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 acquire relevant nutrients from the surrounding tumour microenvironment and effectively utilise these nutrients. 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 and glutamine metabolism to fuel tissue growth (Nature Cell Biology, 2016 and EMBO Journal, 2018). 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.
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 Discov. 7(4):391-9. *Co-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. Nat Cell Biol. 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 Rep. 11(9):1358-66.
Brown KK, Toker A (2015). The phosphoinositide 3-kinase pathway and therapy resistance in cancer. F1000Prime Rep. 7:13.
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. Dev Cell. 23(3):560-72.
An exciting opportunity exists for a postdoctoral researcher to join the Brown Lab to investigate the involvement of metabolic reprogramming in the regulation of malignant transformation, tumour progression and therapy resistance. For additional information contact Dr. Kristin Brown ([email protected]).