What is the M2CH?
Goal is to improve management of triple negative breast cancer
Our overall goal at the M2CH Center for Cancer Systems Biology is to improve management of triple negative breast cancer by preventing cancer cells from developing resistance to chemotherapy. We are looking at how both intrinsic and extrinsic factors shape the ability of cancer cells to become resistant to cancer drugs. Intrinsic factors include DNA modifications, or epigenetic features of cancer cells. Extrinsic factors include molecular signals in the immediate environment, or microenvironment of cancer cells.
A cancer system biology approach to breast cancer
We learn how intrinsic and extrinsic factors influence differentiation state, proliferation and therapeutic response in triple negative breast cancer through experimental manipulation and computational modeling of cancer cell lines, 3D-engineered multicellular systems, xenografts and clinical specimens. We deploy single cell omic and imaging technologies that allow quantitative assessment of molecular, cellular, and structural heterogeneity. We interpret these data using computational models that define control networks and structures in heterogeneous systems as well as transitions between states of therapeutic resistance and sensitivity.
This is accomplished in three related projects:
- Project 1 focuses on measuring and managing resistance-associated heterogeneity intrinsic to cancer cells.
- Project 2 focuses on identifying resistance-associated signals from the microenvironment and on mitigating effects from these signals on therapeutic response.
- Project 3 applies spatial systems biology approaches to triple negative breast cancer specimens and multicell type models thereof to discover molecular control networks that influence how cell intrinsic plasticity and microenvironment signaling alter therapeutic responses in complex tissues. All Projects analyze core cell lines, patient derived cultures, and FDA approved, pathway-targeted drugs (afatinib, ruxolotinib, trametinib, BYL719, cabozantinib, and everolimus).
Learn more about M2CH and each of its three projects at the Cancer Systems Biology Consortium site.
Please direct any inquiries regarding the Measuring, Modeling and Controlling Heterogeneity (M2CH) Center to Heidi Feiler, Scientific Program Manager, firstname.lastname@example.org.
- Risom T, Langer EM, Chapman MP, Rantala J, Fields AJ, Boniface C, Alvarez MJ, Kendsersky ND, Pelz CR, Johnson-Camacho K, Dobrolecki LE, Chin K, Aswani AJ, Wang NJ, Califano A, Lewis MT, Tomlin CJ, Spellman PT, Adey A, Gray JW, Sears RC., 2019. Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer. Nat Commun. 2018 Sep 19;9(1):3815. doi: 10.1038/s41467-018-05729-w. PMID:30232459
- Langer, E.M., Allen-Petersen, B.L., King, S.M., Kendsersky, N.D., Turnidge, M.A., Kuziel, G.M., Riggers, R., Samatham, R., Amery, T.S., Jacques, S.L., Sheppard, B.C., Korkola, J.E., Muschler, J.L., Thibault, G., Chang, Y.H., Gray, J.W., Presnell S.C., Nguyen, D.G., Sears, R.C., 2019. Modeling Tumor Phenotypes In Vitro with Three-Dimensional Bioprinting. Cell reports, 26(3), pp.608-623. PMID: 30650355
- Takahiro Tsujikawa, Guillaume Thibault, Vahid Azimi, Sam Sivagnanam, Grace Banik, Casey Means, Rie Kawashima, Daniel R. Clayburgh, Joe W. Gray, Lisa M. Coussens, Young Hwan Chang, Robust cell detection and segmentation for image cytometry reveal Th17 cell heterogeneity, Cytometry: Part A, PIMD: 30714674
- Luoh, S.W., W. Wagoner, X. Wang, Z. Hu, X. Lai, K. Chin, R. Sears, E. Ramsey. GRB7 dependent proliferation of basal-like, HER-2 positive human breast cancer cell lines is mediated in part by HER-1 signaling. Molecular Carcinogenesis, 2019 Jan 3. doi: 10.1002/mc.22963. [Epub ahead of print] PMID: 30604896.
- Allen-Petersen, B., T. Risom, Z. Feng, Z. Wang, Z. P. Jenny, M. C. Thoma, K. R. Pelz, J. P. Morton, O. J. Sansom, C. D. Lopez, B. C. Sheppard, D. J. Christensen, M. Ohlmeyer, G. Narla, and R. C. Sears*. Activation of PP2A and inhibition of mTOR synergistically reduce MYC signaling and decrease tumor growth in pancreatic ductal adenocarcinoma. Cancer Res. 2018 Nov 2. pii: canres.0717.2018. doi: 10.1158/0008-5472.CAN-18-0717. [Epub ahead of print] PMID: 30389701.
- Su, Y., C. Pelz, T. Huang, K. Torkenczy, X. Wang, A. Cherry, C.J. Daniel, J. Liang, X. Nan, M.S. Dai, A. Adey, S. Impey, R.C. Sears, Post-translational modification localizes MYC to the nuclear pore basket to regulate a subset of target genes involved in cellular responses to environmental signals. Genes & Development, 2018 Nov 1;32(21-22):1398-1419. PMID: 30366908. DOI: 10.1101/gad.314377.118. Epub 2018 Oct 26.
- Sun, X.X., Y. Chen, Y. Su, X. Wang, K.M. Chauhan, J. Liang, C.J. Daniel, R. C. Sears, Mu-Shui Dai. SUMO protease SENP1 deSUMOylates and stabilizes c-Myc. Proc Natl Acad Sci USA. 2018 Oct 10. pii: 201802932. doi: 10.1073/pnas.1802932115. PMID: 30305424.
- McClinch, K., R.A. Avelar, D. Callejas, S. Izadmehr, D. Wiredja, A. Perl, J. Sangodkar, D.B. Kastrinsky, D. Schlatzer, M. Cooper, J. Kiselar, A. Stachnik, S. Yao, D. Hoon, D. McQuaid, N. Zaware, Y. Gong, D.L. Brautigan, S. Plymate, C.C. Sprenger, W.K. Oh, A.C. Levine, A. Kirschenbaum, J.P. Sfakianos, R.C. Sears, A. DiFeo, Y.A. Ioannou, M. Ohlmeyer, G. Narla, and M.D. Galsky. Small molecule activators of protein phosphatase 2A for the treatment of castration-resistant prostate cancer. Cancer Research, 2018 Jan 22. PMID: 29358171. pii: canres.0123.2017. DOI: 10.1158/0008-5472.CAN-17-0123.