SASCO Project 1 Featured image

Project 1. Robust-to-fragile transitions of a phase-separated mitotic organelle in triple-negative breast cancer

Co-Leads and Co-Investigators

Kevin Janes
John Marshall Money Professor of Biomedical Engineering
Email   Lab Website   Twitter  
Todd Stukenberg
Professor of Biochemistry and Molecular Genetics
Email   Lab Website  
Hui Zong
Professor of Microbiology, Immunology, and Cancer Biology
Email   Lab Website  
Shayna Showalter
Associate Professor of Surgery
Email   Profile Website  
Kristen Atkins
Professor of Pathology
Email   Profile Website  

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.

SASCO Project 1 Featured image

Related Publications

A Centromere-Signaling Network Underlies the Coordination among Mitotic Events.
Trivedi P, Stukenberg PT.
Trends Biochem Sci. 2015; 41(2):160-74.
PubMed   DOI
A Comprehensive Approach for Multi-channel Image Registration.
Rohde GK, Pajevic S, Pierpaoli C, Basser PJ, editors.
Biomedical Image Registration; Berlin, Heidelberg: Springer Berlin Heidelberg. 2003; .
A general system for automatic biomedical image segmentation using intensity neighborhoods.
Chen C, Ozolek JA, Wang W, Rohde GK.
Int J Biomed Imaging. 2011; 606857.
PubMed   DOI
A generative model of microtubule distributions, and indirect estimation of its parameters from fluorescence microscopy images.
Shariff A, Murphy RF, Rohde GK.
Cytometry Part A : the journal of the International Society for Analytical Cytology. 2010; 77(5):457-66.
PubMed   DOI
A genetic mosaic mouse model illuminates the pre-malignant progression of basal-like breast cancer.
Jianhao Zeng, Shambhavi Singh, Ying Jiang, Eli Casarez, Kristen A. Atkins, Kevin A. Janes, Hui Zong.
Dis Model Mech. 2023; 2023 Nov 1;16(11).
PubMed   DOI
A linear optimal transportation framework for quantifying and visualizing variations in sets of images.
Wang W, Slepcev D, Basu S, Ozolek JA, Rohde GK.
Int J Comput Vis. 2020; 101(2):254-69.
PubMed   DOI
A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis.
Janes KA, Albeck JG, Gaudet S, Sorger PK, Lauffenburger DA, Yaffe MB.
Science. 2005; 310(5754):1646-53.
PubMed  
A time- and matrix-dependent TGFBR3-JUND- KRT5 regulatory circuit in single breast epithelial cells and basal-like premalignancies.
Wang CC, Bajikar SS, Jamal L, Atkins KA, Janes KA.
Nat Cell Biol. 2014; 16(4):345-56.
PubMed   DOI
Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state.
Fallahi-Sichani M, Becker V, Izar B, Baker GJ, Lin JR, Boswell SA, Shah P, Rotem A, Garraway LA, Sorger PK.
Mol Syst Biol. 2017; 13(1):905.
PubMed   DOI
An analysis of critical factors for quantitative immunoblotting.
Janes KA.
Sci Signal. 2015; 8(371):rs2.
PubMed   DOI
An optimal transportation approach for nuclear structure-based pathology.
Wang W, Ozolek JA, Slepcev D, Lee AB, Chen C, Rohde GK.
IEEE Trans Med Imaging. 2010; 30(3):621-31.
PubMed   DOI
Aurora B is enriched at merotelic attachment sites, where it regulates MCAK.
Knowlton AL, Lan W, Stukenberg PT.
Curr Biol. 2006; 16(17):1705-10.
PubMed   DOI
Aurora B phosphorylates centromeric MCAK and regulates its localization and microtubule depolymerization activity.
Lan W, Zhang X, Kline-Smith SL, Rosasco SE, Barrett-Wilt GA, Shabanowitz J, Hunt DF, Walczak CE, Stukenberg PT.
Curr Biol. 2004; 14(4):273-86.
PubMed   DOI
Automated brightfield morphometry of 3D organoid populations by OrganoSeg.
Borten MA, Bajikar SS, Sasaki N, Clevers H, Janes KA.
Sci Rep. 2018; 8(1):5319.
PubMed   DOI
Automated Learning of Subcellular Variation among Punctate Protein Patterns and a Generative Model of Their Relation to Microtubules.
Johnson GR, Li J, Shariff A, Rohde GK, Murphy RF.
PLoS Comput Biol. 2015; 11(12):e1004614.
PubMed   DOI
Cell Image Classification: A Comparative Overview.
Shifat ERM, Yin X, Fitzgerald CE, Rohde GK.
Cytometry Part A : the journal of the International Society for Analytical Cytology. 2020; 97(4):347-62.
PubMed   DOI
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.
PubMed   DOI
Common effector processing mediates cell- specific responses to stimuli.
Miller-Jensen K, Janes KA, Brugge JS, Lauffenburger DA.
Nature. 2007; 448(7153):604-8.
PubMed  
Comprehensive approach for correction of motion and distortion in diffusion-weighted MRI.
Rohde GK, Barnett AS, Basser PJ, Marenco S, Pierpaoli C.
Magn Reson Med. 2004; 51(1):103-14.
PubMed   DOI
Correction of motion artifact in cardiac optical mapping using image registration.
Rohde GK, Dawant BM, Lin SF.
IEEE Trans Biomed Eng. 2005; 52(2):338-41.
PubMed   DOI
Cyclic Immunofluorescence (CycIF), A Highly Multiplexed Method for Single-cell Imaging.
Lin JR, Fallahi-Sichani M, Chen JY, Sorger PK.
Curr Protoc Chem Biol. 2016; 8(4):251-64.
PubMed   DOI
Data-driven modelling of signal-transduction networks.
Janes KA, Yaffe MB.
Nat Rev Mol Cell Biol. 2006; 7(11):820-8.
PubMed  
Detecting and segmenting cell nuclei in two-dimensional microscopy images.
Liu C, Shang F, Ozolek JA, Rohde GK.
J Pathol Inform. 2017; 7:42.
PubMed   DOI
Detecting and visualizing cell phenotype differences from microscopy images using transport-based morphometry.
Basu S, Kolouri S, Rohde GK.
Proc Natl Acad Sci U S A. 2014; 111(9):3448-53.
PubMed   DOI
Detection and classification of thyroid follicular lesions based on nuclear structure from histopathology images.
Wang W, Ozolek JA, Rohde GK.
Cytometry Part A : the journal of the International Society for Analytical Cytology. 2010; 77(5):485-94.
PubMed   DOI
Enabling early detection of osteoarthritis from presymptomatic cartilage texture maps via transport- based learning.
Kundu S, Ashinsky BG, Bouhrara M, Dam EB, Demehri S, Shifat-E-Rabbi M, Spencer RG, Urish KL, Rohde GK.
Proceedings of the National Academy of Sciences. 2020; 117(40):24709.
DOI
Epigenetic modulation reveals differentiation state specificity of oncogene addiction.
Khaliq M, Manikkam M, Martinez ED, Fallahi-Sichani M.
Nat Commun. 2021; 12(1):1536.
PubMed   DOI
Epithelium-Stroma Classification via Convolutional Neural Networks and Unsupervised Domain Adaptation in Histopathological Images.
Huang Y, Zheng H, Liu C, Ding X, Rohde GK.
IEEE J Biomed Health Inform. 2017; 21(6):1625-32.
PubMed   DOI
Estimating microtubule distributions from 2D immunofluorescence microscopy images reveals differences among human cultured cell lines.
Li J, Shariff A, Wiking M, Lundberg E, Rohde GK, Murphy RF.
PLoS One. 2012; 7(11):e50292.
PubMed   DOI
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.
PubMed   DOI
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.
PubMed   DOI
Identification of Drivers of Aneuploidy in Breast Tumors.
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.
PubMed   DOI
Identifying single-cell molecular programs by stochastic profiling.
Janes KA, Wang CC, Holmberg KJ, Cabral K, Brugge JS.
Nat Methods. 2010; 7(4):311-7.
PubMed   DOI
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.
PubMed   DOI
Inhibition of aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint, and perturbs microtubule dynamics in mitosis.
Kallio MJ, McCleland ML, Stukenberg PT, Gorbsky GJ.
Curr Biol. 2002; 12(11):900-5.
PubMed   DOI
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.
PubMed   DOI
Intersection of FOXO- and RUNX1-mediated gene expression programs in single breast epithelial cells during morphogenesis and tumor progression.
Wang L, Brugge JS, Janes KA.
Proc Natl Acad Sci U S A. 2011; 108(40):E803-12.
PubMed   DOI
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.
PubMed   DOI
Localizing and extracting filament distributions from microscopy images.
Basu S, Liu C, Rohde GK.
J Microsc. 2015; 258(1):13-23.
PubMed   DOI
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.
PubMed   DOI
Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback.
Lopacinski AB, Sweatt AJ, Smolko CM, Gray-Gaillard E, Borgman CA, Shah M, Janes KA.
Cell Syst. 2021; 2021;12(4):304-23 e13.
PubMed   DOI
Mosaic analysis with double markers reveals tumor cell of origin in glioma.
Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, Foreman O, Bronson RT, Nishiyama A, Luo L, Zong H.
Cell. 2011; 146(2):209-21.
PubMed   DOI
Multi-channel registration of diffusion tensor images using directional information.
Rohde GK, Pajevic S, Pierpaoli C, editors.
2004 2nd IEEE International Symposium on Biomedical Imaging: Nano to Macro (IEEE Cat No 04EX821). 2004; .
Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
Cara Abecunas, Audrey D Kidd, Ying Jiang, Hui Zong, Mohammad Fallahi-Sichani.
Cell Rep.. 2024; Sep 20;43(10):114775.
PubMed   DOI
Nucleocytoplasmic transport of active HER2 causes fractional escape from the DCIS-like state.
Lixin Wang, B. Bishal Paudel, R. Anthony McKnight, Kevin A. Janes.
Nature Communications. 2023; 14(1):2110.
PubMed   DOI
Parameterizing cell-to-cell regulatory heterogeneities via stochastic transcriptional profiles.
Bajikar SS, Fuchs C, Roller A, Theis FJ, Janes KA.
Proc Natl Acad Sci U S A. 2014; 111(5):E626-35.
PubMed   DOI
Phenotype-based probabilistic analysis of heterogeneous responses to cancer drugs and their combination efficacy.
Comandante-Lou N, Khaliq M, Venkat D, Manikkam M, Fallahi-Sichani.
PLoS Comput Biol. 2020; 16(2):e1007688.
PubMed   DOI
Proteome-wide copy-number estimation from transcriptomics.
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.
PubMed   DOI
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.
PubMed   DOI
Radon Cumulative Distribution Transform Subspace Modeling for Image Classification.
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.
PubMed   DOI
Registration Methods for Quantitative Imaging [PhD]..
Rohde GK.
Digital Repository at the University of Maryland: University of Maryland (College Park, Md.). 2005; .
Robust latent-variable interpretation of in vivo regression models by nested resampling.
Caulk AW, Janes KA.
Sci Rep. 2019; 9(1):19671.
PubMed   DOI
Simultaneous profiling of 194 distinct receptor transcripts in human cells.
Kang BH, Jensen KJ, Hatch JA, Janes KA.
Sci Signal. 2013; 6(287):rs13.
PubMed   DOI
Sporadic activation of an oxidative stress-dependent NRF2-p53 signaling network in breast epithelial spheroids and premalignancies.
Pereira EJ, Burns JS, Lee CY, Marohl T, Calderon D, Wang L, Atkins KA, Wang CC, Janes KA.
Sci Signal. 2020; 13(627):eaba4200.
PubMed   DOI
Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis.
Fallahi-Sichani M, Moerke NJ, Niepel M, Zhang T, Gray NS, Sorger PK.
Mol Syst Biol. 2015; 11(3):797.
PubMed   DOI
Ten simple rules for being a faculty advocate of first-year graduate students.
Janes KA.
PLoS Comput Biol. 2021; 17(9):e1009379.
PubMed   DOI
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.
PubMed   DOI
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.
PubMed   DOI
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.
PubMed   DOI
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.
PubMed   DOI
TNF-insulin crosstalk at the transcription factor GATA6 is revealed by a model that links signaling and transcriptomic data tensors.
Chitforoushzadeh Z, Ye Z, Sheng Z, LaRue S, Fry RC, Lauffenburger DA, Janes KA.
Sci Signal. 2016; 9(431):ra59.
PubMed   DOI
Toward the virtual cell: automated approaches to building models of subcellular organization “learned” from microscopy images.
Buck TE, Li J, Rohde GK, Murphy RF.
Bioessays. 2012; 34(9):791-9.
PubMed   DOI
Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process.
Galvao RP, Kasina A, McNeill RS, Harbin JE, Foreman O, Verhaak RG, Nishiyama A, Miller CR, Zong H.
Proc Natl Acad Sci U S A. 2014; 111(40):E4214-23.
PubMed   DOI
Tumor-Suppressor Inactivation of GDF11 Occurs by Precursor Sequestration in Triple-Negative Breast Cancer.
Bajikar SS, Wang CC, Borten MA, Pereira EJ, Atkins KA, Janes KA.
Dev Cell. 2017; 43(4):418-35 e13.
PubMed   DOI