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Fergal O'Farrell's picture

Fergal O'Farrell

Associate Professor, Associate Professor

Drosophila as a model for human diseases: Several criteria make Drosophila a meaningful organism in which to model human diseases. Essentially, the majority of disease-related genes (75%) are conserved between the fruit fly and humans. In fact, as many disease-related genes are important for human and fly development these were often first described in the fruit fly. The fruit fly's body plan and internal organs have human counterparts in developmental and functional terms. To be more specific, during development we can take a human gene and use it to replace the function of a purposefully mutated fly gene. In this way, we can say the fly and human genes are so related they can do the same job (functional orthologs). Understandably, we can only check this relationship in one direction, putting human genes into the fly, not the other way around. In terms of organ functionality, we know that many of the cell types that make up human organs have fly counterparts and that these organs accomplish many of the same jobs (digestion, filtration, excretion, oxygenation, buffering starvation, behaviour, sensation) and produce or secrete much the same proteins or hormones to accomplish these tasks.

I make use of a Drosophila Ret-tumor-model with a focused interest on understanding factors that influence the spreading of tumor cells from the site of origin (early stages of metastasis) with an aim to use this knowledge towards cancer prevention. For more information

https://ofarrell.w.uib.no/

Fergal O’Farrell is an Associate Professor and research group leader at the Department of Biological Sciences (BIO) in Bergen. He was awarded his Ph.D. in Cell and Molecular Biology from the Karolinska Institute in Stockholm, Sweden, in 2008. The majority of this work was based on the use of the Drosophila melanogaster (the fruit fly, bananflue på Norsk) model to study gene function and peripheral nervous system development. His post-doctoral studies continued with both the fruit fly as a genetic model and Stockholm City as a base. This was in the lab of Professor Christos Samakovlis at the Wenner Gren Institute/Stockholm University, in the field of Receptor tyrosine kinase (RTK) signalling and role during development, characterising the function of an RTK related to mammalian proto-oncogene Rearranged during Transfection (Ret). Following a move to Norway and the Oslo Cancer Institute in 2011 Fergal continued the research with Drosophila and Ret, in addition to other work together with Professors Stenmark and Rusten establishing and characterising different cancer models and investigating the influence of vesicle transport to tumor development. During this time Fergal’s work was supported by personally awarded funding from Kreftforengingen (the Norwegian cancer society) and well as funding through the SFF center-of-excellence CanCell. Following a move to Bergen in 2020, Fergal still makes use of the Drosophila Ret-tumor-model with a focused interest on understanding factors that influence the spreading of tumor cells from the site of origin (early stages of metastasis) with an aim to use this knowledge towards cancer prevention. 

https://ofarrell.w.uib.no/research/

For more information about flies 

https://www.youtube.com/watch?v=qDbJnFLl3kU

https://www.youtube.com/watch?v=C9FSf6nhDSc

MOL200 Biochemistry.

MOL213 Developmental Genetics.

Academic article
  • 2017. Microenvironmental autophagy promotes tumour growth. Nature. 417-420.
  • 2017. Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation. Nature Cell Biology. 1412-1423.
  • 2017. Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation. Nature Cell Biology. 1412-1423.
  • 2013. Two-Tiered Control of Epithelial Growth and Autophagy by the Insulin Receptor and the Ret-Like Receptor, Stitcher. PLoS Biology. 15 pages.
Academic literature review
  • 2013. Phosphoinositide 3-kinases as accelerators and brakes of autophagy. 6322-6337.

More information in national current research information system (CRIStin)

O'Farrell F, Lobert VH, Sneeggen M, Jain A, Katheder NS, Wenzel EM, et al. Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation. Nature cell biology. 2017;19(12):1412-23. Epub 2017/10/31. DOI:10.1038/ncb3631. PubMed PMID:29084199.

Katheder NS, Khezri R*, O'Farrell F*, Schultz SW, Jain A, Rahman MM, Schink KO, Theodossiou TA, Johansen T, Juhász G, Bilder D, Brech A, Stenmark H, Rusten TE. (2017) Microenvironmental autophagy promotes tumour growth. Nature. Jan 19;541(7637):417-420. PMID: 28077876.

O'Farrell F, Wang S, Katheder N, Rusten TE, Samakovlis C (2013) Two-Tiered Control of Epithelial Growth and Autophagy by the Insulin Receptor and the Ret-like Receptor, Stitcher. PLoS Biol. 11(7):e1001612. PMCID: 3720245.

O'Farrell F, Rusten TE, Stenmark H (2013) Phosphoinositide 3-kinases as accelerators and brakes of autophagy. FEBS J 280: 6322-6337.

Drosophila Melanogaster, the fruit fly.

Small in size but large in its contribution to our understanding of numerous human diseases the fruit fly has played a leading role in the fields of developmental biology, genetics, cancer, and cell biology, to name just a few of the areas in which it has excelled. It's smaller and more compact genome when compared to other common model systems (fish, mouse, human cells) while still containing 75% of all human disease-related genes, has contributed to its attractiveness as a genetic model. The small fruit fly has a wide variety of genetic tools, more advanced than those of rival model systems, at its disposal, following over 100 years of use as a model system. Additionally, the ability to image all tissues during their development, coupled with the range of genetic manipulations possible gives a model system in which a gene or protein function can be assessed at a cell, organ and whole animal level with ease and speed. Welcome to the world of fly genetics where seeing is believing!

https://ofarrell.w.uib.no/research/

https://ofarrell.w.uib.no/research/

 

Ongoing projects: 1. Understanding early metastasis/the decision to migrate. 

I am using the expression of the Ret proto-oncogene in patches of cells in living developing tissue to recreate the early steps in cancer progression to find new ways by which cancer cells manage to survive, grow and escape from the site of origin. Steps leading up to metastasis. This is in the hope to discover new ways in which cancer progression can be blocked.

I am most interested in finding factors important for cancer spreading. What drives cancer cells out of their environment? Observations (ours, unpublished and others) suggest that the hostile nature of the microenvironment surrounding the early tumour cells, which can be nutrient and oxygen-poor can trigger changes that activate cell migration. This project aims to investigate the effects of changes in nutrient-driven signalling pathways to tumour cells tendency to migrate. The majority of this work is performed in vivo using Drosophila melanogaster as a model. 

 

Ongoing projects: 2. The effect of the microenvironment to cancer cell spreading.

Are signals from the neighbouring normal cells involved in the spreading of Ret positive cells? and can we stop this or make elimination more effective? To address this the fly model can serve us well. With the controlled expression of an oncogene in a patch of cells coupled to the ability to disrupt gene function in the surrounding cells, we can now ask which genes within the tumour contribute to its spread, and which genes in the surrounding tissue are needed to resist the spread or invasion by the tumour cells.

Identifying genes and the pathways in which they act in normal cells that surround a tumour that can help eliminate tumour spreading provide a new approach to cancer prevention. Potentially the activity of these pathways can be boosted without harsh and damaging treatments such as chemo or radiation therapy. Perhaps certain people are at greater risk of cancer development due to abnormal expression of such cancer resistance genes and these could be identified and receive “booster” treatments to increase the fitness of normal cells and thereby increase the detection and elimination of cancer cells.

 

Ongoing projects: 3. Drosophila as a model to study the contextual oncogene LKB1.

LKB1 (Liver Kinase B1) is a contextual oncogene, that is, in certain tumours, it promotes growth and survival. It is also thought to be a tumor suppressor and genetic evidence shows it to be responsible for the rare and complex illness, peutz-jeghers syndrome (https://ghr.nlm.nih.gov/condition/peutz-jeghers-syndrome#genes), which inevitably causes death from cancer, typically gastrointestinal. Despite the strong correlation between LKB1 mutations and cancer, how LKB1 mutations cause these symptoms is not well understood.  We (and others) have shown that the activity of LKB1 is controlled in part by its localisation within the cell via its association with intracellular membranes. I aim to precisely pinpoint the interplay between vesicle trafficking and LKB1 activity. Understanding this could give new inroads into understanding LKB1 cancers and potentially generate new therapeutics for sufferers of peutz-jeghers syndrome.  With this in mind, I have registered myself as a participant within the Rare Diseases Models & Mechanisms – Europe (RDMM-Europe)  (http://solve-rd.eu/rdmm-europe/), offering Drosophila as a model for the study of this disease. As the human LKB1 gene can substitute for the Drosophila gene, rescuing lethality, Drosophila offers an attractive model to introduce human LKB1 variants, expressing broadly or as narrowly as a restricted field of cells in a wild-type or heterozygote background and investigate the consequences to cells/tissue development.