Yi Feng's group studies in vivo live imaging and genetic analysis of the earliest events of tumour initiation with the emphasis on the influence of inflammation to cancer progression in a zebrafish model.
Cancer of epithelial origin is initiated by a single cell transformation event and subsequent over-growth within an otherwise normal epithelial sheet environment. During this earliest cancer development stage, intimate interactions between the transformed-cell and its microenvironment are critical and will lead either to exclusion or nurturing so that any retained progeny may proceed onto full blown cancer.
Although the initial interaction between a transformed-cell and its neighbouring host tissue is likely to be a major determinant of whether the transformed-cell establishes a clonal niche and tumour progression ensues, this critical time period has proven intractable to experimental studies. There are few model systems in which the transformed-cell clone can be visualised, in vivo, at its inception and its proliferative progression monitored as it interacts with host tissue. The amenability of zebrafish to genetic manipulation and the facility afforded for direct visualization of cellular events in situ, by live imaging, has created an opportunity to establish a novel model in which transformed-cell:host interaction can be observed and manipulated in real time at the cellular/sub-cellular level.
It has been acknowledged for more than a century that inflammation is linked to tumour progression. Emerging evidence suggests that signals derived from abnormal growth of transformed-cells establish a tumour promoting inflammatory microenvironment. However, most studies are limited to analysis of later down-line aspects of cancer inflammation, whereas early and critical determinants of how such an inflammatory microenvironment is established, particularly the temporal aspects, have proven difficult to study; but such knowledge may provide vital insights for the design of preventive approaches to malignant disease.
Recently we established a transgenic zebrafish larval model in which the oncogene HRASG12V fused with eGFP induces somatic cell transformation, and innate immune cells are visualised by expression of the complementary DsRed marker (Figure 1).
This combination enabled us, for the first time, to visualize the earliest interactions between transformed-cells and leukocytes in vivo. Our data showed that emerging transformed-cells induced an inflammatory response by activating innate immune cells. We see recruitment of innate immune cells by 48hpf when transformed cells are still only singletons or doublets (Movie 1).
Movie 1: An in vivo confocal time-lapse movie showing a red neutrophil interacting with a doublet of pre-neoplastic cells.
Soon thereafter we see intimate associations between immune and transformed cells with frequent examples of cytoplasmic tethers linking the two cell types (Movie 2) as well as engulfment of transformed cells by both neutrophils (Movie 3) and macrophages (Figure 2).
Movie 2: An in vivo confocal time-lapse movie showing a red neutrophil dragging the cell membrane of green PNC to form a green tether, and later on the red neutrophil holding on to the tether and migrating back to the same PNC clone.
Movie 3: An in vivo confocal time-lapse movie showing a red neutrophil engulfing material from a doublet PNC by nibbling small pieces from the cell surface.
We show that a major component of the signal drawing inflammatory cells to oncogenic HRASG12V transformed cells is H2O2 which is also a key "damage cue" responsible for recruiting neutrophils to a wound. Strikingly, we found that recruited leukocytes produce Prostaglandin E2, which is one of the trophic factors that promote transformed-cell growth. More importantly, we showed this trophic function of innate immunity, during the earliest stage of tumourigenesis, is suppressed by COX inhibitors, which provides one mechanistic explanation as to why long-term usage of Non-Steroidal Anti-inflammatory Drugs (eg Aspirin) is cancer preventive.
We use a combination of live imaging and genetic analysis in zebrafish larvae, to study the earliest events of tumour initiation and progression, in vivo and in real time. We focus on the interactions between transformed-cell, normal host tissue and infiltrating innate immune cells which, as we have demonstrated, mount a trophic inflammatory response toward the emergent transformed-cells. Our research is aimed at understanding the underlying cellular and molecular mechanisms regulating tumour initiation, and the contribution of inflammation to tumour promotion with the aim of identifying fundamental mechanisms, which will underpin novel therapeutic approaches.
Main areas that we focus on in the lab:
1. To investigate the regulatory mechanism(s) that select for such a Trophic Inflammatory phenotype by responding leukocytes. Are there distinct transformed-cell derived signals for the induction of a trophic innate immune phenotype?
2. To establish the gene-expression signature, and visualise the characteristic behavior, of innate immune cells with "Trophic inflammatory" phenotype and identify other Trophic factors released in response to the emerging transformed cell.
3. To test whether we can change the phenotype of innate immune cells responding to transformed-cell growth and whether this is effective in preventing tumour progression.
Dr Yi Feng studied biology at Beijing Normal University, and obtained her BSc degree in 1997. She then did her postgraduate research at the Beijing Institute of Biotechnology, Academy of Military Medical Sciences, China, and obtained her PhD in Genetics in 2002.
She came to the UK in November 2004 and joined Dr Qiling Xu’s lab at the National Institute for Medical Research, where she gained experience in zebrafish development and genetics and investigated the function of transcription factors Hmx2&3 during zebrafish sensory organ lateral line development. She soon became aware of the unique opportunities afforded by zebrafish to model human disease; not only being amenable to genetic manipulation but, importantly, translucency of larvae allows for live imaging in real time following genetic or pharmacological interference. This led her to a radical change in research focus.
She joined Professor Paul Martin’s lab at the University of Bristol in March 2007, where she helped him to set up the first zebrafish facility and to lead the zebrafish research projects within the lab. She has successfully established a zebrafish model for live imaging studies of the earliest events of tumourigenesis in vivo, and her research has led to the discovery of a host trophic inflammation response toward newly emerged oncogene transformed-cells within host tissue. She was then funded by an ISSF Wellcome Trust grant from the university of Bristol to consolidate her research before she was awarded a Chancellor’s Fellowship to join the MRC Centre for Inflammation Research at the University of Edinburgh in October 2012, where she continues her research on live imaging of the earliest events of tumourigenesis in a zebrafish model. She received Wellcome Trust Sir Henry Dale Fellowship and Wellcome Trust-Beit prize in 2013.