, Nowicki MO, Bronisz A, Nuovo G, Palatini J, De Lay M, Van Brocklyn J, Ostrowski MC, Chiocca EA, Lawler SE. Molecular Cell. 2010; 37(5):620-32.

18. MicroRNAs and glioblastoma; the stem cell connection. Godlewski J, Newton HB, Chiocca EA, Lawler SE. Cell Death and Differentiation. 2010; 17(2):221-8.

19. The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors. Kefas B, Comeau L, Floyd DH, Seleverstov O, Godlewski J, Schmittgen T, Jiang J, diPierro CG, Li Y, Chiocca EA, Lee J, Fine H, Abounader R, Lawler S, Purow B. The Journal of Neuroscience. 2009; 29(48):15161-8.

20. In situ detection of mature microRNAs by labeled extension on ultramer templates. Nuovo G, Lee EJ, Lawler S, Godlewski J, Schmittgen T. BioTechniques. 2009; 46(2):115-26.

21. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, Raychaudhury A, Newton HB, Chiocca EA, Lawler S. Cancer Research. 2008; 68(22):9125-30.

22. Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3. Nowicki MO, Dmitrieva N, Stein AM, Cutter JL, Godlewski J, Saeki Y, Nita M, Berens ME, Sander LM, Newton HB, Chiocca EA, Lawler S. Neuro-Oncology. 2008; 10(5):690-9.

23. MicroRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, Lee J, Fine H, Chiocca EA, Lawler S, Purow B. Cancer Research. 2008; 68(10):3566-72.

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