William Lockwood
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ADVICE AND INSIGHTS FROM UBC FACULTY ON REACHING OUT TO SUPERVISORS
These videos contain some general advice from faculty across UBC on finding and reaching out to a potential thesis supervisor.
Supervision Enquiry
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.
The MET receptor is a critical mediator of tumour progression, frequently overexpressed in advanced lung adenocarcinomas. Despite the existence of clinically approved MET inhibitors, incorporating MET-targeted therapies seldom improve patient outcomes. Recent genome-wide sequencing efforts identified recurrent splice site mutations in the MET proto-oncogene, pointing to a novel role driving tumour initiation. Using matched RNA-seq analyses, these mutations were shown to produce MET mRNA lacking exon 14, which encodes the juxtamembrane regulatory domain responsible for c-CBL mediated receptor degradation. The detection of MET splicing mutations strongly predicts response to anti-MET targeted therapies, and a causal link is well-established. However, the molecular biology underpinning MET-dependent tumour initiation is less understood. In the era of MET-targeted therapies, elucidating these mechanisms is crucial, as response rates remain short of those achieved by other tyrosine kinase inhibitors (e.g. targeting EGFR or ALK), and the emergence of secondary resistance is predicted to limit long-term efficacy. In this thesis, I used expression profiling to identify transcriptional changes associated with MET splice-mutant tumours. I developed isogenic expression models to demonstrate that mutant MET preferentially engages the RAS/MAPK signaling pathway over parallel alternatives, suggesting a critical dependence that can be selectively targeted. In collaboration with clinical investigators, I confirmed the importance of this pathway by showing that KRAS alterations commonly emerge as a mechanism of resistance in patients receiving MET-targeted therapies. In parallel, I established anti-MET drug-resistant lines from MET-mutant cells, with the aim of uncovering additional alterations that might predict clinical resistance. Using targeted genomic sequencing, I discovered independent mutations in SPOP and MGA, both encoding negative regulators of MYC. Transcriptional profiling further support a mechanistic overlap whereby cells independently reactivate MYC to achieve resistance, subsequently validated through MYC overexpression and knockdown experiments. Finally, I established a murine model of mutant MET-driven lung cancer to demonstrate its in vivo transformative potential. I evaluated the utility of this model for elucidating mechanisms of MET-driven tumour initiation, and as a platform for testing treatment strategies. As a whole, this thesis explores the mechanistic bases of tumour initiation and drug resistance, representing a targeted effort at advancing MET treatment strategies.
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High-throughput phenotype-based screening of large libraries of compounds without known targets can identify small molecules that elicit a desired cellular response, but additional approaches are required to find and characterize their targets and mechanisms of action. Through such a screen, the novel compound LCS3 was previously identified that selectively kills lung adenocarcinoma (LUAD) cells, but its mechanism of action remained unknown. This thesis used gene expression profiling to elucidate the cellular responses of LUAD cells to LCS3. I demonstrated that LCS3 induces NRF2 pathway activation and oxidative stress through the generation of reactive oxygen species in sensitive LUAD cell lines. I then developed and applied a thermal proteome profiling (TPP) approach and identified the disulfide reductases GSR and TXNRD1 as LCS3 targets. Through enzymatic assays using purified protein, I confirmed that LCS3 inhibits disulfide reductase activity through a reversible and uncompetitive mechanism. The results demonstrated that LCS3-sensitive LUAD cells are correspondingly sensitive to the synergistic inhibition of glutathione and thioredoxin pathways, suggesting a mechanistic overlap in cell death induced by LCS3 and lethality arising from disulfide reductase inhibition. I established that challenging resistant cells with oxidative stress increases reliance on the glutathione and thioredoxin pathways and sensitizes cells to LCS3 and dual disulfide reductase inhibition. Finally, a genome-wide CRISPR-Cas9 knockout screen identified the loss of NQO1 as a mechanism of LCS3 resistance. Together, this work shines light on the mechanism of action of LCS3 and demonstrates the potential utility of disulfide reductase inhibition in lung cancer. This work also highlights the ability of TPP to uncover novel targets of novel small molecules identified by high-throughput screens.
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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.
Lung cancer (LC) is the leading cause of cancer-related mortality globally, mainly due to its late diagnosis. Early detection and treatment of LC is therefore imperative to improve disease outcomes. With current LC screening guidelines, it is difficult to assess the importance of genetic predisposition as a predictor for LC risk. While several key genetic drivers of LC have been identified, their ability to be effectively targeted is limited. To identify novel genetic drivers of LC, our group performed integrative genomic analyses on never-smoker patients with lung adenocarcinoma (LUAD). This highlighted SNF2 Histone Linker PHD RING Helicase (SHPRH) as a candidate tumor suppressor gene in LUAD. SHPRH is located within a major lung cancer susceptibility locus and encodes an E3 ubiquitin ligase that facilitates DNA damage tolerance. This study aimed to evaluate the effect of SHPRH alteration on LUAD tumorigenesis and the tolerance of LUAD cells to DNA damage. LUAD datasets were analyzed to determine the association of SHPRH expression on survival outcomes, revealing that LUAD tumors frequently experience SHPRH copy number loss, which coincides with lower SHPRH expression and poorer survival outcomes. CRISPR/Cas9 knockout of SHPRH and a doxycycline-inducible system to express SHPRH in LUAD cell lines with varying SHPRH expression statuses was used to determine whether SHPRH expression affects their tumorigenic potential. It was observed that SHPRH re-expression in LUAD cells with inactivated SHPRH – not knockout or overexpression in cells without SHPRH disruption – reduces their colony growth and tumor formation. Further transcriptomic analyses to elucidate the mechanism that SHPRH may be acting in these cells highlighted several areas of interest for follow-up investigation. Finally, exploration into the influence of SHPRH expression on LUAD cellular fitness in response to DNA damaging lesions showed that it confers a protective effect that may be associated with alterations in cell cycle dynamics. Overall, this work provides phenotypic evidence for SHPRH expression having a tumor suppressive role in LUAD that may impact patient outcomes and the cellular response to DNA damage. Future work will focus on the implication of SHPRH expression and function to effectively predict, understand, and treat LUAD.
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Lung cancer is the leading cause of cancer mortality worldwide. Targeted therapies have improved outcomes for lung cancer patients carrying certain mutations, but challenges remain. Many tumours harbour mutations in uncharacterized genes or genes that are non-actionable due to difficulty of drug development. In addition, patients with lung tumours that initially respond to targeted therapies eventually develop resistance. Therefore, discovery and characterization of new genes that drive lung tumourigenesis is needed to improve treatment. Next-generation sequencing approaches have enabled identification of novel cancer drivers. However, gene discovery in lung cancer remains a challenge, as the high mutational burden frequenting these tumours makes it difficult to distinguish driver versus passenger events. In addition, computational pipelines for analysis of sequence data often use strict filters that may limit their power for gene discovery. This study attempts to identify novel candidate drivers of lung cancer using an approach that leverages greater flexibility in upstream bioinformatic parameters and emphasizes filters that are weighted to account for biological relevance. This is implemented using whole exome sequencing data from 15 never-smoker lung cancers and matched normal lung controls. The novel workflow presented here identified 12 new lung cancer candidate genes, as well as 9 previously identified drivers. Integration with independent datasets and a secondary custom-capture sequencing dataset in an expanded in-house cohort was used to evaluate mutation prevalence. Furthermore, copy number and expression data for the same tumours were used to assess evidence of two-hit alteration for candidate tumour suppressor genes, and correlations between gene status and patient survival were also evaluated. The candidates were also integrated with an in vivo Sleeping Beauty insertional mutagenesis screen in transgenic mouse models of lung cancer to evaluate their causative likelihood and functional relevance for lung tumour development. Three candidates — MAP3K5, SHPRH, and ASCC3, were identified as candidate tumour suppressor genes that passed analysis criteria and are located on or near the chromosomal region 6q23-25, which is frequently deleted in lung cancer and associated with familial lung cancer susceptibility. SHPRH was functionally validated, with preliminary confirmation of its tumour suppressive function presented.
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Lung cancer and its most common subtype, lung adenocarcinoma (LUAD), is the leading cause of global cancer mortality. Mortality is partially attributed to late stage diagnosis, where curative options are limited and less effective for patient survival. Current screening guidelines are prone to false positive results, and there are no lung cancer-specific biomarkers to aid detection. This is especially relevant for never smokers, a lung cancer patient demographic often characterized by the EGFR oncogenic mutation. Never smokers lack concrete screening guidelines; this makes biomarker discovery and validation crucial for earlier detection.The collective set of secreted proteins derived from a cell, known as the secretome, has been explored as a potential source of cancer biomarkers. However, LUAD secretome studies have been limited to late stage or metastatic tumors; investigation of secretome changes during malignant transformation may thus be more suitable for biomarker discovery. This thesis investigated changes in the secretome in an EGFR-driven model of LUAD malignant transformation. In this study, I generated a stepwise model of EGFR-driven malignant transformation by generating stable lung epithelial cell lines and selecting EGFR mutant NSCLC cell lines. I also developed and optimized a mass spectrometry protocol to profile the secretome of my model. With this pipeline, I identified differentially expressed proteins in advanced LUAD. I then validated these findings by performing differential gene expression (DGE) analysis on an EGFR mutant LUAD patient cohort. Finally, validated secreted proteins were assessed for effects on overall patient survival resulting in 4 EGFR-specific and 1 non-specific biomarker candidates. This work provides insight into potential secretome changes during LUAD malignant transformation, biomarker candidates for further validation, and illustrates the potential of the secretome in EGFR mutant LUAD detection.
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Mutations in the Epidermal Growth Factor Receptor (EGFR) and Kirsten Rat Sarcoma (KRAS) genes occur in a mutually exclusive manner in ~15% and ~30% of all lung adenocarcinomas (LACs), respectively. Using Doxycycline (Dox)-regulated gene expression vectors, we have previously demonstrated that the forced co-expression of EGFR and KRAS mutants in LAC cells induces lethality through the hyperactivation of the RAS-mitogen-activated protein kinase (MAPK) pathway. A subsequent phosphoproteomic assay using Tet-O-KRASG12V-PC9 cells, which carry an endogenous EGFR mutation and was engineered to express KRASG12V upon Dox treatment, revealed that phosphorylation of extracellular signal-regulated kinases (ERKs) increased acutely and dramatically compared to the Tet-O-GFP-PC9 control. This suggested that early activation of ERK1/2 is a crucial event in mediating the observed lethality. Additionally, genetic and pharmacological inhibition of ERK1/2 rescued multiple co-expression LAC cells, confirming that ERK is the main mediator of this phenomena. Here, I aim to investigate whether KRAS- or EGFR-driven LAC cells exploit any existing negative regulatory mechanisms of the ERK to maintain its levels below its upper signalling threshold. Because MAPK signalling is typically regulated by phosphatases, our group performed an analysis of the MAPK phosphatase expression data comparing two LAC TCGA tumor subsets – tumors with (n=107) and without (n=123) either EGFR or KRAS mutation. This analysis revealed that Dual-specificity phosphatase 6 (DUSP6) is the only phosphatase that is up-regulated in tumors with a mutation in either two genes in comparison to their wildtype counterparts, suggesting that these tumors may be dependent on a robust DUSP6 activity to moderate the P-ERK1/2 levels and prevent ERK hyperactivation. Furthermore, when DUSP6 was inhibited in mutant KRAS or mutant EGFR bearing LAC cells using DUSP6 small-interfering RNAs (siRNAs) or a DUSP6 inhibitor called (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI), we observed that only the mutant bearing LAC cells were more sensitive to DUSP6 inhibition than the KRAS and EGFR wildtype cells. Such findings suggest a potential therapeutic scenario in EGFR or KRAS mutant LACs can be targeting through inhibiting DUSP6, a key negative feedback regulator that prevents the hyperactivation of ERK.
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Lung cancer is the leading cause of cancer related death in both men and women worldwide, mainly due to the lack of effective therapies. The development of specific chemical compounds that target epigenetic post-translational modifications has recently emerged as an excellent approach for validating new treatment strategies for diseases that have complex underlying mechanisms. JQ1 is a small-molecule inhibitor of the bromodomain and extraterminal (BET) family proteins, which function as important reader molecules of acetylated histones and recruit transcriptional activators to specific promoter sites. In many cancer lines the down-regulation of MYC, a known oncogenic transcription factor and contributor to the pathogenesis in certain cancer types, has been linked to BET inhibitor (BETi) treatment. In addition, resistance to BETis has only been examined in MYC-dependent cancers, with all forms of resistance involving re-expression of MYC, through several mechanisms. Previously, our lab has shown that lung adenocarcinoma (LAC) cells are inhibited by JQ1 through a mechanism independent of MYC down-regulation, identifying FOSL1 as a mediator of response. This suggests that the epigenetic landscape of cells from different origins and differentiation states influences response to JQ1. Therefore, I aim to investigate how LAC cells, independent of MYC down-regulation, acquire resistance to BET inhibition, to elucidate mechanisms of primary resistance and potential treatment strategies for LAC.Here, I establish resistance in two JQ1 sensitive LAC cell lines and demonstrate that MYC levels were not significantly altered, nor was FOSL1 expression reactivated in resistant lines, indicating a novel mechanism of resistance. Interestingly, resistant lines were still dependent on the BET protein BRD4, as demonstrated by siRNA knockdown, suggesting that BRD4 may drive resistance through regulating gene transcription independent of its acetyl-binding domain. Both resistant lines showed increased levels of phosphorylated BRD4, and also up-regulation of casein kinase 2 (CK2), a kinase previously shown to phosphorylate BRD4. Furthermore, combining JQ1 with a CK2 inhibitor showed synergistic effects in both resistant lines, with treatment leading to decreased levels of pBRD4. Overall, we have determined that LAC cells develop JQ1 resistance through mechanisms independent of MYC, identifying CK2 phosphorylation of BRD4 as a likely mechanism of resistance.
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