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Our research:

Cancer biology, Drug resistance, Tumor microenvironment

 
 
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Overview of our goals

Drug resistance hampers the effectiveness of nearly all cancer 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, making them more drug resistant. These studies will allow us to develop better strategies to overcome drug resistance by identifying more effective therapies for the treatment of cancer.

Our previous research suggest that the 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 studying 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 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. These data led us to investigate in more detail how adhesion to matrix proteins and the matrix microenvironment regulates 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 similar mechanisms 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 recently published data show that under starvation the stromal cells provide matrix proteins that the epithelial cells 'eat'. These matrix proteins provide nutrient source and crucial survival cues to the starved epithelial cells allowing them to survive brief periods of starvation. Recently we have observed similar matrix dependent adaptive survival programs in tumor cells treated with PI3K/mTOR inhibitors as well as with chemotherapy agents, such as Gemcitabine. We are currently studying the programs tumor cells use to avoid cell death when treated with targeted therapies or chemotherapies. Our current research efforts are focused on identifying therapeutic vulnerabilities in metastatic hormone receptor positive breast cancer and therapy resistant pancreatic cancer. 

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 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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Jenny Högström-stakem

Post-doctoral fellow

Email: TBD

Former education: University of Helsinki, Ph.D. 2018

Lab phone: 617-735-2607

Jenny recently joined the lab to study drug resistance mechanism is breast cancer.  


 
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Nina kozlova

Post-doctoral fellow. 

Email: nkozlova@bidmc.harvard.edu

Former education: University of Oulu, Ph.D. 2017

Nina joined the lab in the summer of 2017 and she is investigating stroke driven drug resistance in pancreatic cancer.

 

 

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pradeep mangalath

Bioinformatician in-training, volunteer. 

Email: pradeep.mangalath@gmail.com

Former Education: MBA, University of North Carolina at Chapel Hill (2010)

Pradeep grew up in Bangalore, India, where he studied and trained as an electronics engineer.  He moved to Boston in 2010, to work with Deloitte Consulting.  In an attempt to turn a new page in his career, he is now channeling his love for data to study cancer and hopes to contribute to advances in cancer care.  Besides data, he enjoys going on long runs and roasting coffee.

 

 

 
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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

 

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Lab alumni

Caroline Ritchie, B.Sc.: Lab technician 2/2017-9/2018

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, holiday mission to Burma, pancreatic cancer awareness day, and the trip to Nantucket!

December 2018: End of 2018 outing was enjoyed with plenty of bubbly and some very nice sushi. Pictures to follow…

December 2018: Exciting news for Jenny and Nina: New fellowships!!! Both Jenny and Nina got great news as they were awarded post-doctoral fellowships at the end of 2018!!! Great work ladies!!!

September 2018: We said goodbye to Caroline, and she duly dominated the going-away party bowling tournament…

April 2018: The lab was thrilled and honored to receive the Susan G. Komen Career Catalyst award to study drug resistance mechanisms in ER+ breast cancer.

 
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

Twitter: @tarumurmur

Phone:617-735-2037