Measuring, Modeling, and Controlling Heterogeneity Center for Cancer Systems Biology (M2CH)

What is the M2CH?

The Measuring, Modeling and Controlling Heterogeneity Center for Cancer Systems Biology (M2CH-CCSB, or simply M2CH), is one of thirteen "U54 Research Centers" which are part of the Research Network of the National Cancer Institute Cancer Systems Biology Consortium.

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 schematic of the overall project aims of the M2CH

A cancer systems 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.

Contact

Please direct any inquiries regarding the Measuring, Modeling and Controlling Heterogeneity (M2CH) Center to Heidi Feiler, Scientific Program Manager, feiler@ohsu.edu.

Publications

  • Smith R, Devlin K, Kilburn D, Gross S, Sudar D, Bucher E, Nederlof M, Dane M, Gray JW, Heiser L, Korkola JE. Using Microarrays to Interrogate Microenvironmental Impact on Cellular Phenotypes in Cancer. J Vis Exp. 2019 May 21;(147):10.3791/58957. doi: 10.3791/58957. PMID: 31180341; PMCID: PMC6736605.
  • Chapman MP, Risom T, Aswani AJ, Langer EM, Sears RC, Tomlin CJ. Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer. PLoS Comput Biol. 2019;15(3):e1006840. Epub 2019/03/12. doi: 10.1371/journal.pcbi.1006840. PubMed PMID: 30856168; PMCID: PMC6428348.
  • 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.
  • 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.
  • 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.
  • Gray E, Mitchell E, Jindal S, Schedin P, Chang YH. A Method for Quantification of Calponin Expression in Myoepithelial Cells in Immunohistochemical Images of Ductal Carcinoma in Situ. Proc IEEE Int Symp Biomed Imaging. 2018;2018:796-9. Epub 2018/10/27. doi: 10.1109/ISBI.2018.8363692. PubMed PMID: 30364524; PMCID: PMC6196724.
  • 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. 
  • 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.
  • Chang YH, Heo YJ, Cho J, Song SY, Lee J, Kim KM. Computational measurement of tumor immune microenvironment in gastric adenocarcinomas. Sci Rep. 2018;8(1):13887. Epub 2018/09/19. doi: 10.1038/s41598-018-32299-0. PubMed PMID: 30224753; PMCID: PMC6141531.
  • Erik A. Burlingame, Adam A. Margolin, Joe W. Gray, Young Hwan Chang, "SHIFT: speedy histopathological-to-immunofluorescent translation of whole slide images using conditional generative adversarial networks," Proc. SPIE 10581, Medical Imaging 2018: Digital Pathology, 1058105 (6 March 2018); https://doi.org/10.1117/12.2293249
  • 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.
  • Tsujikawa T, Kumar S, Borkar RN, Azimi V, Thibault G, Chang YH, Balter A, Kawashima R, Choe G, Sauer D, El Rassi E, Clayburgh DR, Kulesz-Martin MF, Lutz ER, Zheng L, Jaffee EM, Leyshock P, Margolin AA, Mori M, Gray JW, Flint PW, Coussens LM. Quantitative Multiplex Immunohistochemistry Reveals Myeloid-Inflamed Tumor-Immune Complexity Associated with Poor Prognosis. Cell Rep. 2017;19(1):203-17. Epub 2017/04/06. doi: 10.1016/j.celrep.2017.03.037. PubMed PMID: 28380359; PMCID: PMC5564306.
  • Azimi V, Chang YH, Thibault G, Smith J, Tsujikawa T, Kukull B, Jensen B, Corless C, Margolin A, Gray JW. Breast Cancer Histopathology Image Analysis Pipeline for Tumor Purity Estimation. Proc IEEE Int Symp Biomed Imaging. 2017;2017:1137-40. Epub 2017/04/01. doi: 10.1109/ISBI.2017.7950717. PubMed PMID: 30364881; PMCID: PMC6198647.
  • Chang YH, Thibault G, Johnson B, Margolin A, Gray JW. Integrative Analysis on Histopathological Image for Identifying Cellular Heterogeneity. Proc SPIE Int Soc Opt Eng. 2017;10140. Epub 2017/02/01. doi: 10.1117/12.2250428. PubMed PMID: 30364826; PMCID: PMC6198666.