Karin Grunebaum Cancer Research Foundation Fellow Profile

Neil Ganem Boston, MA

Ph.D; Assistant Professor, Pharmacology and Medicine, Boston University School of Medicine

Fellow Profile

Current Site Of Practice:
Hospital Affiliation: Boston Medical Center
Focus of Research:
Fellowship Year: 2014 – 2016
Attended: Boston University


Cytokinesis failure triggers Hippo pathway activation

Genetically unstable tetraploid cells can promote tumorigenesis. Recent estimates suggest that ∼37% of human tumors have undergone a genome-doubling event during their development. This potentially oncogenic effect of tetraploidy is countered by a p53-dependent barrier to proliferation. However, the cellular defects and corresponding signaling pathways that trigger growth suppression in tetraploid cells are not known. Here, we combine RNAi screening and in vitro evolution approaches to demonstrate that cytokinesis failure activates the Hippo tumor suppressor pathway in cultured cells, as well as in naturally occurring tetraploid cells in vivo. Induction of the Hippo pathway is triggered in part by extra centrosomes, which alter small G protein signaling and activate LATS2 kinase. LATS2 in turn stabilizes p53 and inhibits the transcriptional regulators YAP and TAZ. These findings define an important tumor suppression mechanism and uncover adaptive mechanisms potentially available to nascent tumor cells that bypass this inhibitory regulation.

Ganem NJ*, Cornils H, Chiu, SY, O’Rourke, KP, Yimlamai D, Thery M, Camargo FD, and Pellman D. 2014. Cytokinesis failure triggers Hippo pathway activation. Cell. 158(4):833-848. *Co-corresponding author.

More: http://www.sciencedirect.com/science/article/pii/S0092867414008204

A Mechanism Linking Extra Centrosomes to Chromosome Instability

Co-Authors Neil Ganem, Susana Godinho, David Pellman

Chromosomal instability (CIN) is a hallmark of many tumours and correlates with the presence of extra centrosomes. However, a direct mechanistic link between extra centrosomes and CIN has not been established. It has been proposed that extra centrosomes generate CIN by promoting multipolar anaphase, a highly abnormal division that produces three or more aneuploid daughter cells. Here we use long-term live-cell imaging to demonstrate that cells with multiple centrosomes rarely undergo multipolar cell divisions, and the progeny of these divisions are typically inviable. Thus, multipolar divisions cannot explain observed rates of CIN. In contrast, we observe that CIN cells with extra centrosomes routinely undergo bipolar cell divisions, but display a significantly increased frequency of lagging chromosomes during anaphase. To define the mechanism underlying this mitotic defect, we generated cells that differ only in their centrosome number. We demonstrate that extra centrosomes alone are sufficient to promote chromosome missegregation during bipolar cell division. These segregation errors are a consequence of cells passing through a transient 'multipolar spindle intermediate' in which merotelic kinetochore-microtubule attachment errors accumulate before centrosome clustering and anaphase. These findings provide a direct mechanistic link between extra centrosomes and CIN, two common characteristics of solid tumours. We propose that this mechanism may be a common underlying cause of CIN in human cancer.

Nature 460, 278-282 (2009)

More: http://www.nature.com/nature/journal/v460/n7252/full/nature08136.html

DNA Breaks and Chromosome Pulverization from Errors in Mitosis

Co-Authors Karen Crasta, Neil Ganem, Regina Dagher, Alexandra Lantermann, Elena Ivanova, Yunfeng Pan, Luigi Nezi, Alexei Protopopov, Dipanjan Chowdhury, David Pellman

The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement.

Nature 482, 53-58 (2012)

More: http://www.nature.com/nature/journal/v482/n7383/full/nature10802.html