Prof Kate Sutherland, Lab Head | WEHI Researcher Profile

Q: Exploiting KEAP1 vulnerabilities to treat aggressive lung cancer

Alternations in the KEAP1-NRF2 pathway are found in a high percentage of non-small cell lung cancers and led to enhanced NRF2 activity. Critically, increased expression of NRF2 is associated with poor prognosis, highlighting the urgent need for new therapeutic strategies for this subgroup of patients.To understand the effect of KEAP1-NRF2 pathway alternations on lung cancer, we have engineered in vivo models that faithfully mimic KEAP1-mutant human lung cancers.Current work is focused on identifying effective treatments that target KEAP1-mutant lung cancer. To achieve this, we will utilise CRISPR/Cas9 technologies and perform high-throughput drug screening in collaboration with the National Drug Discovery Centre (NDDC).

Q: Immune regulation in lung cancer

Immunotherapeutic approaches, such as monoclonal antibodies targeting PD-1/PD-L1 and CTLA-4 unleash the T cell response to eliminate tumour cells. While this approach has shown considerable promise in lung cancer patients, not all patients will respond to conventional T cell-based immunotherapies.In response to this, we aim to harness the anti-tumour activity of other immune cell populations, such as Natural Killer cells and macrophages.

Q: Identifying drivers of small cell lung cancer metastasis

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with a five-year survival rate of less than 7 per cent. Critically, SCLC has a high propensity for early spread, with 50-80 per cent of patients harbouring metastatic lesions in multiple organs at the time of diagnosis. To understand underlying mechanisms controlling metastatic dissemination, we have developed in vivo SCLC models to augment metastatic activity.We aim to identify novel therapeutic approaches to restrict primary and metastatic disease in SCLC.

Q: Unravelling small cell lung cancer heterogeneity

Emerging evidence suggests that small cell lung cancer (SCLC) is a heterogeneous disease that can be classified into four distinct subtypes based on the differential expression of the transcription factors ASCL1, NEUROD1, POU2F3 and YAP1. This raises interesting biological questions that could directly inform the therapeutic treatment of SCLC patients.We aim to develop sophisticated CRISPR/Cas9 in vivo models to explore the genetic and cellular drivers of heterogeneity.

About

My laboratory generates preclinical models of lung cancer and employs diverse disciplines such as molecular biology, clinical oncology, immunology and metabolomics to prioritise clinically relevant questions.

One major interest is the development of novel preclinical models that closely resemble human lung cancer. Genetic alterations found in human lung cancer patients can be replicated in our models using Cre-LoxP recombination and CRISPR/Cas9 technology. We also have the ability to direct cancer-associated mutations to specific lung epithelial cell populations, which enables us to interrogate potential cells-of-origin.

Through flow cytometric studies we have developed methods to interrogate the immune microenvironment of lung cancer. We are interested in understanding mechanisms of immunosurveillance with the aim of exploiting this knowledge to harness the immune system to treat lung cancer.

We are also interested in tumour heterogeneity and how this heterogeneity influences metastatic dissemination in lung cancer. We have developed sophisticated preclinical models that mimic the metastatic behaviour of the human disease. Current efforts are focused on testing novel treatment strategies to control cancer spread.

Education

Grants and funding

Publications

Selected publications from Prof Kate Sutherland

Hyslop SR, Corbin J, Gangatirkar P, Lebois M, Au AE, Moujalled D, Pleines I, Sutherland KD, Andrews RK, Gardiner EE, Alexander WS, Josefsson EC. A GPVI signalling defect in newly formed platelets generated in stress thrombopoiesis. Journal of Thrombosis and Haemostasis. 2025;:10.1016/j.jtha.2025.02.035

Chen T, Ashwood LM, Kondrashova O, Strasser A, Kelly G, Sutherland KD. Breathing new insights into the role of mutant p53 in lung cancer. Oncogene. 2025;44(3):10.1038/s41388-024-03219-6

Ng J, Cai L, Girard L, Prall OWJ, Rajan N, Khoo C, Batrouney A, Byrne DJ, Boyd DK, Kersbergen AJ, Christie M, Minna JD, Burr ML, Sutherland KD. Molecular and Pathologic Characterization of YAP1-Expressing Small Cell Lung Cancer Cell Lines Leads to Reclassification as SMARCA4-Deficient Malignancies. Clinical Cancer Research. 2024;30(9):10.1158/1078-0432.ccr-23-2360

Chen T, Lieschke E, Scott L, Boyd D, Sutherland K, Strasser A, Kelly G. Abstract LT06: Understanding the Role of Mutant TP53 in Lung Cancer Using Novel Genetically Engineered Mouse Models. Cancer Research. 2024;84(8_Supplement):10.1158/1538-7445.fcs2023-lt06

Ng J, Pan E, Johnston A, Ribera NT, Kersbergen A, Hess JB, Best SA, Tsui E, Steinfort D, Sutherland KD. A Multiplexed Approach to Assess Small Cell Lung Cancer Subtype Heterogeneity in Primary and Patient-Derived Tumor Samples. Methods in Molecular Biology. 2024;2806:10.1007/978-1-0716-3858-3_10

McDonald JA, Boyd D, Diepstraten S, Scott L, Tai L, Kueh A, Burr M, Best SA, Herold MJ, Sutherland KD. Abstract A043: Identifying critical vulnerabilities that sensitise Lkb1 -mutant lung adenocarcinoma to T cell mediated killing. Cancer Immunology Research. 2023;11(12_Supplement):10.1158/2326-6074.tumimm23-a043

Zeissig MN, Ashwood LM, Kondrashova O, Sutherland KD. Next batter up! Targeting cancers with KRAS-G12D mutations. Trends in Cancer. 2023;9(11):10.1016/j.trecan.2023.07.010

Weeden CE, Gayevskiy V, Marceaux C, Batey D, Tan T, Yokote K, Ribera NT, Clatch A, Christo S, Teh CE, Mitchell AJ, Trussart M, Rankin L, Obers A, McDonald JA, Sutherland KD, Sharma VJ, Starkey G, D’Costa R, Antippa P, Leong T, Steinfort D, Irving L, Swanton C, Gordon CL, Mackay LK, Speed TP, Gray DHD, Asselin-Labat M-L. Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer. Cancer Cell. 2023;41(5):10.1016/j.ccell.2023.03.019

Wang Z, Hu H, Heitink L, Rogers K, You Y, Tan T, Suen CLW, Garnham A, Chen H, Lieschke E, Diepstraten ST, Chang C, Chen T, Moujalled D, Sutherland K, Lessene G, Sieber OM, Visvader J, Kelly GL, Strasser A. The anti-cancer agent APR-246 can activate several programmed cell death processes to kill malignant cells. Cell Death & Differentiation. 2023;30(4):10.1038/s41418-023-01122-3

Wang Z, Hu H, Heitink L, Rogers K, You Y, Tan T, Suen CLW, Garnham A, Chen H, Lieschke E, Diepstraten ST, Chang C, Chen T, Moujalled D, Sutherland K, Lessene G, Sieber OM, Visvader J, Kelly GL, Strasser A. Correction to: The anti-cancer agent APR-246 can activate several programmed cell death processes to kill malignant cells. Cell Death & Differentiation. 2023;30(4):10.1038/s41418-023-01137-w