Analysis of fibroblast modulation of leukocyte functions
Lead Research Organisation:
King's College London
Department Name: Cancer Studies
Abstract
Fibroblasts are critical for the generation and maintenance of the extra-cellular matrix. In addition, they engage in complex paracrine interactions with epithelial cells and leukocytes. Their activity is subverted in various pathologies, such as fibrosis and cancer. This project will systematically examine the mechanisms of fibroblast activation in pathological contexts. In particular, we will identify common mechanisms of fibroblast dysregulation and seek to identify manipulations that can return chronically activated fibroblasts to their normal state. Initially RNAseq data from diverse normal and disease associated fibroblasts will be used to inform molecular hypotheses to test. These will then be explored in a range of functional assays including fibroblast-mediated matrix deposition and remodelling, cytokine production and immune modulation, and epithelial and leukocyte co-cultures. The ultimate aim of this project is to identify and demonstrate novel axes that can be targeted to manipulate fibroblast biology for clinical benefit.
People |
ORCID iD |
| Fiona Watt (Primary Supervisor) | |
| Erik Sahai (Primary Supervisor) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/P50452X/1 | 01/10/2016 | 30/03/2021 | |||
| 1809342 | Studentship | BB/P50452X/1 | 01/10/2016 | 30/09/2020 |
| Description | Co-culturing fibroblasts (cancer associated or normal) with cancer cells highlighted an upregulation of a unique group of cytokines and interferon stimulated genes (ISGs). During the course of my project I have deciphered the signally pathway responsible for this upregulation, key players include cGAS-STING which are members of a cytosolic DNA sensing pathway, and upon sensing DNA triggers an interferon regulatory transcription factor (IRF3), to activate a cytokine known as interferon beta (IFNB1). IFNB1 is a potent activator of type 1 interferon receptors which are present on both cancer cells and fibroblasts, and their activation results in the upregulation of ISGs such as MX2 and OAS2. Interestingly MX2 and OAS2 are particularly important in the normal anti-viral response, and the direct contact between cancer cells and fibroblasts capable of inducing these ISGs has a protective effect when trying to infect cancer cells with an oncolytic virus, a therapy currently used in the clinic which is designed to preferentially infect cancer cells and kill them. I am currently working on the review comments for these experiments and this work should hopefully be published soon in Nature Cell Biology. Following on from this I have also investigated the direct contact that occurs between epithelial cells and fibroblasts in Ideopathic Pulmonary Fibrosis (IPF). Direct contact between type 1 or 2 epithelial cells and IPF fibroblasts results in an upregulation of proinflammatory genes such as GM-CSF and IL-1b. When macrophages are treated with the conditioned media from these co-cultures it stimulates and increase in migration and induction of a more pro-inflammatory phenotype. Treatment of these co-cultures with Nintedanib (currently used in IPF patients) decreases GM-CSF secretion in both co-cultures and in patients IPF lung samples. Nintedanib treatment of just fibroblasts also disrupts their alignment, with the most effect seen in those that have increased levels of PDGFRb. |
| Exploitation Route | We currently know that direct contact between cancer cells and fibroblasts has a protective effect on cancer cells when trying to infect with an oncolytic virus. There is definitely scope to investigate this further and whether this could be applicable in the clinic, with the possibility of being able to screen patients to see if they have a high or low interferon signature may indicate whether they would or would not benefit from oncolytic viral therapy. Another avenue in which to pursue these findings would be to also look at the effect this direct cancer cell-fibroblast contact has on other therapies such and radiotherapy and chemotherapy. I am also looking into the effect that loss of IRF3 may have of tumour development and the immune cell recruitment, currently I am using a full knock out model but ideally in the future it would be worth trying to generate a mouse that only has loss of IRF3 in the stroma and so these finding could be developed further. The work in fibrosis is very early and therefore could be expanded upon further in terms of inverstigating the regulation of the pro-inflammatory genes upregulated upon touch, and also investigating the relationship between Nintedanib treatment and PDGFRB expression, is this a potenial reason why not all patients respond to this treatment? |
| Sectors | Healthcare |