Role of MRL proteins in cell proliferation and migration in vivo

Lead Research Organisation: King's College London
Department Name: Randall Div of Cell and Molecular Biophy

Abstract

During mammalian embryonic development cells migrate through the developing body in order to form some of the tissues. Many cells proliferate and migrate along specific pathways throughout the embryo but better understanding of pathfinding mechanisms are necessary. During cancer progression, cancer cells also proliferate and migrate through tissues and form metastases, the most common reason for cancer deaths. Therefore, it is of fundamental importance to understand how cell proliferation and migration through tissues is regulated in vivo. We have evidence that MRL proteins (Lpd, RIAM) are implicated in regulating cell proliferation and cell migration. We propose to analyze their role in signal transduction cascades regulating proliferation and migration. Furthermore, we will study the role of Lpd and RIAM in cell migration in live cell imaging experiments in vivo. These experiments will give valuable insights in signal transduction cascades controlling cell proliferation and cell migration in vivo.

Technical Summary

The MRL protein family (RIAM, Lpd) acts as a key convergence point regulating cell proliferation and migration downstream of growth factor receptors. Lpd knockout mice display cell proliferation and migration defects. We hypothesize that mammalian MRL proteins function downstream of growth factor receptors to regulate proliferation and efficient, directed migration of cells during vertebrate embryonic development. We propose to biochemically analyze the involvement of MRL proteins in signal transduction cascades downstream of growth factor receptors. We will use transgenenic reporter mice to specifically label a specific subset of cells in mice lacking Lpd and/or RIAM to quantify number and distribution of these cells throughout mouse development. Furthermore, a direct involvement of MRL proteins in cell migration will be analyzed by live cell imaging using tissue explants from mouse embryos deficient for Lpd and/or RIAM using GFP reporter mice.

Planned Impact

Many different beneficiaries might gain from the proposed research including pharmaceutical, biotechnology, and publishing companies, the public sector, and the wider public. Our proposed work aims to increase the knowledge about basic fundamental processes regulating cell proliferation and cell migration. These processes are absolutely essential for the normal development of the human body, for homoeostasis and deregulation of these processes contributes to development and progression of diseases. Therefore, biotechnology and pharmaceutical industry has an obvious interest in any knowledge gained from this work to develop targeted therapies or use this knowledge to develop diagnostic reagents for early detection of molecular alterations in signaling pathways indicative of onset and progression of diseases such as cancer and metastasis. Furthermore, publishing companies will gain by disseminating this knowledge either to beneficiaries in the biotechnology and pharmaceutical industry by publishing specialized journals and books or to the wider public by publishing the science sections in newspapers and magazines. The wider public will gain from the increase in knowledge about how the human body works on the molecular level. A major increase in knowledge about the function of the human body on the molecular level will define how we will live in this century and will transform society and will lead to major improvements in health and wealth. The gain in knowledge from the proposed research might have impact on the nation's health and wealth in several different ways. Increase in basic knowledge about fundamental processes how the human body develops and what is deregulated during development and progression of diseases will increase our basic knowledge. This will increase competitiveness of UK based universities thereby allowing them to attract more foreign students. Furthermore, this knowledge might allow biotechnology companies and the pharmaceutical industry to devise novel, targeted therapies. However, development of novel drugs requires considerable effort and time and the time frame from basic discovery to market introduction of novel drugs might take 10 years. Nevertheless, thorough testing of novel drugs is the only way to ensure that they improve human health and have only minor, acceptable side effects in a wide, diverse population. In addition, staff working on the proposed research project will acquire research and professional skills that they might apply later in a career in basic research, teaching, applied research in industry, publishing or in public services or policy. Furthermore, this potential improvement in public health might allow a longer happier and more productive life. Taken together, this might increase the competitiveness of the United Kingdom and may also foster global economic performance. KCL Public Relations department will disseminate knowledge gained through the proposed research to the general public through press releases. Furthermore, the web pages of the Randall Division disseminate information accessible for both, the general public and experts in academia and industry. Beneficiaries in the biotechnology and pharmaceutical industry and the public sector will be engaged through KCL Business Ltd. that has extensive experience to create significant partnerships with industry. If new discoveries will be made during the course of the proposed research we will liaise with KCL Business to assess potential exploitability of the discovery before any publication. King's Business will ensure successful protection of intellectual property by patenting novel inventions and discoveries and will then liaise with potential partners in industry to ensure exploitation of the novel discoveries.
 
Description We found that Lamellipodin and the Scar/WAVE complex cooperate to promote cell migration in vivo (JCB, 2013).
Exploitation Route Our research outcomes are actively being followed up by the academic research community and the results are of interest to the pharmaceutical industry.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description We envision that the results from our research will form the basis for the better understanding of pathways regulating cell migration in vivo. Since detailed knowledge of these pathways are required for drug developments against cancer metastasis, we envision that our results will create impact in endeavours by drug companies to develop novel targeted drugs.
 
Title METHODS FOR IDENTIFYING AND TREATING INVASIVE/METASTATIC CANCERS 
Description Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. Described herein are compositions and methods for assessing and treating a subject having metastatic cancer or at risk of developing metastatic cancer, e.g., metastatic breast cancer, through the determination of Lamellipodin protein or gene expression levels in the subject. 
IP Reference US2017269093 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. Described herein are compositions and methods for assessing and treating a subject having metastatic cancer or at risk of developing metastatic cancer, e.g., metastatic breast cancer, through the determination of Lamellipodin protein or gene expression levels in the subject.
 
Description Program "Shadow a Scientist" 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The Program "Shadow a Scientist" http://www.scientistsandco.org/projects/shadow-scientist/
The aim of this program is to increase the social mobility of highly motivated 16-18 year old pupils from disadvantaged backgrounds. It involves a 2-day shadowing experience with researchers at King's andtastersessions/workshops delivered in collaboration with KCLSU and King's Widening Participation department. We aim to boost the pupils' confidence in breaking cultural barriers and inspire them to pursue STEM subjects.
Year(s) Of Engagement Activity 2016
URL http://www.scientistsandco.org/projects/shadow-scientist/