Project ID CM-HD2024_36


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Randall Centre for Cell & Molecular BiophysicsWebsite

Co Supervisor 1B Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Craniofacial & Regenerative BiologyWebsite

RNA binding protein regulation of cancer cell metabolism and tumorigenesis

Cancer cells have altered metabolism to cope with high energy demands associated with cell proliferation, migration and survival. The Conte and Grigoriadis labs are exploring the use of metabolic profiling allied to transcriptomics and proteomics to elucidate the role of two RNA binding proteins, LARP4A and LARP4B, that are key regulators of cancer cell behaviour and tumour progression.
Our current work demonstrated that silencing of LARP4A and 4B inhibits cancer cell properties in vitro, and reduces tumour formation in xenograft models in vivo. LARP4A and 4B regulate the translation of a subset of mRNAs but the full list of target RNAs regulated by each LARP protein and the mechanisms linking mRNA translation regulation and cancer cell behaviour and tumourigenesis is not known. Our preliminary studies have used state-of-the-art NMR-based metabolomics and RNAseq transcriptomic analyses of LARP4A/B-depleted cancer cells to identify the metabolic and signalling pathways affected by these proteins, and multi-omics analysis identified targets involving hypoxia and glycolysis that are perturbed in knockdown cells. In this project the student will be trained in complementary skills of both Grigoriadis and Conte labs, including RNA structural biology, cancer cell biology and in vivo technology to achieve the following goals:
Year 1: Perform metabolomics and proteomics profiles of cancer cell lines that are depleted in LARP4A and/or LARP4B using siRNA and CRISPR/Cas9 technologies. Experiments will be conducted under different stress conditions, e.g. hypoxia and starvation. These experiments will be analysed by targeted and untargeted profiling for analysis of global changes.
Year 2: Validation of selected dysregulated genes, and analysis of metabolic profiles and function following small molecule inhibition and use of selected mutagenesis.
Years 3-4: Functional investigation of targets in vivo using multiple xenograft transplantation approaches and write-up.
These studies will shed light for the first time on the mechanisms underlying the cancer-related functions of LARP4A and LARP4B.

Representative Publications

Coleman JC, Hallett SR, Grigoriadis AE, Conte MR*. (2023) LARP4A and LARP4B in cancer: the new kids on the block – Int J Biochem Cell Biol, in press, doi: 10.1016/j.biocel.2023.106441; Cruz-Gallardo, I., Martino, L., Kelly, G., Atkinson, A., Trotta, R., De Tito, S., Coleman, P., Ahdash, Z., Gu, Y., Bui, T.TT Conte, M.R.* (2019) LARP4A recognises polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA. Nucleic Acids Res., 47:4272-4291, doi: 10.1093/nar/gkz144; Graziani. V., Garcia, A.R,, Alcolado, L.S., Le Guennec, A., Henriksson, M.A.*, Conte, M.R.* (2023) Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition. Sci Rep 13:1273. doi: 10.1038/s41598-023-27375-z
Coleman JC, Tattersall L, Yianni V, Knight L, Yu H, Hallett SR, Johnson P, Caetano A, Cosstick C, Ridley A, Gartland A, Conte MR*, Grigoriadis AE*. The RNA binding proteins LARP4A and LARP4B promote sarcoma and carcinoma growth and metastasis doi: – under revision in iScience; Weekes D, Kashima TG, Zandueta C, Perurena N, Thomas DP, Sunters A, Vuillier C, Bozec A, El-Emir E, Miletich I, Patiño-Garcia A, Lecanda F, Grigoriadis AE. (2016) Regulation of osteosarcoma cell lung metastasis by the c-Fos/AP-1 target FGFR1. Oncogene 35:2853; Cottone L, Ligammari L, Lee HM, Knowles HJ, Henderson S, Bianco S, Davies C, Strauss S, Amary F, Leite AP, Tirabosco R, Haendler K, Schultze JL, Herrero J, O’Donnell P, Grigoriadis AE, Salomoni P, Flanagan A. (2022). Aberrant paracrine signalling for bone remodelling underlies the mutant histone-driven giant cell tumour of bone. Cell Death Differ 29:2459. doi: 10.1038/s41418-022-01031-x