Cell stress and Premalignant Ovarian Cancer
Cancer cells are exposed to multiple intrinsic and extrinsic stresses that, rather than inducing cell death, are subverted to drive their malignant behaviour such as angiogenesis, chemotherapy resistance, invasion and metastasis (Cubillos-Ruiz et al 2017). This is achieved by limiting output from the unfolded protein response (UPR) pathway so that effectors of UPR such as XBP1 and BiP are kept in the correct balance to prevent apoptosis and protect autophagy (Chen & Cubillos-Ruiz, 2020). Recent work has demonstrated that RNA binding proteins (RBPs) play a key role in regulating gene expression through alteration of their RNA interactome during the ER stress response (Backlund et al, 2020). We have found high levels of the RBP LARP1 in pre-invasive ovarian cancer lesions and, in cell lines, we have demonstrated LARP1 regulates various aspects of the ER pathway through its interaction with the stress regulator BiP (GRP78). In this project, we will investigate how LARP1 regulates the cellular response to ER stress to drive malignant transformation. We will use murine and human tumour organoids and mouse models to characterise the role played by LARP1 in tumorigenesis and, specifically, in the formation of ovarian cancer from its origins in the fallopian tube.
The Blagden lab uses basic molecular research and RNA biology to address clinical questions. This proposal is led by two clinician scientists with a strong interest in gynaecological oncology and is designed to explore the molecular events that occur in the 6.5 years that it takes a preinvasive ovarian cancer (STIC) lesion to develop into clinical disease. The lab is already part of a UK wide RNA Alliance which will support some of the work – such as generating the mouse models. The project will include Mouse work, crossing GEMMs, extracting fallopian tubes, IHC, multiplex imaging, DNA and RNA extraction and sequencing, proteomic analysis, cell line work, RT-PCR, generating and maintaining organoids.
- Hopkins TG et al. The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer. Nucleic Acids Res. 2016
- Kim J et al. Cell Origins of High-Grade Serous Ovarian Cancer. Cancers (Basel). 2018 Nov 12;10(11):433. Bottom of Form
- Stavraka C, Blagden S. The La-Related Proteins, a Family with Connections to Cancer. Biomolecules. 2015 Oct 16;5(4):2701-22.