Unravelling the Mechanism of the Lung Tumour Suppressor LIMD1 from Cellular Metabolism to Malignant Transformation.

Lung cancer has a very poor survival rate; for disease to be detected earlier, and managed and treated better then more needs to be understood about how healthy cells are transformed into cancer cells.
Our group has identified a gene called LIMD1 which prevents the transformation of normal, healthy cells into cancer. We have found that LIMD1 is lost from cells as they progress towards becoming cancerous and this is a key step in their transformation. Rapidly dividing cancer cells need a constant supply of energy and exciting new data from our lab have revealed that the loss of LIMD1 from cells affects the way they make this energy, a series of processes broadly called metabolism.

Our project has been designed to thoroughly investigate the way in which loss of LIMD1 causes a switch from "normal" cell metabolism to a "cancerous" state. As well as needing a different amount and balance of nutrients, tumours have dramatically reduced supplies of oxygen and this is also linked to the way they adapt to changes in the requirement for energy. In this respect, we have previously shown that LIMD1 is required by cells to sense and adapt to the levels of oxygen around them. Therefore loss of LIMD1 in cancer cells will dramatically affect the way that they respond to changes in oxygen as tumours grow.

To best observe the transformation of normal human lung tissue into cancer we have adopted a 3D model of a small portion of tissue representative of the human upper airways. Using this model we will seek to determine which pathways of metabolism LIMD1 loss affects and, importantly, if these pathways give us new markers of early stages of lung cancer and potential targets for chemotherapy.

Lung cancer is the most common cancer worldwide, with in excess of 1.61 million new cases diagnosed each year, with 1 in 5 leading to death. The gene LIMD1 is lost early in the progression of non-small cell lung cancer including squamous cell carcinoma (SCC) of the lung and normally functions as a tumour suppressor.
In published work we recently demonstrated that LIMD1 loss results in stabilisation of HIF1 in a number of cell lines, new preliminary data shows that this mechanism is also present in primary human bronchial epithelial cells (HBECs).
We have previously shown that loss of LIMD1 leads to enhanced cellular transformation and exciting preliminary data from our groups shows that LIMD1 may also regulate metabolism, potentially driving this cellular transformation. Increased energy production is important for rapidly growing cells within tumours such as SCC and a shift towards a glycolytic Warburg-like phenotype is a common hallmark of cancer. Loss of LIMD1 leads to increased transcription of a number of genes involved in this metabolic shift. Silencing of LIMD1 also resulted in reduced pyruvate utilization and decreased mitochondrial function, suggesting an important role for LIMD1 in regulation of the mitochondrial energy production.
We hypothesise that loss of LIMD1 occurs in the lung epithelium at an early stage in its transformation towards SCC of the lung. This loss of LIMD1 leads to a metabolic re-programming, that may or may not depend mechanistically on HIF1 stabilisation, which drives this transformation. We will investigate this hypothesis using an organotypic primary HBEC culture where cells are grown at an air liquid interface (ALI) to recapitulate the adult upper airways. We believe that reversal of these LIMD1 loss induced metabolic changes by chemical agents may represent a novel therapeutic avenue for the treatment of SCC.
This exciting project will address the key role of LIMD1 as a master regulator of metabolism, and the Warburg-lik

We have designed our project so that we are able to generate multiple potential forms of impact from our findings. These impacts can be broadly separated into academic, healthcare and patient impact, and commercial impact. Our research findings will enhance the knowledge economy both nationally and globally, and we will present our findings in high quality, high readership journals and at national and international conferences to ensure that our research has this intended impact. Whilst the study itself will focus on basic biology to experimentally test our hypothesis regarding metabolism driving the tumourogenesis of non-small cell lung cancer (NSCLC), there are potential long term health benefits from translation of our research into the clinical stage. Our study is designed to find novel biomarkers of disease, namely a potentially unique cancer metabolite profile, and impact upon future drug treatment for identified subsets of NSCLC by identifying novel tractable molecular mechanisms of metabolic shift during the tumourogenesis of normal lung epithelium into NSCLC. Eventually this will have beneficial health care impacts by helping to inform upon clinical decisions in identifying NSCLC and the best course of treatment.
We believe that the findings from our research will allow us to encourage collaboration with industrial partners and we will actively pursue this to increase the impact of our work. We have previous success in securing patents for our technologies and as such we can identify the potential impact of our research for R&D. Patents PCT/GB09/19773.2 and GB1200743.1 are filed for our work in stem cell biology and the hypoxic response. R&D exploitation of our research findings will benefit the UK economy with increased research funding in the field of metabolism.