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.
Australia, The University of Melbourne, BSc (Hons), PhD
2019 Victorian Cancer Agency Mid-Career Fellowship
2016 The Peter and Julie Alston Centenary Fellowship in Cancer Research
2008 National Health and Medical Research (NHMRC) CJ Martin Fellowship
2007 Marie Curie International Incoming Fellowship
2019 NHMRC Project Grant (CIA; 1159955) “Harnessing the innate immune response to treat small cell lung cancer”
2018 NHMRC Project Grant (CIA; 1138275) “Tailoring treatment strategies for NRF2-driven lung cancer”
2014 Worldwide Cancer Research Project Grant (CIA; 14-0433) “Identification of mutations driving lung squamous cell carcinoma
Member of Cancer Council Victoria’s Standing Research Subcommittee
Editorial Board Member Biochemistry and Cell Biology
Best SA*, Hess JB*, Souza-Fonseca-Guimaraes F, Cursons J, Kersbergen A, Dong X, Rautela J, Hyslop SR, Ritchie ME, Davis MJ, Leong TL, Irving TL, Steinfort D, Huntington ND & Sutherland KD. (2020). Harnessing Nature Killer Immunity in Metastatic SCLC. J Thorac Oncol. 15(9):1507-1521 PMID: 32470639
Burr ML, Sparbier CE, Chan, KL, Chan Y, Kersbergen A, Lam EYN, Azidis-Yates E, Vassiliadis D, Bell CC, Gilan O, Jackson S, Tan L, Wong S, Hollizek S, Michalak EM, Siddle H, McCabe MT, Prinjha RK, Solomon BJ, Sandhu S, Dawson SJ, Beavis PA, Tothill R, Cullinane C, Lehner PJ, Sutherland KD and Dawson MA. (2018). An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell. 2019 Sep 24. PMID: 31564637
Best SA, Ding S, Kersbergen A, Dong X, Song JY, Xie Y, Reljic B, Li K, Vince JE, Rathi V, Wright GM, Ritchie ME and Sutherland KD. (2019). Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma. Nat Commun. 2019 Sep 13;10(1):4190. PMID: 31519898
Best SA*, Harapas C*, Kersbergen A, Rathi V, Asselin-Labat ML and Sutherland KD. (2018). FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium. Oncogene 37(46):6096-6104. *Joint-first authors. PMID: 29991799
Best SA, De Souza DP, Kersbergen A, Policheni AN, Dayalan S, Tull D, Rathi V, Gray DH, Ritchie ME, McConville MJ and Sutherland KD. (2018). Synergy between the KEAP1/NRF2 and PI3K pathway drives non-small cell lung cancer with an altered immune microenvironment. Cell Metab. 2018 Apr 3;27(4):935-943.e4. PMID: 29526543
Ferone G, Song JY, Sutherland KD, Bhaskaran R, Monkhorst K, Lambooij JP, Proost N, Gargiulo G and Berns A. (2016). SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin. Cancer Cell 30(4):519-532. PMID: 27728803
Sutherland KD, Song J-Y, Kwon MC, Proost N, Zevenhoven J, Berns A. Multiple cells-of-origin of mutant K-Ras–induced mouse lung adenocarcinoma. Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4952-7. PMID: 24586047
Sutherland K, Proost N, Brouns I, Adriaensen D, Song JY, Berns A. Cell of origin of small cell lung cancer: Inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer Cell. 2011;19(6):754-64. PMID: 21665149
Sutherland KD and Berns A. Cell of origin of lung cancer. Molecular Oncology. 2010;4(5):397-403. PMID: 20594926
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).
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.
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.
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.