The Brown lab investigates the ways in which aberrant cellular metabolism contributes to malignant transformation, tumour progression and therapy resistance in cancer. This knowledge is applied to the pre-clinical development of novel and more effective interventions for cancer therapy.
Almost a century ago, pioneering studies by Otto Warburg revealed a fundamental difference between the metabolism of normal and cancer cells. However, it is only in the last decade that significant inroads have been made to understanding the critical importance of deregulated cellular metabolism in cancer. Consequently, there is growing interest in developing therapeutic strategies to exploit the metabolic vulnerabilities of cancer cells. We are investigating:
- How a variety of cell-intrinsic factors (genetic/epigenetic alterations, tissue of origin, cell of origin) and cell-extrinsic factors (access to nutrients, therapy exposure and microenvironmental interactions) impact the metabolic state of a cancer cell.
- How metabolic reprogramming contributes to cell survival, cell proliferation, therapy resistance, metastasis and immune escape.
Metabolic reprogramming and chemotherapy resistance in triple-negative breast cancer
Triple-negative breast cancer (TNBC) is a subtype of breast cancer for which treatment options are largely limited to conventional chemotherapy agents. Chemotherapy resistance is a major barrier to the successful treatment of TNBC and there is a critical need to identify novel therapeutic strategies to treat this disease. We have previously shown that chemotherapy agents reprogram the de novo pyrimidine synthesis pathway and demonstrated that a clinically approved inhibitor of this metabolic pathway can sensitize TNBC cells to chemotherapy (Cancer Discovery, 2017). We are continuing to investigate metabolic reprogramming events induced by chemotherapy and the contribution of the identified pathways to therapy resistance and tumour progression.
Cutting off the fuel supply to starve cancer: identifying the nutrient dependencies of cancer cells
In order to meet the metabolic demands associated with rapid proliferation, cancer cells must be able to either synthesise critical nutrients de novo (Cancer Discovery, 2021), or acquire these nutrients from the surrounding tumour microenvironment. Nutrient availability has a dramatic effect on gene essentiality and the essentiality of specific metabolic pathways. Until recently, little attention has been paid to the fact that traditional cell culture media does not mimic the in vivo metabolic environment. We have therefore adopted the use of a physiologically relevant culture media that can be manipulated in order to investigate the impact of nutrient availability on cell survival, cell proliferation, therapy resistance, metastasis and immune escape. Coupled with genetic approaches to perturb metabolic pathway activity, we seek to identify the nutrient dependencies of cancer cells with a view to developing novel strategies for cancer therapy.
Transcriptional regulation of cancer cell metabolism
Metabolic pathway activity can be modulated by allosteric, transcriptional or post-translational mechanisms. We are particularly interested in understanding the regulation of cellular metabolism by the oncogenic transcriptional regulator YAP. Taking advantage of integrated metabolomics and transcriptomic approaches, we have previously shown that approximately 34% of YAP target genes are related to cellular metabolism and demonstrated that YAP reprograms glucose/glutamine metabolism and lipogenesis to fuel tissue growth (Nature Cell Biology, 2016; EMBO Journal, 2018; Developmental Cell, 2022). We are continuing to investigate the impact of YAP on cellular metabolism and the involvement of YAP-dependent metabolic reprogramming events in the regulation of cell proliferation, tissue growth and tumour progression.
Metabolic regulation of antigen presentation/processing and tumour immune escape
During tumour development and progression, cancer cells employ diverse strategies to avoid elimination by the immune system. One of the primary mechanisms involves loss of immune recognition as a result of dysfunctions in antigen processing and presentation. Compromised antigen presentation has been observed across diverse tumour types and is associated with poor prognosis. In addition to impairing the ability of the immune system to control cancer, this mechanism of immune evasion negatively impacts the efficacy of clinically relevant immunotherapies. It is therefore of critical importance to understand the fundamental mechanisms regulating antigen presentation in cancer. We are examining the metabolic dependencies of antigen processing and presentation with a view to identifying novel strategies to recover immune surveillance in cancer.
Vaidyanathan S, Salmi TM, Sathiqu RM, McConville MJ, Cox AG*, Brown KK* (2022). YAP regulates an SGK1/mTORC1/SREBP-dependent lipogenic program to support proliferation and tissue growth. Developmental Cell. 57(6):719-31. *Corresponding authors
Bjelosevic S, Gruber E, Newbold A, Shembrey C, Devlin JR, Hogg SJ, Kats LM, Todorovski I, Fan Z, Abrehart TC, Pomilio G, Wei AH, Gregory GP, Vervoort SJ, Brown KK*, Johnstone RW* (2021). Serine biosynthesis is a metabolic vulnerability in FLT3-ITD-driven acute myeloid leukaemia. Cancer Discovery. 11(6):1582-99. *Corresponding authors
Brown KK*, Spinelli JB, Asara JM, Toker A* (2017). Adaptive reprogramming of de novo pyrimidine synthesis is a metabolic vulnerability in triple-negative breast cancer. Cancer Discovery. 7(4):391-9. *Corresponding authors
Cox AG, Hwang KL, Brown KK, Evason KJ, Beltz S, Tsomides A, O'Connor K, Galli GG, Yimlamai D, Chhangawala S, Yuan M, Lien EC, Wucherpfennig J, Nissim S, Minami A, Cohen DE, Camargo FD, Asara JM, Houvras Y, Stainier DY, Goessling W (2016). Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nature Cell Biology. 18(8):886-96.
Brown KK, Montaser-Kouhsari L, Beck AH, Toker A (2015). MERIT40 Is an Akt substrate that promotes resolution of DNA damage induced by chemotherapy. Cell Reports. 11(9):1358-66.
Brown KK*, Toker A* (2015). The phosphoinositide 3-kinase pathway and therapy resistance in cancer. F1000Prime Reports. 7:13. *Corresponding authors
Banerji S*, Cibulskis K*, Rangel-Escareno C*, Brown KK*, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, Sougnez C, Zou L, Cortes ML, Fernandez-Lopez JC, Peng S, Ardlie KG, Auclair D, Bautista-Piña V, Duke F, Francis J, Jung J, Maffuz-Aziz A, Onofrio RC, Parkin M, Pho NH, Quintanar-Jurado V, Ramos AH, Rebollar-Vega R, Rodriguez-Cuevas S, Romero-Cordoba SL, Schumacher SE, Stransky N, Thompson KM, Uribe-Figueroa L, Baselga J, Beroukhim R, Polyak K, Sgroi DC, Richardson AL, Jimenez-Sanchez G, Lander ES, Gabriel SB, Garraway LA, Golub TR, Melendez-Zajgla J, Toker A, Getz G, Hidalgo-Miranda A, Meyerson M (2012). Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 486(7403):405-9. *Equal first authors
Christoforides C, Rainero E, Brown KK, Norman JC, Toker A (2012). PKD controls αvβ3 integrin recycling and tumor cell invasive migration through its substrate Rabaptin-5. Developmental Cell. 23(3):560-72.