Centrosome Clustering In Cancer Cells Research Articles

Abstract 5306: Clinicopathological significance of KIFC1 in human colorectal cancer

Abstract Colorectal cancer (CRC) ranks third in terms of incidence and second in terms of mortality, more than 1.8 million new colorectal cancer cases and 881,000 deaths are reported in Global Cancer Statistics 2018. Therefore, there is an urgent need for a new molecular target in considering treatment strategy. In recent years, cancer has been recognized as a stem cell disease. Spheroid colony formation has been demonstrated as an effective method to characterize cancer stem cells (CSCs). Previously, we analyzed the gene expression profile of spheroid colonies from the gastric cancer cell lines by microarray analysis and found that expression of Kinesin Family Member C1 (KIFC1) was upregulated in gastric spheroid colonies. The kinesin superfamily is a group of proteins that share a motor domain and participate in several biological functions. KIFC1 (or HSET) has been reported to play a vital role in centrosome clustering in cancer cells and is related to pathogenesis in several kinds of cancers. However, the expression of KIFC1 in CRC has not been investigated. The aim of this study is to investigate the expression and the biological function of KIFC1 in CRC. We analyzed the expression and distribution of KIFC1 in 129 CRC cases by immunohistochemistry. In contrast to weak or no staining of KIFC1 in non-neoplastic mucosa, CRC tissue showed stronger, more extensive KIFC1 staining. In total, 67 (52%) of 129 CRC cases were positive for KIFC1. KIFC1-positive CRC cases were significantly associated with CD44-positive and aldehyde dehydrogenase 1 (ALDH1)-positive CRC cases. In the CRC cell proliferation analysis, KIFC1 siRNA-transfected cells showed significantly reduced cell growth ability relative to negative control siRNA-transfected cells. The expression level of phosphorylated Akt and Erk were lower in KIFC1 siRNA-transfected cells compared to negative control siRNA-transfected cells. In the sphere formation analysis, the number and the size of spheres from CRC cells were significantly reduced in KIFC1 siRNA transfected cells than in negative control siRNA-transfected cells. These results indicate that KIFC1 plays an important role in CRC pathogenesis and might be involved in cancer stemness. Although further in-depth studies to clarify the biological significance of KIFC1 in colorectal CSCs are needed, KIFC1 may be a promising therapeutic target for the treatment of CRC. Citation Format: Shintaro Akabane, Naohide Oue, Yuto Fujiki, Naohiro Uraoka, Naoya Sakamoto, Kazuhiro Sentani, Hiroyuki Egi, Hideki Ohdan, Wataru Yasui. Clinicopathological significance of KIFC1 in human colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5306.

KIFC1 Mediates Centrosome Clustering Prior to Proplatelet Formation from Megakaryocytes

Platelets are specialized anucleate cells that circulate in the blood and serve to prevent bleeding and minimize blood vessel injury. In addition to their hemostatic functions, platelets participate in wound healing, angiogenesis, inflammation, and immunity, and are therefore central players in both maintaining normal physiology and in disease pathogenesis. Platelets are derived from their precursor cells, megakaryocytes (MKs), that reside principally in the bone marrow. During maturation, MKs undergo an altered cell cycle called endomitosis in which they replicate their DNA but avoid cell division, resulting in polyploid MKs with amplified microtubule (MT)-organizing centers called centrosomes. Subsequently, MT-dependent forces are responsible for extending long cytoplasmic protrusions called proplatelets into sinusoidal blood vessels, eventually giving rise to circulating platelets. Despite progress in elucidating key steps of platelet production, there is a conspicuous lack of understanding of what triggers mature, polyploid MKs to undergo the MT rearrangements required for proplatelet production. Using live cell imaging of mouse fetal liver-derived MKs expressing fluorescent b1-tubulin, we have identified a novel MT-based structure in MKs termed a monospindle. Our data suggest that monospindles result from polyploid MKs clustering multiple centrosomes into a centralized MT-organizing center during mitosis, leading to an enlarged array of MTs oriented towards the cell cortex. These structures were also apparent in mouse bone marrow- and human cord blood-derived MKs, suggesting that monospindle formation is a general phenomenon in MKs. Interestingly, a higher percentage of MKs contained monospindles at a timepoint directly prior to proplatelet production (50%) compared to when proplatelets were actively being produced (22%), indicating a possible role in initiating proplatelet formation. Centrosome clustering in cancer cells is mediated by the MT-based mitotic motor protein, KIFC1. Consistently, we found that small molecule inhibition of KIFC1 decreased the percentage of MKs containing monospindles (55% ctrl vs. 6% KIFC1 inhibitor). Strikingly, KIFC1 inhibitor treatment also drastically reduced the percentage of MKs producing proplatelets (peak proplatelet formation: 40% ctrl vs. 5% KIFC1 inhibitor), suggesting that KIFC1-mediated centrosome clustering into monospindles is important for proplatelet production. To test how KIFC1 contributes to these phenotypes, we assessed its expression at different timepoints by Western blot and detected increased KIFC1 levels in more mature MKs preceding proplatelet formation. Cell sorting of MKs into distinct ploidy populations followed by Western blot showed that KIFC1 expression increased with higher ploidy. Thus, our results lead us to suggest a working model in which elevated KIFC1 levels in mature MKs drive monospindle formation to trigger proplatelet formation. Investigating the role of KIFC1-mediated monospindle formation for initiating proplatelet formation could yield a coherent, molecular understanding of how mature, polyploid MKs reorganize MTs for proplatelet production. In addition, these data will help inform basic cell biology, as there are important parallels between centrosome clustering in MKs and cancer cells. Finally, our findings could yield novel therapeutic strategies for treating patients with thrombocytopenia (low platelet counts) by directly stimulating platelet production from mature MKs residing in the bone marrow. Disclosures Italiano: Platelet Biogenesis: Employment, Equity Ownership; Ionis Research Funding: Research Funding.

PARP6 inhibition as a strategy to exploit centrosome clustering in cancer cells?

PARP6 inhibition as a strategy to exploit centrosome clustering in cancer cells?

Cell scientist to watch – Susana Godinho

ABSTRACT Susana Godinho graduated with a master's degree in biology from the University of Lisbon, Portugal. She then pursued her PhD with Alvaro Tavares at the Gulbenkian Institute of Science, including a year at the University of Cambridge, UK, in the laboratory of David Glover. In 2006, she joined the laboratory of David Pellman at the Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA, to work on the mechanisms of extra centrosome clustering in cancer cells during mitosis. Susana established her own research group at the Barts Cancer Institute, Queen Mary University of London (QMUL), in 2013. She was the first lecturer of QMUL to be awarded the Lister Prize (2016). Her group investigates how tumour progression is affected by the presence of extra centrosomes in a cancer cell, and how these cancer cells employ mechanisms to adapt to supernumerary centrosomes.

C-terminal kinesin motor KIFC1 participates in facilitating proper cell division of human seminoma.

C-terminus kinesin motor KIFC1 is known for centrosome clustering in cancer cells with supernumerary centrosomes. KIFC1 crosslinks and glides on microtubules (MT) to assist normal bipolar spindle formation to avoid multi-polar cell division, which might be fatal. Testis cancer is the most common human cancer among young men. However, the gene expression profiles of testis cancer is still not complete and the expression of the C-terminus kinesin motor KIFC1 in testis cancer has not yet been examined. We found that KIFC1 is enriched in seminoma tissues in both mRNA level and protein level, and is specifically enriched in the cells that divide actively. Cell experiments showed that KIFC1 may be essential in cell division, but not essential in metastasis. Based on subcellular immuno-florescent staining results, we also described the localization of KIFC1 during cell cycle. By expressing ΔC-FLAG peptide in the cells, we found that the tail domain of KIFC1 might be essential for the dynamic disassociation of KIFC1, and the motor domain of KIFC1 might be essential for the degradation of KIFC1. Our work provides a new perspective for seminoma research.

Stat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1

Cancer cells frequently have amplified centrosomes that must be clustered together to form a bipolar mitotic spindle, and targeting centrosome clustering is considered a promising therapeutic strategy. A high-content chemical screen for inhibitors of centrosome clustering identified Stattic, a Stat3 inhibitor. Stat3 depletion and inhibition in cancer cell lines and in tumours in vivo caused significant inhibition of centrosome clustering and viability. Here we describe a transcription-independent mechanism for Stat3-mediated centrosome clustering that involves Stathmin, a Stat3 interactor involved in microtubule depolymerization, and the mitotic kinase PLK1. Furthermore, PLK4-driven centrosome amplified breast tumour cells are highly sensitive to Stat3 inhibitors. We have identified an unexpected role of Stat3 in the regulation of centrosome clustering, and this role of Stat3 may be critical in identifying tumours that are sensitive to Stat3 inhibitors.

Abstract 2983: Stat3 regulates supernumerary centrosome clustering in cancer cells via Stathmin/PLK1

Abstract Centrosome amplification and supernumerary centrosomal content are common features of cancer cells. Such cells must cluster their centrosomes to form a bipolar spindle and achieve productive mitosis. Targeting the mechanisms that allow cells to cluster extra centrosomes is considered a promising cancer therapeutic strategy. We have now identified Stat3, a protein that is frequently activated in many types of cancers and also regulates stem cell function, as a regulator of centrosome clustering in cancer cells. A high content chemical screen for the identification of inhibitors of centrosome clustering identified Stattic, a Stat3 inhibitor, as a centrosome clustering inhibitor. Stat3 depletion in cell lines as well as in tumors in vivo resulted in significant inhibition of centrosome clustering and in decreased tumor viability and growth. Interestingly, we identify a novel, transcription-independent mechanism for Stat3-mediated centrosome clustering that requires activities of Stathmin, a Stat3 interactor involved in microtubule depolymerisation, and polo-like kinase1 (PLK1). Furthermore, stem cell function in PLK4-driven centrosome amplified breast tumor cells is highly sensitive to Stat3 inhibitors, reflected in higher inhibitor sensitivity of tumors derived from these cells in vivo. We have therefore identified a novel role of Stat3 in the regulation of centrosome clustering, and this role of Stat3 may be critical in identifying tumor types that are sensitive to Stat3 inhibitors. Citation Format: Edward J. Morris, Eiko Kawamura, Jordan Gillespie, Paul McDonald, William Muller, Shoukat Dedhar. Stat3 regulates supernumerary centrosome clustering in cancer cells via Stathmin/PLK1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2983.

Discovery of a novel inhibitor of kinesin-like protein KIFC1.

Historically, drugs used in the treatment of cancers also tend to cause damage to healthy cells while affecting cancer cells. Therefore, the identification of novel agents that act specifically against cancer cells remains a high priority in the search for new therapies. In contrast with normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis. Cancer cells can avoid multipolar mitosis, which can cause cell death, by clustering the extra centrosomes into two spindle poles, thereby enabling bipolar division. Kinesin-like protein KIFC1 plays a critical role in centrosome clustering in cancer cells, but is not essential for normal cells. Therefore, targeting KIFC1 may provide novel insight into selective killing of cancer cells. In the present study, we identified a small-molecule KIFC1 inhibitor, SR31527, which inhibited microtubule (MT)-stimulated KIFC1 ATPase activity with an IC50 value of 6.6 μM. By using bio layer interferometry technology, we further demonstrated that SR31527 bound directly to KIFC1 with high affinity (Kd=25.4 nM). Our results from computational modelling and saturation-transfer difference (STD)-NMR experiments suggest that SR31527 bound to a novel allosteric site of KIFC1 that appears suitable for developing selective inhibitors of KIFC1. Importantly, SR31527 prevented bipolar clustering of extra centrosomes in triple negative breast cancer (TNBC) cells and significantly reduced TNBC cell colony formation and viability, but was less toxic to normal fibroblasts. Therefore, SR31527 provides a valuable tool for studying the biological function of KIFC1 and serves as a potential lead for the development of novel therapeutic agents for breast cancer treatment.

Abstract 1746: Discovery and evaluation of a small molecule KIFC1 inhibitor for breast cancer treatment

Abstract Historically, drugs used in the treatment of certain cancers may cause damage to healthy cells while affecting cancer cells. Therefore, finding compounds that are specific toward cancer cells only is still a high priority in the search for new therapies. In contrast with normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis. Cancer cells can avoid multipolar mitosis which can cause cell death by clustering the extra centrosomes into two spindle poles, thereby enabling bipolar division. Kinesin-like protein KIFC1 plays a critical role in centrosome clustering in cancer cells, but is not essential for normal cell survival. Therefore, targeting KIFC1 may give some insight into how a novel therapy can selectively target only cancer cells. Here, we report that KIFC1 up-regulation is a frequent event in human breast cancer and that KIFC1 is highly expressed in all 8 tested human breast cancer cell lines, but is absent in normal human mammary epithelial cells and weakly expressed in 2 human lung fibroblast lines. We also found that depletion of KIFC1 in breast cancer cells induced cell death. From a high throughput screen of 30,000 compounds, we identified a small molecule KIFC1 inhibitor, SRH06, which has an enzymatic IC50 value of 6.5 μM versus KIFC1 and binds directly to KIFC1 without interacting with the microtubule. Results from our computer modeling studies suggested that SRH06 binds to a novel allosteric site on KIFC1 that appears suitable for the development of selective KIFC1 inhibitors. Importantly, SRH06 prevented bipolar clustering of extra-centrosomes in breast cancer cells and significantly reduced colony formation and cell viability, but was less toxic to normal LL47 fibroblasts. Therefore, SRH06 provides a very valuable tool to study the biological function of KIFC1 and serves as a potential lead for the development of a novel therapeutic agent for the treatment of breast cancer. Citation Format: Wei Zhang, Ling Zhai, Wenyan Lu, Yimin Wang, Vandana V. Gupta, Indira Padmalayam, Robert J. Bostwick, Lucile White, Ross Larry, Joseph Maddry, Sam Ananthan, Mark Suto, Bo Xu, Rongbao Li, Yonghe Li. Discovery and evaluation of a small molecule KIFC1 inhibitor for breast cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1746. doi:10.1158/1538-7445.AM2015-1746

KIFC1 is a novel potential therapeutic target for breast cancer

Kinesin-like protein KIFC1, a normally nonessential kinesin motor, plays a critical role in centrosome clustering in cancer cells and is essential for the survival of cancer cells. Herein, we reported that KIFC1 expression is up-regulated in breast cancer, particularly in estrogen receptor negative, progesterone receptor negative and triple negative breast cancer, and is not associated with epidermal growth factor receptor 2 status. In addition, KIFC1 is highly expressed in all 8 tested human breast cancer cell lines, but is absent in normal human mammary epithelial cells and weakly expressed in 2 human lung fibroblast lines. Moreover, KIFC1 silencing significantly reduced breast cancer cell viability. Finally, we found that PJ34, a potent small molecule inhibitor of poly(ADP-ribose) polymerase, suppressed KIFC1 expression and induced multipolar spindle formation in breast cancer cells, and inhibited cell viability and colony formation within the same concentration range, suggesting that KIFC1 suppression by PJ34 contributes to its anti-breast cancer activity. Together, these results suggest that KIFC1 is a novel promising therapeutic target for breast cancer.

Abstract B96: Design, synthesis and biological evaluation of a novel allosteric inhibitor of HSET that damages cancer cells with supernumerary centrosomes.

Abstract Almost a century ago Theodor Boveri suggested that tumor cells differ from normal cells in their high incidence of centrosome amplification. However, only recently have new therapeutic strategies been explored in an attempt to exploit these differences and the role of kinesins in mitosis. Intense interest in the field has led to development of KSP and CENP-E inhibitors that have been tested clinically as treatments for human cancer. Success has been limited because both motor proteins are essential to normal mitosis and inhibition leads to mitotic arrest and associated neutropenia toxicity in normal cells. In contrast HSET is essential for survival of cancer cells with centrosome amplification and has been shown to be dispensable in normal cells. Hence, HSET inhibition offers a unique opportunity to selectively damage malignant cells with supernumerary centrosomes without affecting normal cells. In keeping with these findings we report discovery of a novel allosteric inhibitor of HSET, CW069, that does not disrupt division in normal human fibroblast cells, or in MCF-7 cells with normal centrosome numbers. In fact, CW069 induces multipolar mitosis exclusively in cancer cells with extra centrosomes, causing apoptosis via catastrophic aneuploidy. The increased multipolar mitoses induced in N1E-115 cells by inhibitor CW069 recapitulates the phenotype described here, and by others, for siRNA depletion of HSET. The inhibitor also reduces cell growth and centrosome clustering in cancer cells with a lower incidence of centrosome amplification, including BT549 and MDA-MB-231 breast cancer cells. This is consistent with recent reports that depletion of HSET in DNA damage repair deficient cells may be lethal even to cancer cells with low-level centrosome amplification. Taken together, these data indicate that CW069 inhibition of HSET is not restricted to use in N1E-115 cells with high centrosome amplification, and could be broadly applicable to a range of human cancers. What is more, CW069 does not decrease the clonogenic capacity of primary adult human bone marrow cells, suggesting that it would not cause neutropenia toxicity in normal cells. It is anticipated that HSET inhibition could have a greater therapeutic margin than KSP or CENP-E inhibition, and, to the best of our knowledge we have described the first allosteric inhibitor of HSET that reduces centrosome clustering but does not induce the mitotic phenotypes associated with inhibition of KSP or CENP-E. This selectivity for HSET is consistent with our computational model, which indicates that the HSET loop 5 displays dynamic conformational selection for CW069 that cannot be achieved by closely related KSP. In summary, CW069 not only represents a substantial advance toward new cancer therapeutics, but also offers researchers a unique tool to unveil the full details of HSET function in mitosis. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B96. Citation Format: Ciorsdaidh A. Watts, Frances M. Richards, Andreas Bender, Peter J. Bond, Oliver Korb, Oliver Kern, Michelle Riddick, Paul Owen, Rebecca M. Myers, Jordan Raff, Fanni Gergely, Duncan I. Jodrell, Steven V. Ley. Design, synthesis and biological evaluation of a novel allosteric inhibitor of HSET that damages cancer cells with supernumerary centrosomes. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B96.

Identification of novel small molecule inhibitors of centrosome clustering in cancer cells

Most normal cells have two centrosomes that form bipolar spindles during mitosis, while cancer cells often contain more than two, or "supernumerary" centrosomes. Such cancer cells achieve bipolar division by clustering their centrosomes into two functional poles, and inhibiting this process then leads to cancer-specific cell death. A major problem with clinically used anti-mitotic drugs, such as paclitaxel, is their toxicity in normal cells. To discover new compounds with greater specificity for cancer cells, we established a high-content screen for agents that block centrosome clustering in BT-549 cells, a breast cancer cell line that harbors supernumerary centrosomes. Using this screen, we identified 14 compounds that inhibit centrosome clustering and induce mitotic arrest. Some of these compounds were structurally similar, suggesting a common structural motif important for preventing centrosome clustering. We next compared the effects of these compounds on the growth of several breast and other cancer cell lines, an immortalized normal human mammary epithelial cell line, and progenitor-enriched primary normal human mammary epithelial cells. From these comparisons, we found some compounds that kill breast cancer cells, but not their normal epithelial counterparts, suggesting their potential for targeted therapy. One of these compounds, N2-(3-pyridylmethyl)-5-nitro-2-furamide (Centrosome Clustering Chemical Inhibitor-01, CCCI-01), that showed the greatest differential response in this screen was confirmed to have selective effects on cancer as compared to normal breast progenitors using more precise apoptosis induction and clonogenic growth endpoints. The concentration of CCCI-01 that killed cancer cells in the clonogenic assay spared normal human bone marrow hematopoietic progenitors in the colony-forming cell assay, indicating a potential therapeutic window for CCCI-01, whose selectivity might be further improved by optimizing the compound. Immunofluorescence analysis showed that treatment with CCCI-01 lead to multipolar spindles in BT-549, while maintaining bipolar spindles in the normal primary human mammary epithelial cells. Since centrosome clustering is a complex process involving multiple pathways, the 14 compounds identified in this study provide a potentially novel means to developing non-cross-resistant anti-cancer drugs that block centrosome clustering.

HURP permits MTOC sorting for robust meiotic spindle bipolarity, similar to extra centrosome clustering in cancer cells

In contrast to somatic cells, formation of acentriolar meiotic spindles relies on the organization of microtubules (MTs) and MT-organizing centers (MTOCs) into a stable bipolar structure. The underlying mechanisms are still unknown. We show that this process is impaired in hepatoma up-regulated protein (Hurp) knockout mice, which are viable but female sterile, showing defective oocyte divisions. HURP accumulates on interpolar MTs in the vicinity of chromosomes via Kinesin-5 activity. By promoting MT stability in the spindle central domain, HURP allows efficient MTOC sorting into distinct poles, providing bipolarity establishment and maintenance. Our results support a new model for meiotic spindle assembly in which HURP ensures assembly of a central MT array, which serves as a scaffold for the genesis of a robust bipolar structure supporting efficient chromosome congression. Furthermore, HURP is also required for the clustering of extra centrosomes before division, arguing for a shared molecular requirement of MTOC sorting in mammalian meiosis and cancer cell division.

A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells

Many cancer cells contain more than two centrosomes, which imposes a potential for multipolar mitoses, leading to cell death. To circumvent this, cancer cells develop mechanisms to cluster supernumerary centrosomes to form bipolar spindles, enabling successful mitosis. Disruption of centrosome clustering thus provides a selective means of killing supernumerary centrosome-harboring cancer cells. Although the mechanisms of centrosome clustering are poorly understood, recent genetic analyses have identified requirements for both actin and tubulin regulating proteins. In this study, we demonstrate that the integrin-linked kinase (ILK), a protein critically involved in actin and mitotic microtubule organization, is required for centrosome clustering. Inhibition of ILK expression or activity inhibits centrosome clustering in several breast and prostate cancer cell lines that have centrosome amplification. Furthermore, cancer cells with supernumerary centrosomes are significantly more sensitive to ILK inhibition than cells with two centrosomes, demonstrating that inhibiting ILK offers a selective means of targeting cancer cells. Live cell analysis shows ILK perturbation leads cancer cells to undergo multipolar anaphases, mitotic arrest and cell death in mitosis. We also show that ILK performs its centrosome clustering activity in a focal adhesion-independent, but centrosome-dependent, manner through the microtubule regulating proteins TACC3 and ch-TOG. In addition, we identify a specific TACC3 phosphorylation site that is required for centrosome clustering and demonstrate that ILK regulates this phosphorylation in an Aurora-A-dependent manner.

Proteins Required for Centrosome Clustering in Cancer Cells

Current cancer chemotherapies are limited by the lack of tumor-specific targets, which would allow for selective eradication of malignant cells without affecting healthy tissues. In contrast to normal cells, most tumor cells contain multiple centrosomes, which tend to cause the formation of multipolar mitotic spindles, chromosome segregation defects, and cell death. Nevertheless, many cancer cells divide successfully because they can cluster multiple centrosomes into two spindle poles. Inhibition of this centrosomal clustering, with consequent induction of multipolar spindles and subsequent cell death, would specifically target cancer cells and overcome one limitation of current cancer treatments. We have performed a genome-wide RNA interference screen to identify proteins involved in the prevention of spindle multipolarity in human cancer cells with supernumerary centrosomes. The chromosomal passenger complex, Ndc80 microtubule-kinetochore attachment complex, sister chromatid cohesion, and microtubule formation via the augmin complex were identified as necessary for centrosomal clustering. We show that spindle tension is required to cluster multiple centrosomes into a bipolar spindle array in tumor cells with extra centrosomes. These findings may explain the specificity of drugs that interfere with spindle tension for cancer cells and provide entry points for the development of therapeutics.