Christopher Maxwell: Associate Professor at Department of Pediatrics, UBC Faculty of Medicine

Associate Professor

Faculty of Medicine

Research Classification

Cancer

Research Interests

Hereditary Cancer

Cell division

Cell migration

Differentiation

Cell polarity

Relevant Thesis-Based Degree Programs

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Affiliations to Research Centres, Institutes & Clusters

BC Children's Hospital Research Institute

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Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Hyaluronan mediated motility receptor regulates daughter cell size control pathways during mitosis (2023)

During cell division, one mitotic cell generates two daughter cells. Molecular pathways that build, stabilize and orient the mitotic spindle are critical during cell division as the mitotic spindle ensures equal segregation of chromosomes and controls the size of the daughter cells. During anaphase, the spindle mid-zone signals the cleavage site, a site that defines the separation of the daughter cells in most animal cells. Under normal conditions, the spindle is centred in the dividing cell, leading to equal-sized daughter cells. However, daughter cells with different physical sizes can be generated due to an off-centre spindle during anaphase. Unequal-sized daughter cells differ in their relative amounts of cytoplasmic content, such as organelles, which can affect their survival, growth, and behavior. Several mechanisms regulate daughter cell size in mitosis, including asymmetric cortical dynein pulling forces on the spindle and asymmetric membrane elongation at the cell surface. The Maxwell Lab revealed that the gene product hyaluronan mediated motility receptor (HMMR) plays an important role in the asymmetric cortical localization and activity of dynein, a pulling-force generating microtubule motor protein. Moreover, HMMR is a breast cancer susceptibility gene. My research now shows that HMMR also regulates asymmetric membrane elongation to control daughter cell size. My results reveal that HMMR-overexpressing cells display ectopic membrane elongation at anaphase as well as the ultimate loss of daughter cell size control; moreover, elevated HMMR expression correlates with activation of Aurora kinase A and mis-localization of components of the ARP2/3 complex, which potentially disrupts the stability of the cortex during mitosis. Collectively, my research identifies a new role for HMMR in the regulation of cortical integrity and daughter cell sizes potentially through an Aurora kinase A-dependent control of ARP2/3 complex localization to the mitotic spindle poles. The disruption of daughter cell size control mediated by elevated HMMR expression may contribute to heterogeneous cell size and genome instability that often occurs during tumorigenesis.

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Persistence of targetable genomes and proteomes through disease evolution in pediatric acute lymphoblastic leukemia (2023)

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. The five-year event free survival is 85% but the incidence of relapse is high and prognosis after relapse remains poor. To improve outcomes for those patients, precision medicine programs are designed to target specific genomic alterations. Although many biomarkers have been identified, targeted therapies have been less successful than expected. This is primarily a consequence of the aggressiveness of relapse cancers and the limited understanding of functional changes underlying genetic biomarkers. Ideally, the molecular and functional characterization of potential targets could start earlier to prepare for potential relapse. However, there are conflicting reports of how targetable lesions persist through disease progression and little known about progression in ALL proteomes. I hypothesize that the targetable lesions detected in childhood leukemias will be stable through disease progression and the combined genome and proteome analysis will better clarify dysregulated pathways. I first assessed the performance of a recently developed childhood cancer-specific next generation sequencing (NGS) assay in 28 childhood tumour specimens. The childhood cancer-specific assay detected almost 10% more targets than a broad cancer panel and both panels showed high concordance with whole-genome sequencing (WGS). I next investigated genomic stability and persistence of druggable events in paired diagnosis (Dx)-relapse (R) samples from 11 patients treated at BC Children’s Hospital, and whole exome sequencing data from paired Dx-R samples from 69 patients treated at St. Jude’s Hospital. Approximately 64% of patients had at least one druggable target retained between diagnosis and relapse. Six paired specimens were treated in-vitro with variant-matched targeted inhibitors, and although the sensitivity to inhibitors was low, IC50 doses of paired samples were highly correlated (r=0.8486). Similarly, a comprehensive proteome analysis of paired ALL specimens revealed high statistical equivalence (median = 85%) and similar abundance profiles of cancer-associated proteins between diagnosis and relapse. Finally, discovery whole-proteome analysis identified PARP1 as a potential new pan-ALL therapeutic target, and sensitivity to PARP1/2 inhibitors was confirmed via in-vitro drug assays. My thesis indicates that comprehensive interrogation of tumour genomes and proteomes through disease progression may provide support for implementing a prospective precision oncology approach.

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Aurora kinase A, regulated by HMMR and TPX2, controls cell migration and engraftment via centrosome polarization (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.

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BRCA1 regulates the PLK1-mediated spindle positioning pathway that promotes luminal features and may suppress tumorigenesis in mammary epithelial cells (2021)

Female carriers of mutations in Breast cancer, early onset 1 (BRCA1) show an elevated risk to develop breast cancers that resemble the primitive and proliferative cells of the mammary gland. BRCA1 is proposed to regulate the homeostasis of mammary progenitor cells, but its actions are not completely known. I hypothesize that BRCA1 regulates the positioning of the mitotic spindle, which ultimately controls the luminal features displayed in the progeny cells produced. I first used lentivirus transduction to silence BRCA1 expression in human mammary epithelial cells, including immortal MCF10A cells and primary cells isolated from reduction mammoplasty tissues. I found that the loss of BRCA1 function perturbed the cell division axis, which induced aneuploidy in progeny cells, reduced colony output, and perturbed the expression of luminal features. Mechanistically, a dynein-based pathway was disturbed by loss of BRCA1 function. I then studied the ex vivo growth of human mammary cells isolated directly from female carriers with pathogenic BRCA1 mutations. These progenitor-derived cells exhibited lower BRCA1 levels, higher radiosensitivity, and changes to the cell division axis. I used genome editing in MCF10A cells to model and study heterozygous BRCA1 mutations. These studies identified low BRCA1 expression and an inability to correctly orient the cell division axis in cells encoding pathogenic mutations. Subsequent proteomic analysis indicated PLK1 hyperactivity and treatment with a PLK1 inhibitor recovered the cell division axis and the acquisition of luminal features in primary mammary cells isolated from Brca1 mutant mice or female carriers with pathogenic BRCA1 mutations. Finally, I examined the tumorigenic processes that are altered through tissue-specific overexpression of a BRCA1 modifier, termed HMMR. From BLG-Cre;Brca1f/f;Trp53+/- mammary tissues, I isolated and studied epithelial cells that showed a loss of genome stability and activation of cGAS-STING and NF-κB signaling. HMMR overexpression increased the expression of immune-related genes that are known to recruit macrophages and promote a pro-tumorigenic microenvironment. Together, these research findings indicate BRCA1 controls mitotic spindle orientation. The disruption of this mechanism may underlie the changes observed in mammary epithelial cells and the increased risk to develop basal-like breast cancer that is observed in female carriers of BRCA1 mutations.

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The non-motor protein RHAMM locates TPX2 to coordinate spindle assembly and balance motor forces needed to segregate chromosomes and complete cell division (2017)

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.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Targeting centrosome amplification in aneuploid B-cell precursor acute lymphoblastic leukemia (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.

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Modification of rhamm and TPX2 optimizes Aurora Kinase A (aurica) inhibition in malignant peripheral nerve sheath tumours (2013)

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.

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