A5071933887- Microtubule and mitosis dynamics
- Cancer-related Molecular Pathways
- Cancer Genomics and Diagnostics
- Cancer Treatment and Pharmacology
- Cellular Mechanics and Interactions
- DNA Repair Mechanisms
- Ubiquitin and proteasome pathways
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Cellular transport and secretion
- BRCA gene mutations in cancer
- Estrogen and related hormone effects
- Breast Cancer Treatment Studies
- Neurobiology and Insect Physiology Research
- DNA and Nucleic Acid Chemistry
- Genomic variations and chromosomal abnormalities
- Computational Drug Discovery Methods
- Genetics, Bioinformatics, and Biomedical Research
- Chromosomal and Genetic Variations
- Phagocytosis and Immune Regulation
- Chromatin Remodeling and Cancer
- Zebrafish Biomedical Research Applications
- Cancer Cells and Metastasis
- Nuclear Structure and Function
- Axon Guidance and Neuronal Signaling
Dana-Farber Cancer Institute
2024
University of Wisconsin–Madison
2012-2021
Howard Hughes Medical Institute
2017-2021
Massachusetts Institute of Technology
2017-2021
University of Wisconsin Carbone Cancer Center
2016
University of Wisconsin System
2013
Regenerative Medicine Institute
2012
University of Pittsburgh
2010
The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, it does at concentrations routinely used culture. However, we determine here that levels primary breast are well below those required elicit sustained arrest. Instead, cells these lower proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting chromosome missegregation death. Consistent with culture data, most...
Significance Aneuploidy, an abnormal chromosome content that commonly occurs because of errors in segregation, can promote or suppress tumor formation. What determines how aneuploidy influences tumorigenesis has remained unclear. Here we show the rate missegregation, rather than level accumulated aneuploidy, effect on tumors. Increasing missegregation beyond a certain threshold suppresses tumors by causing cell death. segregation did not affect formation caused genetic mutations do...
Centrosome amplification (CA) has been reported in nearly all types of human cancer and is associated with deleterious clinical factors such as higher grade stage. However, previous reports have not shown how CA affects cellular differentiation outcomes breast cancer. We analyzed centrosomes by immunofluorescence compared to ploidy chromosomal instability (CIN) assessed 6-chromosome FISH a cohort 362 cancers median follow-up 8.4 years. Centrosomes were recognized using antibodies for...
Paclitaxel cytotoxicity in breast tumors depends on multipolar spindle maintenance and preexisting chromosomal instability.
The mitotic checkpoint is the major cell cycle acting during mitosis to prevent aneuploidy and chromosomal instability, which are hallmarks of tumor cells. Reduced expression component Mad1 causes promotes tumors in mice [Iwanaga Y, et al. (2007) Cancer Res 67:160–166]. However, prevalence consequences overexpression currently unclear. Here we show that frequently overexpressed human cancers up-regulation a marker poor prognosis. Overexpression instability through weakening signaling caused...
Summary Microtubules control cell motility by positively regulating polarization in many types. However, how microtubules regulate leukocyte migration is not well understood, particularly living organisms. Here we exploited the zebrafish system to study role of neutrophil vivo. The localization was visualized motile neutrophils using various bioprobes, revealing that, contrast what has been seen studies vitro, microtubule organizing center positioned front nucleus (relative direction...
Chromosome gains and losses are a frequent feature of human cancers. However, how these aberrations can outweigh the detrimental effects aneuploidy remains unclear. An initial comparison existing chromosomal instability (CIN) mouse models suggests that accumulates to low levels in animals. We therefore developed novel model enables unprecedented chromosome missegregation adult animal. At earliest stages T-cell development, cells with random and/or selected against, but CIN eventually results...
Aneuploidy, an abnormal chromosome number that deviates from a multiple of the haploid, has been recognized as common feature cancers for >100 yr. Previously, we showed rate missegregation/chromosomal instability (CIN) determines effect aneuploidy on tumors; whereas low rates CIN are weakly tumor promoting, higher cause cell death and suppression. However, whether high inhibits initiation or suppresses growth progression already initiated tumors remained unclear. We tested this using...
Abstract Increased ploidy is common in tumors but treatments for with excess chromosome sets are not available. Here, we characterize high-ploidy breast cancers and identify potential anticancer compounds selective the state. Among 354 human cancers, 10% have mean copy number exceeding 3, this most triple-negative HER2-positive types. Women higher risk of recurrence death two patient cohorts, demonstrating that it represents an important group improved treatment. Because aneuploid, rather...
Abstract Background Targeting Protein for Xenopus Kinesin Like 2 (TPX2) is a microtubule associated protein that functions in mitotic spindle assembly. TPX2 also localizes to the nucleus where it DNA damage repair during S-phase. We and others have previously shown RNA levels are strongly with chromosomal instability (CIN) breast other cancers, been demonstrated correlate aggressive behavior poor clinical outcome across range of solid malignancies, including cancer. Methods perform IHC on...
The ARF tumor suppressor is part of the CDKN2A locus and mutated or undetectable in numerous cancers. best-characterized role for stabilizing p53 response to cellular stress. However, has suppressive functions outside this pathway that have not been fully defined. Primary mouse embryonic fibroblasts (MEFs) lacking contain abnormal numbers chromosomes. no cell division previously proposed. Here we demonstrate a novel, p53-independent mitotic checkpoint. Consistent with this, loss results...
Vertebrate Shroom proteins define cytoskeletal organization and cellular architecture by binding directly to F-actin Rho-kinase spatially regulating the activity of nonmuscle myosin II (myosin II). Here, we report characterization gain-of-function analysis Drosophila Shroom. The dShrm locus expresses at least two protein isoforms, dShrmA dShrmB, which localize adherens junctions apical membrane, respectively. dShrmB exhibit differing abilities induce constriction that are based on their...
Abstract Background: Collective evidence highlights that agonism of the host STING pathway plays a critical role in eliciting robust and durable anti-tumor immunity. Dazostinag (TAK-676) is novel systemically delivered agonist ignites innate immune system mobilizes adaptive Preclinical studies with dazostinag demonstrated strong, persistent CD8+ T cell response driven by derived type I IFN pro-inflammatory cytokines. The cells to was further supported previously correlation between frequency...
Abstract Paclitaxel is a microtubule-stabilizing drug that binds to the β-tubulin subunit and accumulates in mitotic cells. As chemotherapeutic agent, paclitaxel used for treatment of variety cancers including breast. Currently, no biomarker available predict which patients will benefit from treatment. studies cells focus primarily on relatively high concentrations drug, cause die following long-term arrest. The clinically relevant concentration currently unknown, although it widely...
Abstract Polyploidy, the presence of extra chromosome sets, is a feature many cancers. Polyploid cells have weaknesses that can be exploited for treatment–termed synthetic lethal. We identified polyploid breast cancers and polypoid-selective lead compound. METHODS: performed 6-chromosome FISH on 354 human correlated with cancer subtype clinical outcomes up to 10 years (cohort 1). To validate findings, we analyzed chromosome-17 ploidy second cohort 1095 samples 2). identify...
Abstract Background: Paclitaxel is one of the most effective therapies for breast cancer, although many patients do not benefit. Our goal to identify those who will benefit, by understanding how this drug contributes chromosomal instability (CIN). CIN gradual gain/loss whole chromosomes that can occur with mitotic errors as tumors proliferate. Some cancers inherently have whereas others lack CIN. Previous work suggests low rates promote tumor growth creating genetic diversity. By contrast,...
Abstract Paclitaxel is a chemotherapeutic, microtubule-stabilizing drug used to treat variety of cancers, including those the breast. In neoadjuvant setting, paclitaxel effects tumor shrinkage in up half patients. Identification biomarker predict response would reduce side and improve patient outcomes. It has long been known that micromolar concentrations cause cells culture arrest mitosis, which can lead cell death. However, concentration range found within tumors remains unclear, both...
<p>This file contains supplementary figures S1-S4. These illustrate correlation of ploidy from chromosome 17 FSIH versus 6-chromosome FISH, spreads cell lines, additional dose-response curves, and data demonstrating DPBQ does not operate by binding DNA or inhibiting topoisomerase II.</p>
<p>This file contains supplementary figures S1-S4. These illustrate correlation of ploidy from chromosome 17 FSIH versus 6-chromosome FISH, spreads cell lines, additional dose-response curves, and data demonstrating DPBQ does not operate by binding DNA or inhibiting topoisomerase II.</p>