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William Lockwood, Ph.D.

Scientist - Genetics Unit, Integrative Oncology

 wlockwood@bccrc.ca, 604-675-8264, Rm 10-113 ▪ 675 West 10th Avenue, Vancouver, B.C., V5Z 1L3, Canada 

Administration  

Heather Saprunoffhlsaprunoff@bccrc.ca , 604-675-8111

BCCA | BCCRC | Integrative Oncology |


 Will Lockwood


Current Appointments

Scientist, Integrative Oncology, BC Cancer Agency
Assistant Professor, Pathology and Laboratory Medicine, University of British Columbia


Training

BSc (Microbiology and Immunology), University of British Columbia, 2004
PhD (Pathology and Laboratory Medicine), University of British Columbia, 2009
Post-Doctoral Fellow (Cancer Biology and Genetics), with Harold Varmus, Memorial Sloan-Kettering Cancer Center, 2009-2010
Post-Doctoral Fellow (Cancer Genetics), with Harold Varmus, National Human Genome Research Institute, 2010-2014


Selected Awards

Postgraduate Scholarship. National Sciences and Engineering Research Council of Canada. 2004-2006 
Research Trainee Award (Junior). Michael Smith Foundation for Health Research. 2006-2008
Canadian Graduate Scholarship (Doctoral). National Sciences and Engineering Research Council of Canada. 2006-2008
Research Trainee Award (Senior). Michael Smith Foundation for Health Research. 2008-2010
Postdoctoral Fellowship. Canadian Institutes of Health Research. 2010-2013 
Scholar Award. Michael Smith Foundation for Health Research. 2014-2019
New Investigator Award. Canadian Institutes of Health Research. 2016-2021

Other Awards

British Columbia Cancer Agency Betty Rice Memorial Award for Lung Cancer Research. 2008 
International Association for the Study of Lung Cancer Young Investigator Award. 2009
Canadian Institutes of Health Research Jean-Francois St. Dennis Fellowship in Cancer Research. 2010-2013  


Research Interests

Lung cancer, genomics, drug discovery, mouse models, cell lineage, oncogene signaling, immune response


Lockwood Lab Members

Current Members: 

Bryant Harbourne (Research Technician)

Jack Calder (MSc Student)

Tanya De Silva (PhD Student)

Daniel Lu (MSc Student)

Min Oh (MSc Student)

Hannah O'Farrell (Research Assistant)

Jennie Dolberg (Co-op Student)

Past Members: 

Amy Nagelberg (Co-op Student)

Jenny Wu (Directed Studies Student)

Sophia Wild (MSc Student)

Graduate Student and Postdoc Opportunities: Interested candidates please send CV and cover letter to Dr. Lockwood at wlockwood@bccrc.ca

| BCCA | BCCRC | Integrative Oncology | 


Research Program

Lung cancer is the leading cause of cancer mortality worldwide, suffering from a late stage of disease at the time of diagnosis and a paucity of effective therapeutic strategies to treat advanced tumours. However, with our increasing understanding of lung cancer biology has come the advent of targeted therapies to combat this devastating disease. These therapies target mutated components of key cellular pathways on which tumours have become dependent on for survival, yielding drastic initial response rates without the major side effects of traditional chemotherapies. Despite these successes two major problems remain: first, the majority of lung cancer patients have tumours without mutations in targetable genes and; second, all patients eventually develop resistance to treatment with these targeted agents. In addition, since lung tumours commonly have hundreds of mutated genes, it is difficult to pinpoint those that are responsible for tumour growth and resistance to therapy, creating a clear bottleneck in the translation of laboratory findings to a clinical setting.

My lab utilizes an integrative strategy to address these issues. Through analysis of the genomic profiles of human lung tumours, we aim to identify novel genes and pathways that are altered during lung cancer development. Furthermore, by combining this information with the characterization of mice genetically engineered to develop lung tumours, we attempt to elucidate the key genes driving lung cancer initiation, progression and response to therapy. Lastly, by screening libraries of chemical compounds across lung cancer cells, we aim to characterize novel inhibitors of these identified genes and their corresponding pathways that show promise for use as targeted therapies. Together, this work will further our understanding of lung cancer biology and create insight toward the development of new approaches to diagnose and treat patients suffering from this disease.

 

New

 

Figure 1. Genomics approaches to identify genes and pathways involved lung tumourigenesis.

Multiple genomics approaches are used to explore cancer biology. Clinical genomics involves the analysis of clinical tumour samples. Functional genomics entails either forward (i.e. insertion mutagenesis in mice) or reverse (shRNA in cancer cell lines) genetic screens. Chemical genomics involves interrogating cancer biology using small molecule probes. However, studies typically use these approaches in isolation, which magnifies their limitations. We utilize an integrative platform that coordinates these approaches to answer specific questions about lung cancer biology and define strategies for diagnosis and therapeutic intervention.

Funding: 

 MSFHR LogoCIHR LogoTFRI LogoImage result for iaslcBCCF Logo


Publications

*Citation Metrics: http://scholar.google.com/citations?user=He7XywkAAAAJ&hl=en

Refereed Journal Publications: 

1) Yadav S, Shah P, Rowbotham D, Singh N, Malik D, Lam W, Lockwood W, Beverly L (2015) Repression of Ubiquilin family members by MIR155 drives metastatic properties of cancer cells. Submitted to Molecular Oncology.

2) Becker-Santos DD, Thu KL, Pikor LA, English JC, Vucic EA, MacAulay CE, Robinson WP, Jurisica I, Lockwood WW, Lam S, Lam WL (2016) The developmental transcription factor NFIB is a potential target of oncofetal miRNAs and has significant clinical implications in lung adenocarcinoma. Journal of Pathology. In Press. 

3) Unni A*,†, Lockwood WW*,†, Zejnullahu K, Lee-Lin S, Varmus H (2015) Evidence that synthetic lethality underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma. eLIFE. 2015;4:e06907 [*co-first authorship]. †Corresponding author. 

4) Kulic I, Robertson G, Chang L, Baker J, Lockwood WW, Mok W, Fuller M, Fournier M, Wong N, Chou V, Robinson M, Chun H, Gilks B, Kempkes B, Thomson B, Hirst M, Minchinton A, Lam W, Jones S, Marra M, Karsan A (2015) Loss of the Notch effector RBPJ promotes tumorigenesis. Journal of Experimental Medicine. 212(1):37-52.

5) Saurabh K, Scherzer MT, Shah PP, Mims AS, Lockwood WW, Kraft AS, Beverly LJ (2014) The PIM family of oncoproteins: small kinases with huge implications in myeloid leukemogenesis and as therapeutic targets. Oncotarget. 30;5:8503-14.

6) Radulovich N, Leung L, Ibrahimov E, Navab R, Sakashita S, Zhu CQ, Kaufman E, Lockwood WW, Thu KL, Fedyshyn Y, Moffat J, Lam WL, Tsao MS (2014) Coiled-coil domain containing 68 (CCDC68) demonstrates a tumor-suppressive role in pancreatic ductal adenocarcinoma. Oncogene. In Press. Epub. 10.1038/onc.2014.357.

7) Lockwood W and Politi K (2014) MYCxing It Up with FGFR1 in Squamous Cell Lung Cancer. Cancer Discovery. 4(2): 152‑4.

8) Shah P, Lockwood WW, Saurabh K, Kurlawala M, Shannon S, Waigel S, Zacharias W, Beverley LJ (2014) Ubiquilin1 represses migration and epithelial to mesenchymal transition of human non-small cell lung cancer cells. Oncogene. 21 April 2014; doi:10.1038/onc.2014.97. 

9) Thu KL, Radulovich N, Becker-Santos DD, Pikor LA, Pusic A, Lockwood WW, Lam WL, Tsao MS. SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/β-catenin signaling. Oncogene. 2014 Jan 16;33(3):279-88.

10) Pikor LA, Lockwood WW, Thu KL, Vucic EA, Chari R, Gazdar AF, Lam S, Lam WL. YEATS4 Is a Novel Oncogene Amplified in Non-Small Cell Lung Cancer That Regulates the p53 Pathway. Cancer Res. 2013 Dec 15;73(24):7301-12.

11) Lockwood WW, Chandel SK, Stewart GL, Erdjument-Bromage H, Beverly LJ. The novel ubiquitin ligase complex, SCF(Fbxw4), interacts with the COP9 signalosome in an F-box dependent manner, is mutated, lost and under-expressed in human cancers. PLoS One. 2013 May 2;8(5):e63610.

12) Rodriguez-Blanco J, Schilling NS, Tokhunts R, Giambelli C, Long J, Liang Fei D, Singh S, Black KE, Wang Z, Galimberti F, Bejarano PA, Elliot S, Glassberg MK, Nguyen DM, Lockwood WW, Lam WL, Dmitrovsky E, Capobianco AJ, Robbins DJ. The hedgehog processing pathway is required for NSCLC growth and survival. Oncogene. 2013 May 2;32(18):2335-45.

13) Lockwood WW†, Zejnullahu K, Bradner JE, Varmus H (2012) Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci U S A. 109:19408-13.  †Corresponding author- Highlighted in Nature Reviews Cancer (Dec. 2012) - Recommended as an article of special significance by F1000  

14) Wilson IM, Vucic EA, Enfield KS, Thu KL, Zhang YA, Chari R, Lockwood WW, Radulovich N, Starczynowski DT, Banáth JP, Zhang M, Pusic A, Fuller M, Lonergan KM, Rowbotham D, Yee J, English JC, Buys TP, Selamat SA, Laird-Offringa IA, Liu P, Anderson M, You M, Tsao MS, Brown CJ, Bennewith KL, Macaulay CE, Karsan A, Gazdar AF, Lam S, Lam WL. EYA4 is inactivated biallelically at a high frequency in sporadic lung cancer and is associated with familial lung cancer risk. Oncogene. 2013 Oct 7. Dec 2012

15) Li M, Lockwood W, Zielenska M, Northcott P, Ra YS, Bouffet E, Yoshimoto M, Rutka JT, Yan H, Taylor MD, Eberhart C, Hawkins CE, Lam W, Squire JA, Huang A (2012) Multiple CDK/CYCLIND genes are amplified in medulloblastoma and supratentorial primitive neuroectodermal brain tumor. Cancer Genetics. 205:220-31.

16) Lockwood WW†, Wilson IM, Coe BP, Chari R, Pikor LA, Thu KL, Solis LM, Nunez MI, Behrens C, Yee J, English J, Murray N, Tsao MS, Minna J, Gazdar AF, Wistuba II, MacAulay CE, Lam S, Lam WL (2012) Divergent genomic and epigenomic landscapes of lung cancer subtypes underscore the selection of different oncogenic pathways during tumor development. PLoS One. 7(5):e37775. †Corresponding author.

17) Thu KL, Vucic EA, Chari R, Zhang W, Lockwood WW, English JC, Fu R, Wang P, Feng Z, MacAulay CE, Gazdar AF, Lam S, Lam WL (2012) Lung adenocarcinoma of never smokers and smokers harbor differential regions of genetic alteration and exhibit different levels of genomic instability. PLoS One. 7(3):e33003.

18) Lockwood WW*†, Thu KL*, Lin L, Pikor LA, Chari R, Lam WL, Beer DG (2012) Integrative genomics identified RFC3 as an amplified candidate oncogene in esophageal adenocarcinoma. Clinical Cancer Research. 18:1936-46. [*co-first authorship] †Corresponding author.

19) Lin L, Bass AJ*, Lockwood WW*, Wang Z, Silvers AL, Thomas DG, Li W, Chang AC, Orringer MB, Glover TW, Giordano TJ, Lam WL, Meyerson M, Beer DG (2012) Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma. Proc Natl Acad Sci U S A. 109:4251-6. [*co-second authorship].

20) Beverly LJ, Lockwood WW, Erdjument-Bromage H, Varmus HE (2012) Ubiquitination, localization and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1. Proc Natl Acad Sci U S A. 109:E119-26.

21) Somwar R, Erdjument-Broonage H, Larsson E, Shum D, Lockwood WW, Yang G, Sander C, Ouerfelli O, Tempst PJ, Djaballah H, Varmus H (2011) SOD1 is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines. Proc Natl Acad Sci U S A. 08:16375-80.

22) Taguchi A, Politi K, Pitteri SJ, Lockwood WW, Faça VM, Kelly-Spratt K, Wong CH, Zhang Q, Chin A, Park KS, Goodman G, Gazdar AF, Sage J, Dinulescu DM, Kucherlapati R, DePinho RA, Kemp CJ, Varmus HE, Hanash SM (2011) Lung cancer signatures in plasma based on proteome profiling of mouse tumor models. Cancer Cell. 20:289-99.

23) Starczynowski DT, Lockwood WW, Delehouzee S, Chari R, Wegrzyn J, Fuller M, Tsao M, Lam S, Gazdar AF, Lam WL, Karsan A (2011) TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer. Journal of Clinical Investigation. 21:4095-105.

24) Thu KL, Pikor LA, Chari R, Wilson IM, MacAulay CE, Tsao M, Gazdar AF, Lam S, Lam WL, Lockwood WW (2011) Disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-kappaB pathway activation in lung cancer. Journal of Thoracic Oncology. 6:1521-1529.

25) Thu KL, Chari R, Lockwood WW, Lam S, Lam WL (2011) miR-101 DNA Copy Loss is a Prominent Subtype Specific Event in Lung Cancer. Journal of Thoracic Oncology. 6:1594-8.

26) Lockwood WW, Stack D, Morris T, Grehan D, O’Keane C, Cumiskey J, Lam WL, Squire JA, Thomas D, O’Sullivan M (2011) Cyclin E1 is amplified and over-expressed in osteosarcoma. Journal of Molecular Diagnostics. 13:289-96.

27) Lockwood WW†, Chari R, Coe BP, Thu KL, Garnis C, Malloff CA, Campbell J, Williams AC, Hwang D, Buys TPH, Yee J, English JC, MacAulay C, Tsao MS, Gazdar AF, Minna JD, Lam S, Lam WL (2010) Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma. PLoS Medicine. 7(7):e1000315. †Corresponding author.

28) Gazdar AF, Girard L, Lockwood WW, Lam WL, Minna JD (2010) Lung cancer cell lines as tools for biomedical discovery and research. Journal of the National Cancer Institute. 102:1310-21.

29) Chari R, Coe BP, Vucic EA, Lockwood WW, Lam WW (2010) An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer. BMC Systems Biology. 7; 4:67.

30) Chari R, Thu KL, Wilson IM, Lockwood WW, Lonergan KM, Coe BP, Malloff CA, Gazdar AF, Lam S, Garnis C, MacAulay CE, Alvarez CE, Lam WL (2010) Integrating the multiple dimensions of genomic and epigenomic landscapes of cancer. Cancer and Metastasis Reviews. 29:73-93.

31) Soh J, Okumura N, Lockwood WW, Yamamoto H, Shigematsu H, Zhang W, Chari R, Shames D, Tang X, MacAulay C, Varella-Garcia M, Vooder T, Wistuba II, Lam S, Brekken R, Toyooka S, Minna JD, Lam WL, Gazdar AF (2009) Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. PLoS One. 4(10):e7464.

32) Kubo T, Yamamoto H, Lockwood WW, Fujii T, Ouchida M, Soh J, Takigawa J, Kiura K, Shimizu K, Date H, Minna JD, Lam WL, Gazdar AF, Toyooka S (2009) MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors. International Journal of Cancer. 24:1778-84.

33) Gandhi J, Zhang J, Xie Y, Shigematsu H, Soh J, Zhang W, Yamamoto H, Peyton M, Girard L, Lockwood WW, Lam WL, Garcia M, Minna JD, Gazdar AF (2009) Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. PLoS One. 4(2):e4576.

34) Lockwood WW†, Chari R, Coe BP, Girard L, MacAulay C, Lam S, Gazdar AF, Minna JD, Lam WL (2008) DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. Oncogene 27:4615-24. †Corresponding author.

35) Campbell JM*, Lockwood WW*,†, Buys THP, Chari R, Coe BP, Lam S, Lam WL (2008) Integrative genomic and gene expression analysis of chromosome 7 identified novel oncogene loci in non-small cell lung cancer. Genome 51: 1032-39. [*co-first authorship]. †Corresponding author.

36) Gao K, Lockwood WW, Li J, Lam WL, Li G (2008) Genomic analyses identify gene candidates for acquired irinotecan resistance in melanoma cells. International Journal of Oncology 32: 1343-50.

37) Coe BP, Chari R, Lockwood WW, Lam WL (2008) Evolving strategies for global gene expression analysis of cancer. Journal of Cellular Physiology 217:590-7.

38) Yamamoto H, Shigematsu H, Nomura M, Lockwood WW, Sato M, Okumura N, Soh J, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Date H, Lam WL, Minna JD, Gazdar AF (2008) PIK3CA mutations and gene copy number in human lung cancers. Cancer Research. 68:6913-21.

39) Thiberville C, Guillaud M, Lockwood WW, Lam WL, Follen M, Richards-Kortum R, MacAulay C (2007) Multi-scale systems biology applied to cervical inter-epithelial neoplasia. Gynaecologic Oncology 107:S72-82.

40) Lockwood WW†, Coe BP, Williams AC, MacAulay C, Lam WL (2007) Whole genome tiling path array CGH analysis of segmental copy number alterations in cervical cancer cell lines. International Journal of Cancer 120:436-43. †Corresponding author.

41) Chari R, Lockwood WW, Coe BP, Chu A, Macey D, Thomson A, Davies JJ, MacAulay C, Lam WL (2006) SIGMA: a system for integrative genomic microarray analysis of cancer genomes. BMC Genomics 7: 324.

42) Garnis C, Lockwood WW, Vucic E, Ge Y, Girard L, Minna JD, Gazdar AF, Lam S, MacAulay C, Lam WL (2006) High resolution analysis of non-small cell lung cancer cell lines by whole genome tiling path array CGH. International Journal of Cancer 118: 1556-64.

43) Chari R*, Lockwood WW*, Lam WL (2006) Computational methods for the analysis of array comparative genomic hybridization. Cancer Informatics 2:48-58. [*co-first authorship].

44) Lockwood WW*,†, Chari R*, Chi B, Lam WL (2006) Recent advances in array comparative genomic hybridization technologies and their applications in human genetics. European Journal of Human Genetics 14: 139-48. [*co-first authorship] †Corresponding author.

45) *Coe BP, *Lockwood WW, Girard L, Chari R, MacAulay C, Lam S, Gazdar AF, Minna JD, Lam WL (2006) Differential regulation of cell cycle pathways in small cell and non-small cell lung cancer. British Journal of Cancer 94: 1927-35. [*co-first authorship].

Journal Commentaries:

1) Lockwood W and Politi K (2014) MYCxing It Up with FGFR1 in Squamous Cell Lung Cancer. In the Spotlight. Cancer Discovery. February 2014.

Published Books and Book Chapters:

1) Coe BP, Lockwood WW, Chari R, Lam WL (2009) Comparative genomic hybridization on BAC arrays. Methods in Molecular Biology 556:7-19.

2) Buys TP, Wilson IM, Coe BP, Lockwood WW, Davies JJ, Chari R, DeLeeuw RJ, Shadeo A, MacAulay C, and Lam WL (2007) Key Features of BAC Array Production and Usage. In DNA Microarrays (Methods Express Series) (Schena M, ed), Scion Publishing, Ltd., Bloxham.

3) Buys TPH, Wilson IM, Coe BP, Lee EHL, Kennett JY, Lockwood WW, Tsui IFL, Shadeo A, Chari R, Garnis C, Lam WL (2007) Detailed comparisons of cancer genomes. In Comparative Genomics: Basic and Applied Perspectives. (Brown JR, ed.), CRC Press / Taylor & Francis, LLC. Boca Raton.