Investigator, Hale Family Center For Pancreatic Cancer Research
Department Of Data Sciences, Dana-Farber Cancer Institute
Professor Of Computational Biology, Department Of Biostatistics, Harvard T.H. Chan School Of Public Health
Department Of Stem Cell And Regenerative Biology, Harvard University
Bio Research Interests Key Publications Michor Lab Website
Bio
Dr. Franziska Michor, PhD is a Professor Of Computational Biology in the Department Of Data Sciences at the Dana-Farber Cancer Institute, in the Department Of Biostatistics at the Harvard T.H. Chan School Of Public Health, and in the Department Of Stem Cell And Regenerative Biology at Harvard University. Dr. Michor obtained her undergraduate training in mathematics and molecular biology from the University Of Vienna, Austria, and her PhD from the Department Of Organismic And Evolutionary Biology at Harvard University. Afterwards, she was awarded a fellowship from the Harvard Society Of Fellows. From 2007 until 2010, she was an Assistant Professor in the Computational Biology Program at Memorial Sloan-Kettering Cancer Center. Dr. Michor is the director of the Dana-Farber Cancer Institute Physical Sciences-Oncology Center and the Center For Cancer Evolution. She has been the recipient of the Theodosius Dobzhansky Prize of the Society For The Study Of Evolution, the Alice Hamilton Award, the Vilcek Prize For Creative Promise In Biomedical Science, the 36th Annual AACR Award For Outstanding Achievement In Cancer Research, and others. Dr. Michor’s laboratory investigates the evolutionary dynamics of cancer initiation, progression, response to therapy, and emergence of resistance.
Research Interests
Pancreatic cancer is a leading cause of cancer related death, largely due to metastatic dissemination. The goal of our research is to employ the tools of applied mathematics, statistics, bioinformatics and computational biology to address important questions in pancreatic cancer research. For instance, we have investigated pancreatic cancer progression by utilizing a mathematical framework of metastasis formation together with the largest longitudinal patient dataset analyzed to date. Using this approach, we estimated the rates of pancreatic cancer growth and dissemination and determined that patients likely harbor metastases at diagnosis. We also predicted the number and size distribution of metastases as well as patient survival. These findings were validated in an independent database. We also analyzed the effects of different treatment modalities, finding that therapies that efficiently reduce the growth rate of cells earlier in the course of treatment are superior to upfront tumor resection. Furthermore, pancreatic ductal adenocarcinoma (PDAC) exhibits a variety of phenotypes with regard to disease progression and treatment response. This variability complicates clinical decision making despite the improvement of survival due to the recent introduction of FOLFIRINOX (FFX) and nab-paclitaxel. Questions remain as to the timing and sequence of therapies and the role of radiotherapy for unresectable PDAC. We have developed a computational analysis platform to investigate the dynamics of growth, metastasis and treatment response to FFX, gemcitabine (GEM), and GEM+nab-paclitaxel for this specific cancer type. We found a logistic growth pattern of PDAC and defined the Local Advancement Index (LAI), which determines the eventual primary tumor size and predicts the number of metastases. We found that a smaller LAI leads to a larger metastatic burden. Furthermore, our analyses ascertain that i) radiotherapy after induction chemotherapy improves survival in cases receiving induction FFX or with larger LAI, ii) neoadjuvant chemotherapy improves survival in cases with resectable PDAC, and iii) temporary cessations of chemotherapies do not impact overall survival, which supports the feasibility of treatment holidays for patients with FFX-associated adverse effects. Our findings inform clinical decision-making for PDAC patients and allow for the rational design of clinical strategies using FFX, GEM, GEM+nab-paclitaxel, neoadjuvant chemotherapy, and radiation. We are continuing these investigations to develop comprehensive modeling frameworks for PDAC treatment response and metastatic dissemination in several other projects.
Key Publications
Yamamoto KN, Nakamura A, Liu LL, Stein S, Tramontano AC, Kartoun U, Shimizu T, Inoue Y, Asakuma M, Haeno H, Kong CY, Uchiyama K, Gonen M, Hur C, Michor F. Computational modeling of pancreatic cancer patients receiving FOLFIRINOX and gemcitabine-based therapies identifies optimum intervention strategies. PLoS One. 2019;14(4):e0215409. Epub 2019/04/27. doi: 10.1371/journal.pone.0215409. PubMed PMID: 31026288; PMCID: PMC6485645.
Yamamoto KN, Liu LL, Nakamura A, Haeno H, Michor F. Stochastic Evolution of Pancreatic Cancer Metastases During Logistic Clonal Expansion. JCO Clin Cancer Inform. 2019;3:1-11. Epub 2019/03/23. doi: 10.1200/CCI.18.00079. PubMed PMID: 30901235.
Shank K, Dunbar A, Koppikar P, Kleppe M, Teruya-Feldstein J, Csete I, Bhagwat N, Keller M, Kilpivaara O, Michor F, Levine RL, de Vargas Roditi L. Mathematical modeling reveals alternative JAK inhibitor treatment in myeloproliferative neoplasms. Haematologica. 2019. Epub 2019/08/16. doi: 10.3324/haematol.2018.203729. PubMed PMID: 31413098.
Janiszewska M, Tabassum DP, Castano Z, Cristea S, Yamamoto KN, Kingston NL, Murphy KC, Shu S, Harper NW, Del Alcazar CG, Aleckovic M, Ekram MB, Cohen O, Kwak M, Qin Y, Laszewski T, Luoma A, Marusyk A, Wucherpfennig KW, Wagle N, Fan R, Michor F, McAllister SS, Polyak K. Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments. Nat Cell Biol. 2019;21(7):879-88. Epub 2019/07/03. doi: 10.1038/s41556-019-0346-x. PubMed PMID: 31263265; PMCID: PMC6609451.
Hinohara K, Wu HJ, Sebastien V, McDonald TO, Igarashi KJ, Yamamoto KN, Madsen T, Fassl A, Egri SB, Papanastasiou M, Ding L, Peluffo G, Cohen O, Kales SC, Lal-Nag M, Rai G, Maloney DJ, Jadhav A, Simeonov A, Wagle N, Brown M, Meissner A, Sicinski P, Jaffe JD, Jeselsohn R, Gimelbrant AA, Michor F, Polyak K. KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. Cancer Cell. 2019;35(2):330-2. Epub 2019/02/13. doi: 10.1016/j.ccell.2019.01.012. PubMed PMID: 30753830; PMCID: PMC6428693.
Ferlic J, Shi J, McDonald TO, Michor F. DIFFpop: a stochastic computational approach to simulate differentiation hierarchies with single cell barcoding. Bioinformatics. 2019;35(19):3849-51. Epub 2019/03/01. doi: 10.1093/bioinformatics/btz074. PubMed PMID: 30816920.
Van Egeren D, Madsen T, Michor F. Fitness variation in isogenic populations leads to a novel evolutionary mechanism for crossing fitness valleys. Commun Biol. 2018;1:151. Epub 2018/10/03. doi: 10.1038/s42003-018-0160-1. PubMed PMID: 30272027; PMCID: PMC6158234.
Stover DG, Gil Del Alcazar CR, Brock J, Guo H, Overmoyer B, Balko J, Xu Q, Bardia A, Tolaney SM, Gelman R, Lloyd M, Wang Y, Xu Y, Michor F, Wang V, Winer EP, Polyak K, Lin NU. Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer. NPJ Breast Cancer. 2018;4:10. Epub 2018/05/16. doi: 10.1038/s41523-018-0060-z. PubMed PMID: 29761158; PMCID: PMC5935675.
Stein S, Zhao R, Haeno H, Vivanco I, Michor F. Mathematical modeling identifies optimum lapatinib dosing schedules for the treatment of glioblastoma patients. PLoS Comput Biol. 2018;14(1):e1005924. Epub 2018/01/03. doi: 10.1371/journal.pcbi.1005924. PubMed PMID: 29293494; PMCID: PMC5766249.
Riester M, Xu Q, Moreira A, Zheng J, Michor F, Downey RJ. The Warburg effect: persistence of stem-cell metabolism in cancers as a failure of differentiation. Ann Oncol. 2018;29(1):264-70. Epub 2017/10/19. doi: 10.1093/annonc/mdx645. PubMed PMID: 29045536; PMCID: PMC6658717.
McDonald TO, Chakrabarti S, Michor F. Currently available bulk sequencing data do not necessarily support a model of neutral tumor evolution. Nat Genet. 2018;50(12):1620-3. Epub 2018/10/31. doi: 10.1038/s41588-018-0217-6. PubMed PMID: 30374067; PMCID: PMC6467055.
Karaayvaz M, Cristea S, Gillespie SM, Patel AP, Mylvaganam R, Luo CC, Specht MC, Bernstein BE, Michor F, Ellisen LW. Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq. Nat Commun. 2018;9(1):3588. Epub 2018/09/06. doi: 10.1038/s41467-018-06052-0. PubMed PMID: 30181541; PMCID: PMC6123496.
Jun HJ, Appleman VA, Wu HJ, Rose CM, Pineda JJ, Yeo AT, Delcuze B, Lee C, Gyuris A, Zhu H, Woolfenden S, Bronisz A, Nakano I, Chiocca EA, Bronson RT, Ligon KL, Sarkaria JN, Gygi SP, Michor F, Mitchison TJ, Charest A. A PDGFRalpha-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine. Nat Commun. 2018;9(1):3116. Epub 2018/08/08. doi: 10.1038/s41467-018-05036-4. PubMed PMID: 30082792; PMCID: PMC6078993.
Hinohara K, Wu HJ, Vigneau S, McDonald TO, Igarashi KJ, Yamamoto KN, Madsen T, Fassl A, Egri SB, Papanastasiou M, Ding L, Peluffo G, Cohen O, Kales SC, Lal-Nag M, Rai G, Maloney DJ, Jadhav A, Simeonov A, Wagle N, Brown M, Meissner A, Sicinski P, Jaffe JD, Jeselsohn R, Gimelbrant AA, Michor F, Polyak K. KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. Cancer Cell. 2018;34(6):939-53 e9. Epub 2018/11/26. doi: 10.1016/j.ccell.2018.10.014. PubMed PMID: 30472020; PMCID: PMC6310147.
Cimino PJ, Kim Y, Wu HJ, Alexander J, Wirsching HG, Szulzewsky F, Pitter K, Ozawa T, Wang J, Vazquez J, Arora S, Rabadan R, Levine R, Michor F, Holland EC. Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma. Genes Dev. 2018;32(7-8):512-23. Epub 2018/04/11. doi: 10.1101/gad.312157.118. PubMed PMID: 29632085; PMCID: PMC5959235.
Chakrabarti S, Paek AL, Reyes J, Lasick KA, Lahav G, Michor F. Hidden heterogeneity and circadian-controlled cell fate inferred from single cell lineages. Nat Commun. 2018;9(1):5372. Epub 2018/12/19. doi: 10.1038/s41467-018-07788-5. PubMed PMID: 30560953; PMCID: PMC6299096.
Altrock PM, Ferlic J, Galla T, Tomasson MH, Michor F. Computational Model of Progression to Multiple Myeloma Identifies Optimum Screening Strategies. JCO Clin Cancer Inform. 2018;2:1-12. Epub 2019/01/18. doi: 10.1200/CCI.17.00131. PubMed PMID: 30652561.
Zhao R, Catalano P, DeGruttola VG, Michor F. Estimating mono- and bi-phasic regression parameters using a mixture piecewise linear Bayesian hierarchical model. PLoS One. 2017;12(7):e0180756. Epub 2017/07/21. doi: 10.1371/journal.pone.0180756. PubMed PMID: 28723910; PMCID: PMC5516991.
Yu HA, Sima C, Feldman D, Liu LL, Vaitheesvaran B, Cross J, Rudin CM, Kris MG, Pao W, Michor F, Riely GJ. Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers. Ann Oncol. 2017;28(2):278-84. Epub 2017/01/12. doi: 10.1093/annonc/mdw556. PubMed PMID: 28073786; PMCID: PMC5834093.
Temko D, Cheng YK, Polyak K, Michor F. Mathematical Modeling Links Pregnancy-Associated Changes and Breast Cancer Risk. Cancer Res. 2017;77(11):2800-9. Epub 2017/04/01. doi: 10.1158/0008-5472.CAN-16-2504. PubMed PMID: 28360138; PMCID: PMC5477484.
Smith ZD, Shi J, Gu H, Donaghey J, Clement K, Cacchiarelli D, Gnirke A, Michor F, Meissner A. Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature. 2017;549(7673):543-7. Epub 2017/09/30. doi: 10.1038/nature23891. PubMed PMID: 28959968; PMCID: PMC5789792.
Smith KS, Liu LL, Ganesan S, Michor F, De S. Nuclear topology modulates the mutational landscapes of cancer genomes. Nat Struct Mol Biol. 2017;24(11):1000-6. Epub 2017/10/03. doi: 10.1038/nsmb.3474. PubMed PMID: 28967881; PMCID: PMC5744871.
Riester M, Wu HJ, Zehir A, Gonen M, Moreira AL, Downey RJ, Michor F. Distance in cancer gene expression from stem cells predicts patient survival. PLoS One. 2017;12(3):e0173589. Epub 2017/03/24. doi: 10.1371/journal.pone.0173589. PubMed PMID: 28333954; PMCID: PMC5363813.
Mishima Y, Paiva B, Shi J, Park J, Manier S, Takagi S, Massoud M, Perilla-Glen A, Aljawai Y, Huynh D, Roccaro AM, Sacco A, Capelletti M, Detappe A, Alignani D, Anderson KC, Munshi NC, Prosper F, Lohr JG, Ha G, Freeman SS, Van Allen EM, Adalsteinsson VA, Michor F, San Miguel JF, Ghobrial IM. The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma. Cell Rep. 2017;19(1):218-24. Epub 2017/04/06. doi: 10.1016/j.celrep.2017.03.025. PubMed PMID: 28380360; PMCID: PMC5439509.
McDonald TO, Michor F. SIApopr: a computational method to simulate evolutionary branching trees for analysis of tumor clonal evolution. Bioinformatics. 2017;33(14):2221-3. Epub 2017/03/24. doi: 10.1093/bioinformatics/btx146. PubMed PMID: 28334409; PMCID: PMC5870718.
Maruvka YE, Mouw KW, Karlic R, Parasuraman P, Kamburov A, Polak P, Haradhvala NJ, Hess JM, Rheinbay E, Brody Y, Koren A, Braunstein LZ, D’Andrea A, Lawrence MS, Bass A, Bernards A, Michor F, Getz G. Analysis of somatic microsatellite indels identifies driver events in human tumors. Nat Biotechnol. 2017;35(10):951-9. Epub 2017/09/12. doi: 10.1038/nbt.3966. PubMed PMID: 28892075.
Malone CF, Emerson C, Ingraham R, Barbosa W, Guerra S, Yoon H, Liu LL, Michor F, Haigis M, Macleod KF, Maertens O, Cichowski K. mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors. Cancer Discov. 2017;7(12):1450-63. Epub 2017/10/01. doi: 10.1158/2159-8290.CD-17-0177. PubMed PMID: 28963352; PMCID: PMC5718976.
Han L, Wu HJ, Zhu H, Kim KY, Marjani SL, Riester M, Euskirchen G, Zi X, Yang J, Han J, Snyder M, Park IH, Irizarry R, Weissman SM, Michor F, Fan R, Pan X. Bisulfite-independent analysis of CpG island methylation enables genome-scale stratification of single cells. Nucleic Acids Res. 2017;45(10):e77. Epub 2017/01/28. doi: 10.1093/nar/gkx026. PubMed PMID: 28126923; PMCID: PMC5605247.
Gil Del Alcazar CR, Huh SJ, Ekram MB, Trinh A, Liu LL, Beca F, Zi X, Kwak M, Bergholtz H, Su Y, Ding L, Russnes HG, Richardson AL, Babski K, Min Hui Kim E, McDonnell CH, 3rd, Wagner J, Rowberry R, Freeman GJ, Dillon D, Sorlie T, Coussens LM, Garber JE, Fan R, Bobolis K, Allred DC, Jeong J, Park SY, Michor F, Polyak K. Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition. Cancer Discov. 2017;7(10):1098-115. Epub 2017/06/28. doi: 10.1158/2159-8290.CD-17-0222. PubMed PMID: 28652380; PMCID: PMC5628128.
Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J, Jaiswal S, Bosworth A, Francisco L, He J, Bansal A, Morgan EA, Lacasce AS, Freedman AS, Fisher DC, Jacobsen E, Armand P, Alyea EP, Koreth J, Ho V, Soiffer RJ, Antin JH, Ritz J, Nikiforow S, Forman SJ, Michor F, Neuberg D, Bhatia R, Bhatia S, Ebert BL. Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J Clin Oncol. 2017;35(14):1598-605. Epub 2017/01/10. doi: 10.1200/JCO.2016.71.6712. PubMed PMID: 28068180; PMCID: PMC5455707.
