Keith Lawson

Appointments

Scientist, Princess Margaret Cancer Centre
Assistant Professor, Department of Surgery
Assistant Professor, Department of Medical Biophysics

At A Glance

• Our group has a particular focus on employing locoregional or “surgically” delivered cell-based therapies against genitourinary cancers, with the goal of developing minimally invasive, organ sparing, curative treatments for these patients
• We use innovative CRISPR-based genetic screening approaches applied to patient-derived humanized models to develop more effective cell based therapies
• Our work resides within the intersection of surgery, engineering, immunology and genetics, providing a highly collaborative, stimulating and multidisciplinary ecosystem to conduct research within.

Short Bio

Keith Lawson is a Urologic Surgeon and Scientist at the Princess Margaret Cancer Centre, and Assistant Professor of Surgery and Medical Biophysics at the University of Toronto. Dr. Lawson completed his Medical Degree and MSc at the University of Calgary and his residency in Urology at the University of Toronto where he also earned a PhD in Molecular Genetics through the Surgeon-Scientist Training program. He subsequently completed a fellowship in Urologic Oncology at the National Cancer Institute working in the laboratory of Dr. Marston Linehan.

Research Synopsis

Overview
By integrating innovative CRISPR-based genetic screening approaches with patient-derived humanized models, we aim to elucidate novel therapeutic strategies that bestow engineered cell therapies the ability to provide long term cures for patients. We have a particular focus on employing locoregional or “surgically” delivered cell-based therapies against genitourinary cancers, with the goal of developing minimally invasive, organ sparing, curative treatments for these patients. Our work resides within the intersection of surgery, engineering, immunology and genetics, providing a highly collaborative, stimulating and multidisciplinary ecosystem to conduct research within.

Theme 1: Overcoming the solid tumor microenvironment
The solid tumor microenvironment of genitourinary cancers are characterized by profound immune suppression with the accumulation of cytokines, regulatory cells and harsh physiochemical properties that pose significant barriers for successful immunotherapy. Our group is focused on identifying strategies to circumvent these barriers through an integrative genomics approach coupling multi-dimensional immune profiling of surgical samples with high-content spatial CRISPR screens. The goal of this work is to identify targets within the tumor microenvironment that can be exploited to improve engineered cell therapy.

Theme 2: Mapping the genetic architecture of inflammatory cell death
The induction of an inflammatory cell death response capable of priming protective antitumor immunity following cancer therapy is highly desirable and likely necessary to impart long term durable remissions. However, the genetic circuits that wire cancer cells towards an inflammatory (e.g. pyroptosis, necroptosis) vs. sterile cell death (e.g. apoptosis) response remains poorly understood given the significant cross-talk, redundancy and pleiotropy inherent in cell death signaling pathways. To address this fundamental knowledge gap our group is systematically mapping how genes interact to promote inflammatory cell death using high-content spatial and single cell CRISPR screens. We also study the subsequent immune response following inflammatory cell death initiation to understand how these intrinsic genetic interactions can be exploited to improve long term generation of protective immunity following cellular immunotherapy.

Theme 3: Developing novel humanized model systems
A major barrier to identifying mechanisms of response and resistance to cellular immunotherapy is the lack of experimental models required for their discovery and interrogation. Our group is exploring the utility of patient derived organoid and humanized murine models for capturing the genetic and immunological heterogeneity that is pervasive amongst genitourinary cancers.

Recent Publications

1. Bock, C., Datlinger, P., Chardon, F., Coelho, M., Dong, M., Lawson, K. A., Lu, T., Maroc, L., Norman, T., Song, B., Stanley, G., Chen, S., Garnett, M., Li, W., Moffat, J., Qi, L., Shapiro, R., Shendure, J., Weissman, J., & Zhuang, X. (2022). High-content CRISPR screening. Nature Reviews Methods Primers, 2, 8.
2. Lawson, K. A.*, Sousa, C. M.*, Zhang, X., Kim, E., Akthar, R., Caumanns, J. J., Yao, Y., Fan, Z. P., Hui, S., Krall, J. A., Simons, D., Slater, C., De Jesus, V., Tang, L., Huang, Q., Francis, E. A., Tong, A. H. Y., Brown, K. R., Ross, C., Aregger, M., Chan, K., Wang, X., Mero, P., Finelli, A., Ailles, L. A., Bader, G., Smolen, G. A., Kingsbury, G., Hart, T., Kung, C., & Moffat, J. (2020). Functional genomic landscape of cancer-intrinsic evasion of killing by T-cells. Nature, 586(7827), 120-126.
3. Aregger, M.*, Lawson, K. A.*, Billmann, M.*, Costanzo, M., Tong, A. H. Y., Chan, K., Rahman, M., Brown, K. R., Ross, C., Usaj, M., Nedyalkova, L., Sizova, O., Habsid, A., Pawling, J., Lin, Z., Abdouni, H., Weiss, A., Mero, P., Dennis, J. W., Gingras, A. C., Myers, C. L., Andrews, B. J., Boone, C., & Moffat, J. (2020). Systematic mapping of genetic interactions for de novo fatty acid synthesis. Nature Metabolism, 2, 499-513.
4. Lawson, K. A.*, Mostafa, A. A.*, Shi, Z. Q., Spurrell, J., Chen, W., Kawakami, J., Gratton, K., Thakur, S., Morris, D. G. (2016). Repurposing Sunitinib with Oncolytic Reovirus as a Novel Therapeutic Strategy for Renal Cell Carcinoma. Clinical Cancer Research, 22(23), 5839-5850