Chromosome segregation errors: a double-edged sword - TI Pharma

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Chapter 7 Docetaxel affects in vivo tumor cell viability independent of its effects on mitosis Aniek Janssen 1,2,‡ , Evelyne Beerling 3,‡ , René Medema 1,2,†,** , Jacco van Rheenen 3,†,* 1 Division of Cell Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands. 2 Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands 3 Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, Utrecht 3584CT, The Netherlands ‡ These authors contributed equally † These authors contributed equally Manuscript submitted 133 Intravital imaging of Docetaxel response in tumors 7
7 Abstract Taxanes, such as docetaxel, are microtubule-targeting chemotherapeutics that have been successfully used in the treatment of cancer. Based on data obtained from cell cultures, it is believed that taxanes induce tumor cell death by specifically perturbing mitotic progression. However, recent studies suggest that tumor cell death in vivo might not be caused by mitotic perturbations. Here we describe a high-resolution intravital imaging method to simultaneously visualize mitotic progression and the onset of apoptosis. To directly compare in vitro and in vivo data, we have visualized the effect of docetaxel on mitotic progression in mouse and human colorectal tumor cell lines both in vitro and in isogenic tumors in mice. We show that docetaxel-induced apoptosis in vitro occurs via mitotic cell death, whereas tumor cells in their natural environment die independently of mitotic defects. Our data demonstrate that docetaxel exerts its anti-tumor effects in vivo through means other than mitotic perturbation. 134
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Chromosome segregation errors: a do
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Chromosome segregation errors: a do
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Get up, stand up, stand up for your
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Chapter 1 General Introduction Anie
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cytoplasms and pinches off the memb
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which sister-chromatids are not pro
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Non-MCC members, but important mito
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completely separated. Following cle
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Two striking features of cancer cel
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predisposition at a very young age,
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that aberrant spindle formation inc
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(Fig.7C). As discussed in section 4
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Thesis outline Chromosome segregati
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286,395,407,408 Increase (thymus) I
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2 Abstract Various types of chromos
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2 34 A C D E % of cells Control 100
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2 assess whether cytokinesis induce
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2 A Asynchronous Monastrol release
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2 for 14 hours (unless indicated ot
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2 Immuno Blotting Cells were lysed
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2 Supplemental figures 44 A B C % o
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2 A MCF7 B C 53BP1 foci/cell 46 % o
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2 A siLuc siATM C 48 p-S1981 ATM me
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2 50 A B C % of EdU positive cells
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Chapter 3 Studying Chromosomal inst
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Introduction Aneuploidy is a common
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activity by ~80% 170-172 . With the
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A WT/CiMKi T649A Embryo’s: Figure
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control treated MEFs (unpaired t te
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Materials and Methods Cloning targe
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- Loop out BamHI site with site-dir
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Primers: pGH_pA_FW#2: TCTATGGCTTCTG
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was prepared using standard procedu
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71 Cre-inducible Mps1 knock-in mous
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4 Abstract Most of the current drug
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4 Two other interesting mitotic tar
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4 inhibition of the anti-apoptotic
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4 cluster their centrosomes. This
Page 83 and 84: 4 of checkpoint function can be ach
Page 85 and 86: 4 4.5 Disadvantages of exploiting m
Page 88 and 89: Chapter 5 Elevating the frequency o
Page 90 and 91: Introduction Error-free chromosome
Page 92 and 93: Partial depletion of Mps1 or BubR1
Page 94 and 95: death is not induced in the short t
Page 96 and 97: had survived growth for 7 days in t
Page 98 and 99: The following antibodies have been
Page 100 and 101: Supplemental data Supplemental figu
Page 102 and 103: A BubR1 α-tubulin Hela-TetRBubR1 -
Page 104 and 105: - doxycycline + doxycycline - doxyc
Page 106 and 107: A B C percentage of cells % PI posi
Page 108 and 109: Abstract One of the most common hal
Page 110 and 111: clear accumulation of cells in mito
Page 112 and 113: the mice did not receive any doxycy
Page 114 and 115: 113 Chromosome missegregations kill
Page 116 and 117: Chapter 6 Aneuploid tumor cells are
Page 118 and 119: Introduction Equal segregation of t
Page 120 and 121: S1A, data not shown). Based on thes
Page 122 and 123: A B U2OS + H2B-YFP percentage of ce
Page 124 and 125: tumor cells, leaving diploid cells
Page 126 and 127: A B p-S10-Histone H3 DAPI C µmol/l
Page 128 and 129: Supplemental Figure-1. Protein bioc
Page 130 and 131: Bioavailability of compound-5 after
Page 132: A B U2OS (7.5nM) Hela (10nM) RPE-1
Page 137 and 138: 7 of mitotic aberrations. These dat
Page 139 and 140: 7 A Low CFP lifetime High CFP lifet
Page 141 and 142: 7 docetaxel treatment in vitro resu
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Page 145 and 146: 7 Cells (~50.000/well) were plated
Page 147 and 148: 7 Supplemental data Supplemental fi
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Page 151 and 152: 8 Thesis summary Unequal separation
Page 153 and 154: 8 exerted through contraction of th
Page 155 and 156: 8 1.4 NoCut: preventing the inducti
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Page 160 and 161: Addendum References Nederlandse sam
Page 162 and 163: 41. McEwen, B.F., et al., CENP-E is
Page 164 and 165: 2010. 6(5): p. 359-68. 124. Liu, S.
Page 166 and 167: 210. Stucki, M., et al., MDC1 direc
Page 168 and 169: tumors in mice. Cancer Res, 2007. 6
Page 170 and 171: adiotherapy in breast cancer. Breas
Page 172 and 173: 470. Marcus, A.I., et al., Mitotic
Page 174 and 175: 559. Kienitz, A., et al., Partial d
Page 176 and 177: Nederlandse Samenvatting Celdeling,
Page 178 and 179: verdeling van tumorcellen compleet
Page 180 and 181: Publications A. Janssen, R.H.Medema
Page 182 and 183: En dan zijn er nu nog een aantal li
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promotie-stukjes! Je bent een voorb
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edankt voor al jullie hulp bij de i
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