Project 1. Robust-to-fragile transitions of a phase-separated mitotic organelle in triple-negative breast cancer
Co-Leads and Co-Investigators
Research
Aneuploidy arising from defective chromosome segregation is pervasive among nearly all solid tumors. In TP53-mutant breast cancer, the dysregulation of core mitotic transcription factors generates error-prone chromosome segregation by the scattershot upregulation of genes tied to kinetochore functions. Many of the dysregulated genes participate in a spatially-regulated positive-feedback network that controls the spindle-assembly checkpoint and kinetochore-microtubule attachments. At the heart of this network is the chromosome passenger complex (CPC)—comprised of Aurora B kinase (AURKB), INCENP, Survivin (BIRC5), and Borealin (CDCA8)—that accumulates at the inner centromere to control mitotic events. Our team discovered that the CPC phase separates upon reaching a critical concentration during mitosis, creating a dynamic subcompartment with specialized functions. How the phase-separated CPC adapts to the unbalancing effect of mitotic transcription factor dysregulation is unknown. The hypothesis of Project 1 is that phase-separated CPC acts as a “phenotypic capacitor” during mitosis by buffering small-to-moderate imbalances (storage) and unleashing dramatic rearrangements when a systems-level threshold is reached (discharge). We will test this hypothesis using biochemical reaction-diffusion models of spatially regulated CPC phase separation, which will be tailored to primary mammary organoids derived from a mosaic GEMM of triple-negative mammary cancer and extended to clinical samples through standard diagnostic assays. The specific aims are to 1) develop and validate a spatial systems model of CPC recruitment that isolates phase separation and predicts critical network imbalances in cancer-predisposed mammary organoids; 2) test the instability-generating potential of critical network imbalances by quantitatively perturbing triple-negative mammary premalignancies in vivo; and 3) leverage routine clinical diagnostics to predict druggable chromosomal instability signatures in any primary breast cancer. Patient-specific, systems-level models of aneuploidy susceptibility will nominate kinase inhibitors in the network that are predicted to shift cells from robust to fragile states of segregation fidelity.
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Biomedical Image Registration; Berlin, Heidelberg: Springer Berlin Heidelberg. 2003; .
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Janes KA.
Sci Signal. 2015; 8(371):rs2.
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Wang W, Ozolek JA, Slepcev D, Lee AB, Chen C, Rohde GK.
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Knowlton AL, Lan W, Stukenberg PT.
Curr Biol. 2006; 16(17):1705-10.
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Lan W, Zhang X, Kline-Smith SL, Rosasco SE, Barrett-Wilt GA, Shabanowitz J, Hunt DF, Walczak CE, Stukenberg PT.
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Johnson GR, Li J, Shariff A, Rohde GK, Murphy RF.
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Centromeric Aurora-B activation requires TD-60, microtubules, and substrate priming phosphorylation.
Rosasco-Nitcher SE, Lan W, Khorasanizadeh S, Stukenberg PT.
Science. 2008; 319(5862):469-72.
Common effector processing mediates cell- specific responses to stimuli.
Miller-Jensen K, Janes KA, Brugge JS, Lauffenburger DA.
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Magn Reson Med. 2004; 51(1):103-14.
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Rohde GK, Dawant BM, Lin SF.
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Curr Protoc Chem Biol. 2016; 8(4):251-64.
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J Pathol Inform. 2017; 7:42.
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Kundu S, Ashinsky BG, Bouhrara M, Dam EB, Demehri S, Shifat-E-Rabbi M, Spencer RG, Urish KL, Rohde GK.
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Nat Commun. 2021; 12(1):1536.
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Huang Y, Zheng H, Liu C, Ding X, Rohde GK.
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Li J, Shariff A, Wiking M, Lundberg E, Rohde GK, Murphy RF.
PLoS One. 2012; 7(11):e50292.
Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method.
Lin JR, Fallahi-Sichani M, Sorger PK.
Nat Commun. 2015; 6:8390.
Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis.
Wang F, Dai J, Daum JR, Niedzialkowska E, Banerjee B, Stukenberg PT, Gorbsky GJ, Higgins JM.
Science. 2010; 330(6001):231-5.
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Pfister K, Pipka JL, Chiang C, Liu Y, Clark RA, Keller R, Skoglund P, Guertin MJ, Hall IM, Stukenberg PT.
Cell Rep. 2018; 23(9):2758-69.
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Janes KA, Wang CC, Holmberg KJ, Cabral K, Brugge JS.
Nat Methods. 2010; 7(4):311-7.
In situ 10-cell RNA sequencing in tissue and tumor biopsy samples.
Singh S, Wang L, Schaff DL, Sutcliffe MD, Koeppel AF, Kim J, Onengut-Gumuscu S, Park KS, Zong H, Janes KA.
Sci Rep. 2019; 9(1):4836.
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Curr Biol. 2002; 12(11):900-5.
Interpolation artifacts in sub-pixel image registration. IEEE Trans Image Process.
Rohde GK, Aldroubi A, Healy DM, Jr.
IEEE Trans Image Process. 2009; 18(2):333-45.
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Wang L, Brugge JS, Janes KA.
Proc Natl Acad Sci U S A. 2011; 108(40):E803-12.
Joint modeling of cell and nuclear shape variation.
Johnson GR, Buck TE, Sullivan DP, Rohde GK, Murphy RF.
Mol Biol Cell. 2012; 26(22):4046-56.
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Basu S, Liu C, Rohde GK.
J Microsc. 2015; 258(1):13-23.
Mechanism of Aurora B activation by INCENP and inhibition by hesperadin.
Sessa F, Mapelli M, Ciferri C, Tarricone C, Areces LB, Schneider TR, Stukenberg PT, Musacchio A.
Mol Cell. 2005; 18(3):379-91.
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Cell Syst. 2021; 2021;12(4):304-23 e13.
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Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, Foreman O, Bronson RT, Nishiyama A, Luo L, Zong H.
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2004 2nd IEEE International Symposium on Biomedical Imaging: Nano to Macro (IEEE Cat No 04EX821). 2004; .
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Cara Abecunas, Audrey D Kidd, Ying Jiang, Hui Zong, Mohammad Fallahi-Sichani.
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Lixin Wang, B. Bishal Paudel, R. Anthony McKnight, Kevin A. Janes.
Nature Communications. 2023; 14(1):2110.
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Bajikar SS, Fuchs C, Roller A, Theis FJ, Janes KA.
Proc Natl Acad Sci U S A. 2014; 111(5):E626-35.
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Comandante-Lou N, Khaliq M, Venkat D, Manikkam M, Fallahi-Sichani.
PLoS Comput Biol. 2020; 16(2):e1007688.
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Andrew J Sweatt, Cameron D Griffiths, Sarah M Groves, B Bishal Paudel, Lixin Wang, David F Kashatus, and Kevin A Janes.
Mol Syst Biol. 2024; online ahead of print.
Protocol for iterative indirect immunofluorescence imaging in cultured cells, tissue sections, and metaphase chromosome spreads.
Hsu J, Nguyen KT, Bujnowska M, Janes KA, Fallahi-Sichani M.
STAR Protoc. 2024; 5, 103190.
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Shifat-E-Rabbi M, Yin X, Rubaiyat AHM, Li S, Kolouri S, Aldroubi A, Nichols JM, Rohde GK.
Journal of Mathematical Imaging and Vision. 2021; 63(9):1185-203.
Registration Methods for Quantitative Imaging [PhD]..
Rohde GK.
Digital Repository at the University of Maryland: University of Maryland (College Park, Md.). 2005; .
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Caulk AW, Janes KA.
Sci Rep. 2019; 9(1):19671.
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Kang BH, Jensen KJ, Hatch JA, Janes KA.
Sci Signal. 2013; 6(287):rs13.
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Pereira EJ, Burns JS, Lee CY, Marohl T, Calderon D, Wang L, Atkins KA, Wang CC, Janes KA.
Sci Signal. 2020; 13(627):eaba4200.
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Fallahi-Sichani M, Moerke NJ, Niepel M, Zhang T, Gray NS, Sorger PK.
Mol Syst Biol. 2015; 11(3):797.
Ten simple rules for being a faculty advocate of first-year graduate students.
Janes KA.
PLoS Comput Biol. 2021; 17(9):e1009379.
The adaptive bases algorithm for intensity-based nonrigid image registration.
Rohde GK, Aldroubi A, Dawant BM.
IEEE Trans Med Imaging. 2003; 22(11):1470-9.
The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex.
Trivedi P, Palomba F, Niedzialkowska E, Digman MA, Gratton E, Stukenberg PT.
Nat Cell Biol. 2019; 21(9):1127-37.
The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations.
Keenan AB, Jenkins SL, Jagodnik KM, Koplev S, He E, Torre D, Wang Z, Dohlman AB, Silverstein MC, Lachmann A, Kuleshov MV, Ma'ayan A, Stathias V, Terryn R, Cooper D, Forlin M, Koleti A, Vidovic D, Chung C, Schurer SC, Vasiliauskas J, Pilarczyk M, Shamsaei.
Cell Syst. 2017; 6(1):13-24.
The Radon Cumulative Distribution Transform and Its Application to Image Classification.
Kolouri S, Park SR, Rohde GK.
IEEE Trans Image Process. 2015; 25(2):920-34.
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Chitforoushzadeh Z, Ye Z, Sheng Z, LaRue S, Fry RC, Lauffenburger DA, Janes KA.
Sci Signal. 2016; 9(431):ra59.
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Buck TE, Li J, Rohde GK, Murphy RF.
Bioessays. 2012; 34(9):791-9.
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Galvao RP, Kasina A, McNeill RS, Harbin JE, Foreman O, Verhaak RG, Nishiyama A, Miller CR, Zong H.
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Dev Cell. 2017; 43(4):418-35 e13.