Deciphering LIMD1’s Impact on Lung Cancer Progression and Therapeutic Response Using Novel Conditional Mouse Models

Primary supervisor: Tyson Valentine Sharp, Queen Mary University of London

Secondary supervisor: Adam Januszewski, Queen Mary University of London, Nicholas McGranahan, UCL

Project

The central thesis of this research project revolves around elucidating the pivotal role of LIMD1, a recognized tumour suppressor gene, in lung cancer progression, with a particular focus on non-small cell lung cancer (NSCLC). Leveraging the expertise of Prof. Tyson Valentine Sharp in the cancer molecular biology of LIMD1, Dr. Adam Januszewski’s clinical insights in oncology, and Dr. Nicky McGranahan’s pioneering contributions to cancer evolution and genomics, this project aims to shed light on the complex interplay between LIMD1 loss and lung cancer pathogenesis. Utilizing recently developed and first of it kind new lung cancer mouse model in the world new (LIMD1-conditional and LIMD1;KP-conditional mouse models), alongside comprehensive patient cohorts from Dr. Januszewski and TRACERx genomic landscapes curated by Dr. McGranahan, this initiative is poised to offer groundbreaking insights into the mechanistic underpinnings of LIMD1’s tumour-suppressive functions and its implications for therapeutic resistance and cancer evolution.

The inception phase of this project involves a detailed characterization of the novel mouse models, focusing on the molecular and phenotypic alterations ensuing from LIMD1 deletion, which recapitulate the human disease for the first time. This phase is designed to establish foundational knowledge of LIMD1’s role in lung tumorigenesis. Concurrently, an analysis of patient-derived cohorts will be conducted to identify correlative patterns of LIMD1 expression and lung cancer progression, providing a translational bridge between animal models and human disease. This dual approach ensures a comprehensive understanding of LIMD1’s biological significance, setting the stage for subsequent phases of the project.

As the research progresses into its second year, a deeper dive into the molecular pathways impacted by LIMD1 loss will be undertaken. Through integrative analyses combining data from our novel mouse models and patient cohorts, we aim to dissect the cellular mechanisms by which LIMD1 influences the tumour microenvironment, immune evasion, and therapeutic response. Special attention will be given to understanding how LIMD1’s interactions with key signalling pathways, such as the Hypoxia/HIFs, miRNA-mediated gene silencing and ferroptosis pathways, contribute to lung cancer heterogeneity and evolution. This multi-dimensional analysis is expected to unravel novel vulnerabilities associated with LIMD1 deficiency, providing a rational basis for targeted therapy development.

The final year of the project will focus on translating our findings into actionable therapeutic strategies. Leveraging insights gleaned from the molecular characterization of LIMD1’s role, we will initiate pre-clinical trials employing targeted therapies in our mouse models. This will involve a rigorous evaluation of therapeutic efficacy, resistance mechanisms, and potential synergies with existing treatment modalities, such as immunotherapy. Parallelly, collaborative efforts with Dr. Januszewski will explore the clinical applicability of our findings, aiming to identify biomarkers of response and resistance to targeted therapies in lung cancer patients. The culmination of these efforts will be the integration of our research findings into a comprehensive framework that delineates LIMD1’s significance in lung cancer biology and therapy.

This project represents a convergence of cutting-edge research methodologies, clinical insights, and genomic analytics, orchestrated under the guidance of a multidisciplinary team of experts. By unravelling the complexities of LIMD1’s role in lung cancer, we aim not only to advance our understanding of tumour biology but also to pave the way for the development of innovative therapeutic approaches. For a clinician scientist, this project offers an unparalleled opportunity to be at the forefront of translational lung cancer research, contributing to the next generation of cancer therapeutics.

References

1. Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes.
   Davidson K, Grevitt P, Contreras-Gerenas MF, Bridge KS, Hermida M, Shah KM, Mardakheh FK, Stubbs M, Burke R, Casado P, Cutillas PR, Martin SA, Sharp TV. Cell Death Dis. 2021 Nov 11;12(11):1075. doi: 10.1038/s41419-021-04355-7.PMID: 34764236
2. A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia.Foxler DE, Bridge KS, Foster JG, Grevitt P, Curry S, Shah KM, Davidson KM, Nagano A, Gadaleta E, Rhys HI, Kennedy PT, Hermida MA, Chang TY, Shaw PE, Reynolds LE, McKay TR, Wang HW, Ribeiro PS, Plevin MJ, Lagos D, Lemoine NR, Rajan P, Graham TA, Chelala C, Hodivala-Dilke KM, Spendlove I, Sharp TV.EMBO Mol Med. 2018 Aug;10(8):e8304. doi: 10.15252/emmm.201708304.PMID: 29930174
3. Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins.Bridge KS, Shah KM, Li Y, Foxler DE, Wong SCK, Miller DC, Davidson KM, Foster JG, Rose R, Hodgkinson MR, Ribeiro PS, Aboobaker AA, Yashiro K, Wang X, Graves PR, Plevin MJ, Lagos D, Sharp TV. Cell Rep. 2017 Jul 5;20(1):173-187. doi: 10.1016/j.celrep.2017.06.027.PMID: 28683311
4. The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Foxler DE, Bridge KS, James V, Webb TM, Mee M, Wong SC, Feng Y, Constantin-Teodosiu D, Petursdottir TE, Bjornsson J, Ingvarsson S, Ratcliffe PJ, Longmore GD, Sharp TV. Nat Cell Biol. 2012 Jan 29;14(2):201-8. doi: 10.1038/ncb2424.PMID: 22286099
5. The chromosome 3p21.3-encoded gene, LIMD1, is a critical tumor suppressor involved in human lung cancer development. Sharp TV, Al-Attar A, Foxler DE, Ding L, de A Vallim TQ, Zhang Y, Nijmeh HS, Webb TM, Nicholson AG, Zhang Q, Kraja A, Spendlove I, Osborne J, Mardis E, Longmore GD. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19932-7. doi: 10.1073/pnas.0805003105. Epub 2008 Dec 5.PMID: 19060205