Researchers in the Pearson laboratory investigate the molecular basis of the regulation of signalling pathways and their control of cell growth.
We aim to understand how deregulation of this process contributes to cancer and how it can be targeted to treat the disease, by:
- Understanding the signal transduction pathways underpinning cell growth control.
- Conducting biochemical and cell biology analysis of the role of deregulated cell growth in cancer.
- Analysing novel therapies targeting cell growth to treat cancer in pre-clinical models of lymphoma, ovarian and prostate cancers.
- Pharmacogenomic analysis of the pathogenesis of ovarian cancer and predictors of response to emerging targeted therapies.
Biochemical and molecular dissection of the mechanisms controlling ribosome biogenesis by the PI3K/AKT/mTORC1 network
Dysregulation of the PI3K/AKT/mTORC1 signalling pathway occurs in a wide variety of cancers and is thought to play an essential role in malignant transformation. The downstream actions of this pathway to regulate ribosome biogenesis and translation are essential for its oncogenic effects. The oncogene MYC, which is dysregulated in 15 to 20 per cent of human malignancies, interacts with the PI3K/AKT/mTORC1 pathway to form a super-signalling network in malignancy.
We hypothesise that PI3K/AKT/mTORC1 and MYC cooperate during malignancy to ensure ribosome biogenesis remains hard-wired in tumour cells. Our Science Signalling publication (Chan et al., 2011) illustrated MYC and PI3K/AKT/mTORC1 cooperation in the regulation of ribosomal DNA transcription by RNA polymerase I (Pol I) and ribosome biogenesis. More recently, we have demonstrated that combination therapy targeting Pol I transcription and the PI3K/AKT/mTORC1 pathway leads to significantly improved efficacy in treating MYC-driven lymphoma (Devlin et al., 2016). Thus, the next step is to elucidate the mechanism(s) underlying the cooperation between the MYC transcription network and the PI3K/AKT/mTORC1 pathway in the regulation of Pol I transcription, which forms the basis for this project.
- To identify mechanisms by which PI3K/AKT/mTORC1 and MYC pathways modulate Pol I elongation by candidate analysis and high-throughput functional genomics screens.
- To define the interactions between PI3K/AKT/mTORC1 and MYC required for control of Pol I transcription in MYC-driven lymphoma cells in vitro and in vivo.
- To investigate interactions between PI3K/AKT/mTORC1 and MYC required for regulating ribosome function by ribosome profiling and translatomics.
Metabolic control of ribosome biogenesis by PI3K/AKT/mTORC1 and MYC in cancer
Ribosome biogenesis is the major energy-consuming process in proliferating cells, and is rate limiting for the protein synthesis required for cell growth and division. Given the high-energy demand to make new ribosomes, it is not surprising that ribosome biogenesis is tightly linked to cellular metabolism.
We hypothesise that the PI3K/AKT/mTORC1 pathway and MYC are critical for nutrient regulation of ribosome biogenesis. We recently demonstrated that amino acid-dependent signalling via mTORC1 activation of S6K1 and MYC is essential for regulation of ribosome biogenesis.
The following aims will investigate this hypothesis:
- Define the mechanism(s) of ribosome biogenesis control in response to changes in nutrient (and energy) levels.
- Define the requirement for nutrient signalling and/or glutaminolysis in the regulation of ribosome biogenesis, cell growth and survival in MYC-driven B-cell lymphoma.
- Identify effective metabolism-modifying therapies that improve the efficacy of/overcome the resistance to ribosome biogenesis-targeting therapies.
AKT-driven senescence and cancer
Hyperactivation of the PI3K/AKT/mTORC1 signalling pathway is a hallmark of many sporadic human cancers. However, we and others have demonstrated that chronic activation of this pathway in normal cells induces senescence, which effectively acts as a “brake” on the progression to malignancy.
We hypothesise that specific genetic changes overcome this brake and permit the increased cell proliferation and transformation required for cancer development. Our previous work showed that AKT-induced senescence in normal human cells occurs via a p53 and mTORC1-dependent mechanism (Astle et al., 2011). Understanding the basis of oncogene-induced senescence in normal cells and how this is subverted in cancer cells will provide insight into the mechanism of cancer development and how it can be targeted. To investigate this, we have performed a multi-parametric genome-wide RNAi screen for bypass of AKT-induced senescence and identified several candidates.
This project aims to follow up on the screen results to:
- Define the mechanism underlying AKT-induced senescence in normal cells.
- Determine the genetic changes required to overcome AKT-induced senescence.
Hein N, Cameron DP, Hannan KM, Nguyen NN, Fong CY, Sornkom J, Wall M, Pavy M, Cullinane C, Diesch J, Devlin JR, George AJ, Sanij E, Quin J, Poortinga G, Verbrugge I, Baker A, Drygin D, Harrison SJ, Rozario JD, Powell JA, Pitson SM, Zuber J, Johnstone RW, Dawson MA, Guthridge MA, Wei A, McArthur GA, Pearson RB, Hannan RD (2017). Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. Blood. 129(21)2882-2895.
Rebello RJ, Kusnadi E, Cameron DP, Pearson HB, Lesmana A, Devlin JR, Drygin D, Clark AK, Porter L, Pedersen J, Sandhu S, Risbridger GP, Pearson RB*, Hannan RD*, Furic L* (2016). The dual inhibition of RNA Pol I transcription and PIM kinase as a new therapeutic approach to treat advanced prostate cancer. Clin Cancer Res. 22(22):5539-52. *Joint senior author
Devlin JR, Hannan KM, Hein N, Cullinane C, Kusnadi E, Ng PY, George AJ, Shortt J, Bywater MJ, Poortinga G, Sanij E, Kang J, Drygin D, O'Brien S, Johnstone RW, McArthur GA, Hannan RD, Pearson RB (2016). Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discov.6(1):59-70.
Wall M, Poortinga G, Stanley KL, Lindemann RK, Bots M, Chan CJ, Bywater MJ, Kinross KM, Astle MV, Waldeck K, Hannan KM, Shortt J, Smyth MJ, Lowe SW, Hannan RD, Pearson RB, Johnstone RW, McArthur GA (2013). The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discov.3(1):82-95.
Sheppard KE, Cullinane C, Hannan KM, Wall M, Chan J, Barber F, Foo J, Cameron D, Neilsen A, Ng P, Ellul J, Kleinschmidt M, Kinross KM, Bowtell DD, Christensen JG, Hicks RJ, Johnstone RW, McArthur GA, Hannan RD, Phillips WA, Pearson RB (2013). Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors. Eur J Cancer.49(18):3936-44.
Astle MV, Hannan KM, Ng PY, Lee RS, George AJ, Hsu AK, Haupt Y, Hannan RD, Pearson RB (2012). AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene.31(15):1949-62.
Bywater M, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, Wall M, Cluse L, Drygin D, Anderes K, Huser N, Proffitt C, Bliesath J, Haddach M, Schwaebe MK, Ryckman DM, Rice WG, Schmitt C, Lowe SW, Johnstone RW, Pearson RB, McArthur GA, Hannan RD (2012). Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53. Cancer Cell.22(1):51-65.