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Our research:

Cancer biology, Drug resistance, Tumor microenvironment

 

Overview of our goals

Drug resistance hampers the effectiveness of nearly all cancer targeting therapies. Tumors that initially respond to treatment, eventually become resistant to therapy, resulting relapse.

Our lab researches how cancer cells develop drug resistance, and more specifically, how the tumor microenvironment provides support and protection to tumor cells. Results from these studies will allow us to develop better strategies to overcome drug resistance by finding more effective therapies for the treatment of cancer.

Our previous research suggests that tumor microenvironment plays a critical role in protecting cancer cells from drug treatments, and part of our research is aimed at finding drug targets in the tumor microenvironment that could be either used to circumvent the development of drug resistance or prevent the protective signals from the microenvironment from reaching the tumor cells. As an alternative approach we are also identifying molecules within the tumor cells themselves that regulate the emergence of drug resistance, and developing ways to target these molecules.


 
 

Research

Our research is focused on understanding how the tumor microenvironment and the stroma influence drug resistance and cells' ability to survive stresses such as nutrient deprivation. 

 
 
Schematic representation of the PI3K/mTOR pathway under drug treatment conditions. 

Schematic representation of the PI3K/mTOR pathway under drug treatment conditions. 

Extracellular matrix driven drug resistance

PI3K/mTOR (Phosphatidylinositol-4,5-bisphosphate 3-kinase/mechanistic Target of Rapamycin) pathway is one of the most commonly mutated pathways in cancer. It is estimated that approximately ~70% of cancers have this pathway activated. Therefore it is a very attractive target for cancer therapy, and several small molecule inhibitors targeting this pathway are currently in clinical trials. However, these inhibitors have not performed as well as expected due to emergence of drug resistance. Our previous work (Muranen et al, Cancer Cell, 2012) identified a context specific emergence of drug resistance, where tumor cells which were adhered to extracellular matrix (stroma) survived drug treatments and developed resistance, whereas tumor cells without matrix attachment died. This indicated that matrix attachment provides critical survival cues for tumor cells and promotes emergence of drug resistance. Furthermore, our data showed that this drug resistance was a combination of FOXO-mediated transcription and specific internal ribosome entry site (IRES) mediated protein synthesis of pro-survival proteins, specifically in adhered cells. These data led us to investigate in more detail how adhesion to matrix regulates drug resistance and protein synthesis of pro-survival proteins under drug treatments. Currently we are studying what cellular pathways and proteins are important in drug resistance, and identifying molecules that could be targeted to overcome drug resistance. 


stromal contribution to survival under stress

Our data from the drug resistance studies with PI3K/mTOR inhibitors was reminiscent of similar response as seen in lower eukaryotes under caloric restriction. In flies and worms that are nutrient starved the animals survive through FOXO mediated transcription and IRES-mediated translation, just as we had seen in the tumor cells. This was not surprising given that PI3K/mTOR inhibition is known to mimic starvation, leading to reduced nutrient uptake and reduced proliferation. Our unpublished data suggest that in mice under caloric restriction we see that the stromal cells provide a matrix environment that provide crucial survival cues to the epithelial cells, and similar adaptive survival program is seen as in tumor cells treated with PI3K/mTOR inhibitors. We are currently interested in identifying similarities and differences between these two programs in tumor cells vs. normal cells to identify tumor specific vulnerabilities that could be used to target tumor cells specifically. 

3D spheroids undergoing drug treatment, dying cells are displayed in red, extracellular matrix in green, and living cells in blue. Image courtesy of Rachel Davidowitz (racheldavidowitz.com)

3D spheroids undergoing drug treatment, dying cells are displayed in red, extracellular matrix in green, and living cells in blue.

Image courtesy of Rachel Davidowitz (racheldavidowitz.com)


3D cancer spheroids in culture

3D cancer spheroids in culture

three dimensional models of cancer progression and biology

To investigate these topics we utilize both normal and cancer cells in three-dimensional cell culture systems, which mimic the architecture and organization of living tissues much more accurately than traditional two-dimensional tissue culture systems. We use this platform to in co-culture systems to understand how stromal and epithelial cells communicate with each other, and have also adopted the use of this 3D platform to do proteomics and metabolomics studies as well as to study protein translation by ribosome foot-printing to gain insight into multiple pathways and mechanisms the cells use when developing drug resistance.

 

People

We are constantly looking for new and enthusiastic people to join our team!

 
 

Taru muranen, Ph.D.

Principal Investigator

Assistant Professor of Medicine at Harvard Medical School

Email: tmuranen@bidmc.harvard.edu

Phone:617-735-2037

Instructor, Harvard Medical School, 2008-2016

Ph.D, University of Helsinki, 2004-2008

Address:

Beth Israel Deaconess Medical Center and Cancer Center at BIDMC,

Center for Life Sciences, 3 Blackfan Circle,

Boston 02115, MA

Taru grew up in a small town in eastern Finland, and did her Ph.D in the University of Helsinki studying the Neurofibromatosis 2 tumor suppressor. She moved to Boston in 2008 to start her post-doctoral training in the laboratory of Joan Brugge, and started her lab at Beth Israel in 2016. She loves seeing new places, trying new things, cooking, snorkeling and scuba diving.

 


Byanjana thapa

Research Assistant/Lab Manager

Email: bthapa@bidmc.harvard.edu

Former education: Fairleigh Dickinson University, M.Sc. 2016

Lab Phone: 617-735-2607

Byanjana is originally from Kathmandu, Nepal, but has lived in many countries around the world, and therefore is a "third-culture kid". When she isn't working in the lab, she is reading or writing science-fiction/dystopian literature with a cup of tea. She speaks four and a half languages and loves camping, theatre and travel. 

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Caroline ritchie

Research Assistant

Email: TBD

Former education: Tufts University, B.Sc. 2016

Lab phone: 617-735-2607

Caroline grew up in the San Francisco Bay Area and moved to Boston to attend Tufts University, where she majored in Biomedical Engineering. She is interested in women's health and reproductive rights and hopes to attend medical school in the future. In her spare time, she enjoys cooking new recipes and exploring Boston. 


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THis could be you!!!

Come join our team!

We are looking for enthusiastic post-doctoral fellows to join our team to explore the cancer microenvironment and develop novel therapies for cancer.

 

Contact: tmuranen@bidmc.harvard.edu

 

PUBLICATIONS

 

1. Taru Muranen, Marcin P. Iwanicki, Natasha L. Curry, Julie Hwang, Cory D. DuBois, Jonathan L. Coloff, Daniel S. Hitchcock, Clary B. Clash, Joan S. Brugge and Nada Y. Kalaany. Starved Epithelial Cells Uptake Extracellular Matrix for Survival. (2017). Nature Communications. Jan 10. http://rdcu.be/oqQ6

2. Taru Muranen, Laura M. Selfors, Julie Hwang, Lisa L. Gallegos, Jonathan L. Coloff, Carson C. Thoreen, Seong A. Kang, David M. Sabatini, Gordon B. Mills and Joan S. Brugge. ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition Via Regulation of MYC and YAP. (2016). Cancer Research. Dec 15;76(24):7168-7180. 

3. Marcin P. Iwanicki, Hsing-Yu Chen, Claudia Iavarone, Ioannis K. Zervantonakis, Taru Muranen,  Marián Noval, Tan A. Ince, Ronny Drapkin and Joan S. Brugge. (2016) Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition. Journal of Clinical Investigation Insights. 2016 Jul 7;1(10).

4. Muranen T, Meric-Bernstam F, Mills GB. Promising rationally derived combination therapy with PI3K and CDK4/6 inhibitors. (2014). Preview. Cancer Cell. 21(2):227-239.

5. Elkabets M*, Vora S*, Juric D, Morse N, Mino-Kenudson M, Muranen T, Tao J, Campos A.B, Rodon J, Ibrahim Y.H, Serra V, Rodrik-Outmezguine V, Hazra S, Singh S, Kim P, Quadt C, Liu M, Huang A, Rosen N, Engelman J.A, Scaltriti M, Baselga J. (2013) mTORC1 Inhibition Is Required for Sensitivity to PI3K p110α Inhibitors in PIK3CA- Mutant Breast Cancer. Sci. Transl. Med. 5, 196ra99. * equal contribution.

6. Muranen T. Cell-cell and cell-matrix interaction. (2013). Mol Biol Cell. Mar;24(6):671.  

7. Laulajainen M, Melikova M, Muranen T, Carpén O and Grönholm M. (2012)Distinct overlapping sequences at the carboxy-terminus of merlin regulate its tumour suppressor and morphogenic activity.J Cell Mol Med. 16:2165-75. 

8. Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC, Gao S, Mills GB and Brugge JS. (2012).Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell. 21:227-39.

9. Iwanicki M.P, Davidowitz R.A, Ng M.R, Besser A, Muranen T, Merritt M, Danuser G, Ince T, and Brugge J.S. (2011).Ovarian cancer spheroids use myosin-generated force to clear the mesothelium. Cancer Discovery. 1:144-157. 

10. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG. (2011) Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genetics. 43(9):869-74. 

11. Laulajainen M, Muranen T, Nyman TA, Carpén O and Grönholm M. (2011)Multistep phosphorylation by oncogenic kinases enhances the degradation of the NF2 tumor suppressor merlin.Neoplasia. 7:643-52. 

12. Laulajainen M*, Muranen T*, Carpén O and Grönholm M. (2008) Protein kinase A mediated phosphorylation of the NF2 tumor suppressor protein merlin at serine 10 affects actin cytoskeleton. Oncogene. 27(23):3233-43. *equal contribution.

13. Muranen T, Grönholm M, Lampin A, Lallemand D, Zhao F, Giovannini M and Carpén O. (2007).The tumor suppressor merlin interacts with microtubules in a regulated manner and modulates the microtubule cytoskeleton of primary mouse Schwann cells. Hum Mol Genet. 16:1742-1751.

14. Grönholm M*, Muranen T*, Toby GG, Utermark T, Hanemann CO, Golemis EA, and Carpén O. (2006).A functional association between merlin and HEI10, a cell cycle regulator. Oncogene. 25:4389-98. *equal contribution.

15. Muranen T*, Grönholm M*, Renkema HG, and Carpén O. (2005).Cell cycle-dependent nucleocytoplasmic shuttling of the neurofibromatosis 2 tumour suppressor merlin.Oncogene. 24:1150-58. *equal contribution.

 

 

 

 

 
 

News/Events: More coming soon! 

 

Lab opening, moving in, and the holiday mission to Burma!

 
Center For Life Sciences, Cancer center at Beth Israel Deaconess Medical center, 3 Blackfan Circle, Boston, MA. 

Center For Life Sciences, Cancer center at Beth Israel Deaconess Medical center, 3 Blackfan Circle, Boston, MA. 

 
 

Contact us at:

We are located at the Cancer Center at Beth Israel Deaconess Medical Center at the Harvard Medical School campus in Boston Massachusetts. 

Mail: Muranen Lab, 3 Blackfan Circle, CLS0406, Boston 02115, MA

Email: tmuranen@bidmc.harvard.edu

Phone:617-735-2037