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G+PS regularly provides virtual sessions that focus on admission requirements and procedures and tips how to improve your application.
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - May 2021)
BACKGROUND- Cell migration and proliferation are hallmarks of carcinoma cells. These critical processes are often perceived as independent, but the control of microtubule nucleation at centrosomes may interconnect them. HYPOTHESIS- Aurora kinase A (AURKA) – hyaluronan mediated motility receptor (HMMR) – targeting protein for XKlp2 (TPX2), which control microtubule nucleation during mitosis, enable cancer cell engraftment and migration via microtubule organization at polarized centrosomes.METHODS AND RESULTS- We measured the engraftment kinetics of breast cancer cells in immunocompromised or immunocompetent mice and found that enrichment of cells in G1- phase reduced engraftment kinetics. I then used multi-parameter imaging of wound closure assays to track and measure cell cycle progression and the kinetics of cell migration individually and collectively in both mammary epithelial cells or breast carcinoma cells. I also assessed migratory kinetics following the impairment or overexpression of AURKA activity via small molecular inhibition or lentiviral transduction of green fluorescence protein (GFP)-AURKA, respectively.I found that S-phase or G2-phase cells exhibited an elevated velocity and directionality with front-polarized centrosomes and augmented microtubule nucleation capacity. AURKA, regulated by HMMR-TPX2, enabled this directed cell migration, and the silencing of HMMR dampened kinase activity, which associated with impaired nuclear transport of TPX2. Next, I found that AURKA is specifically expressed in leader cells, which polarize centrosomes towards the leading edge, whereas non-leader cells possess random centrosome polarity. Both the inhibition and ectopic expression of AURKA impacted collective migration as well as the emergence of leader cells. Finally, in 3,922 clinically annotated mammary carcinoma tissues, we find AURKA predicts breast cancer-specific survival and relapse-free survival in patients with estrogen receptor (ER)-negative (n= 941), triple negative phenotype (n= 538), or basal-like subtype (n= 293) breast cancers, but not in those patients with ER-positive breast cancer (n= 2,218). CONCLUSION- Epithelial cell migration relies on the organization of the microtubule cytoskeleton through the AURKA-TPX2-HMMR axis. The establishment of front-rear polarity mediated by AURKA activity in leader cells is one dissectible phenotype within a cohesive sheet of migratory cells. Thus, the AURKA molecular axis offers a therapeutic target for ER-negative breast cancer to potentially reduce the migration, colonization and expansion of metastatic cells.
Cell division requires the assembly and organization of a microtubule-based mitotic spindle. Microtubule assembly at multiple sites is dependent on Aurora kinase A activity, which is promoted through a complex with TPX2 (targeting protein for XKlp2). Subsequent organization of these microtubules and progression into anaphase requires balance between forces orchestrated by antagonistic motor complexes. My studies show that the non-motor protein RHAMM (receptor for hyaluronan mediated motility) integrates structural and biochemical pathways to ensure the fidelity of cell division. Silencing RHAMM in HeLa cells delayed the kinetics of spindle assembly. I located RHAMM to centrosomes and non-centrosome sites for microtubule nucleation and found it necessary for TPX2 localization and Aurora A activity at kinetochores. The RHAMM-TPX2 complex requires a conserved leucine zipper motif in RHAMM and a domain that includes the nuclear localization signal in TPX2. These findings indicate RHAMM is needed for spatially-regulated activation of Aurora A by TPX2, which coordinates spindle assembly. I monitored mouse embryonic fibroblasts deficient for RHAMM through division and identified defects progressing through the spindle checkpoint. In RHAMM-silenced HeLa cells, I identified sustained activation of the checkpoint with unfocused spindles and unattached kinetochores, implicating unbalanced motor activities mediated by kinesins. In metaphase-delayed cells, the abundance or location of checkpoint proteins was not altered. Moreover, aberrant spindle orientation could not account for each delayed division. In RHAMM-silenced cells, I found that the reciprocal immunoprecipitation of Eg5-TPX2, an inhibitory complex, was reduced and that the concurrent inhibition of Eg5-generated force recovered division kinetics. I also observed a prolonged metaphase delay in a proportion of RHAMM-silenced cells, which resolved through cohesion fatigue. Together, my findings indicate that RHAMM-mediated attenuation of Eg5-dependent outward forces is needed to align chromosomes and progress through division. Lastly, I identified defects in spindle structure and function in redundant models for RHAMM over-expression. Collectively, my studies demonstrate that RHAMM coordinates Aurora A signaling and balances motor forces that are needed for cell division. These findings provide novel insights into processes that are essential for mammalian cell division and the maintenance of genome stability.
Master's Student Supervision (2010 - 2020)
B-cell precursor acute lymphoblastic leukemia (B-ALL) remains the single largest contributor to relapse in the pediatric leukemia patient population and new treatments are sorely needed to address this clinical challenge. Centrosomes play an important role in cell division, and centrosome abnormalities are a common feature in cancer cells. Mitotic cells with centrosome amplification are likely to form multipolar spindles, which generally lead to cell death. Cancer cells, therefore, must cluster supernumerary centrosomes to form pseudo-bipolar mitotic spindles and maintain cancer cell viability. My study investigates the efficacy of emerging inhibitors of centrosome clustering as new therapies to target pediatric B-ALL cells. As normal cells do not need to use centrosome clustering pathways, these inhibitors have the potential for low toxicity to healthy and growing tissues. However, tumor cells often resist targeted therapies and it is prudent to expect tumor adaption. My study shows that centrosome clustering inhibitors induce genetic and genomic instability in refractory leukemia cells, including micronuclei, which localize the DNA sensor cGAS and increase production of pro-inflammatory signals. Thus, refractory tumor cells may be immunogenic and activate an innate immune response. Overall, these findings identify centrosome clustering inhibitors as potential therapies to kill tumor cells and condition an immunogenic population that may be targeted by immune-based therapies to achieve long-term immune protection.
Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatments as they often resist chemotherapies and have high rates of disease recurrence. Published analysis of copy number variation identified hemizygous loss of Hyaluronan Mediated Motility Receptor (HMMR, encodes RHAMM) in half of the examined high-grade MPNST, but not in benign neurofibromas or low grade tumours. RHAMM is a molecular brake for the mitotic kinase Aurora A (AURKA), so this loss of HMMR in high-grade MPNST may cause tumours to rely on AURKA activity and sensitizes them to aurora kinase inhibitors (AKI).Three MPNST cell-lines were profiled for the expression and activity of AURKA, as well as their responses to three AKI. The sensitivity of cell-lines with amplification of AURKA was reliant upon kinase activity, which correlated with the expression of the regulatory gene products TPX2 and RHAMM. Silencing of RHAMM, but not TPX2, increased AURKA activity and sensitized MPNST cells to AKI. All three AKIs reduced kinase activity in a dose-dependent manner, and AKI treatment induced cellular responses such as apoptosis, endoreduplication and cellular senescence. Additionally, two primary human MPNSTs grown in vivo as xenotransplants were treated with the AURKA-specific inhibitor MLN8237. Treatment resulted in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulated in stabilized disease. The MPNST cell-line S462 has a population of tumorigenic stem-like cells that can be grown in sphere culture. AURKA activity was critical to the propagation and self-renewal of sphere-enriched MPNST stem-like cells. AKI treatment significantly reduced the formation of spheroids, attenuated the self-renewal of spheroid forming cells, and promoted their differentiation. Silencing of TPX2 decreased AURKA activity, while silencing of RHAMM was sufficient to endow MPNST cells with an ability to form and maintain sphere culture. Collectively, our data indicate that AURKA is a rationale therapeutic target for MPNST, and tumour cell responses to AKI, which include differentiation, are modulated by the abundance of RHAMM and TPX2.
- A cross-standardized flow cytometry platform to assess phenotypic stability in B-ALL xenografts. (2021)
Cytometry. Part A : the journal of the International Society for Analytical Cytology,
- Diet as a Potential Moderator for Genome Stability and Immune Response in Pediatric Leukemia (2021)
- PDX models reflect the proteome landscape of pediatric acute lymphoblastic leukemia but divert in select pathways. (2021)
Journal of experimental & clinical cancer research : CR,
- A Model of Differential Mammary Growth Initiation by Stat3 and Asymmetric Integrin-α6 Inheritance. (2020)
- Hyaluronan Mediated Motility Receptor (HMMR) Encodes an Evolutionarily Conserved Homeostasis, Mitosis, and Meiosis Regulator Rather than a Hyaluronan Receptor (2020)
- FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning. (2019)
- Genetic Instability (2019)
Encyclopedia of Cancer (3rd edition),
- CD44-mediated hyaluronan binding marks proliferating hematopoietic progenitor cells and promotes bone marrow engraftment. (2018)
- Hyaluronan-binding by CD44 reduces the memory potential of activated murine CD8 T cells. (2018)
European journal of immunology,
- The non-motor adaptor HMMR dampens Eg5-mediated forces to preserve the kinetics and integrity of chromosome segregation. (2018)
Molecular biology of the cell,
- Tumor Variant Identification That Accounts for the Unique Molecular Landscape of Pediatric Malignancies. (2018)
Jnci Cancer Spectrum,
- Anti-angiogenic treatment for breast cancer? (2017)
Cancer treatment reviews,
- BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells. (2017)
- Cell Cycle-Dependent Tumor Engraftment and Migration Are Enabled by Aurora-A. (2017)
Molecular cancer research : MCR,
- HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development. (2017)
- Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers. (2015)
- Designing a broad-spectrum integrative approach for cancer prevention and treatment. (2015)
Seminars in cancer biology,
- Genomic Instability and Cancer Metastasis (2015)
Cancer Metastasis - Biology and Treatment,
- Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. (2015)
Seminars in cancer biology,
- Spatial regulation of Aurora A activity during mitotic spindle assembly requires RHAMM to correctly localize TPX2. (2014)
Cell cycle (Georgetown, Tex.),
- The Generation, Detection, and Prevention of Genomic Instability During Cancer Progression and Metastasis (2014)
Genomic Instability and Cancer Metastasis, , 15--38
- Tubers from patients with tuberous sclerosis complex are characterized by changes in microtubule biology through ROCK2 signalling. (2014)
The Journal of pathology,
- YB-1 transforms human mammary epithelial cells through chromatin remodeling leading to the development of basal-like breast cancer. (2014)
Stem cells (Dayton, Ohio),
- Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition. (2013)
- The cytoskeletal protein RHAMM and ERK1/2 activity maintain the pluripotency of murine embryonic stem cells. (2013)
- Exploring the link between MORF4L1 and risk of breast cancer. (2011)
Breast cancer research : BCR,
- Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. (2011)
- YB-1 evokes susceptibility to cancer through cytokinesis failure, mitotic dysfunction and HER2 amplification. (2011)
- Multifunctional proteins bridge mitosis with motility and cancer with inflammation and arthritis. (2010)
- TACC3-TSC2 maintains nuclear envelope structure and controls cell division. (2010)
Cell cycle (Georgetown, Tex.),
- Targeting tumour-initiating cells to improve the cure rates for triple-negative breast cancer. (2010)
Expert reviews in molecular medicine,
- Biological convergence of cancer signatures. (2009)
- Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells. (2008)
Leukemia & lymphoma,
- Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? (2008)
Journal of cell science,
- Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility. (2008)
- Genetic interactions: the missing links for a better understanding of cancer susceptibility, progression and treatment. (2008)
- Targeted and nontargeted effects of ionizing radiation that impact genomic instability. (2008)
- Geometric approach to segmentation and protein localization in cell culture assays. (2007)
Journal of microscopy,
- Targeting aurora kinases as therapy in multiple myeloma. (2007)
- The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma. (2007)
British journal of haematology,
- Intensity-based signal separation algorithm for accurate quantification of clustered centrosomes in tissue sections. (2006)
Microscopy research and technique,
- The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs. (2006)
- A potential role for centrosomal deregulation within IgH translocation-positive myeloma. (2005)
- Hyaluronan and hyaluronan synthases: potential therapeutic targets in cancer. (2005)
Current drug targets. Cardiovascular & haematological disorders,
- Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. (2005)
- Receptor for hyaluronan-mediated motility correlates with centrosome abnormalities in multiple myeloma and maintains mitotic integrity. (2005)
- RHAMM expression and isoform balance predict aggressive disease and poor survival in multiple myeloma. (2004)
- Fluorescence imaging of multiple myeloma cells in a clinically relevant SCID/NOD in vivo model: biologic and clinical implications. (2003)
- RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability. (2003)
Molecular biology of the cell,
- In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. (2002)
- The integration of tissue structure and nuclear function. (2001)
Biochemistry and cell biology = Biochimie et biologie cellulaire,
- Lymphagenesis and cancer metastasis. (1998)
British journal of cancer,