First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Boris Sieber and Fangfang Lu are co-first authors on ‘ iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells’, published in JCS. Boris is a postdoc in the lab of Sophie Martin at University of Lausanne, Lausanne, Switzerland, investigating the regulation of Ras signalling and the MAPK cascade upon receptor activation. Fangfang is a PhD student in the lab of Matthew Freeman at University of Oxford, Oxford, UK, investigating control of cell signalling and its implications in health and diseases.

Boris Sieber

How would you explain the main findings of your paper in lay terms?

B.S. and F.L.: Lung cancers can be divided into two types – those in which the growth factor receptor is hyperactive and those where the oncogene KRAS is mutated. Until recently, the dogma was that mutated KRAS is sufficient to drive the formation of lung tumours. We first show that depletion of iRhoms, the cofactors of the growth factor releasing sheddase ADAM17, are essential for formation of lung tumours. This led us to further investigate the role of growth factors in these KRAS-dependent tumours. We found that iRhom2 is activated by oncogenic KRAS to increase the release of growth factors, which in turn maintains high KRAS activity in the cell, thus placing iRhoms at the centre of a positive feedback loop to keep high oncogenic activity in lung cancer cells. Mutations associated with tylosis and oesophageal cancer (TOC) in the iRhom2 cytoplasmic domain further increase this positive feedback loop, thus reinforcing the general involvement of iRhoms in cancer formation.

Were there any specific challenges associated with this project? If so, how did you overcome them?

B.S. and F.L.: Once we realised that the cytoplasmic domain of iRhoms regulates KRAS-driven shedding, the main challenge was to investigate the oncogenic potential of iRhoms. This took us out of our comfort zone of mechanistic cell biology, into the ‘real’ cancer biology field, and this was a challenge. We were very lucky to have colleagues to advise us about, for example, the proliferation and spheroid assays. We were also glad to develop a collaboration with Stephen Stribbling and Anderson Ryan in Oxford's Department of Oncology, who contributed a really important experiment, showing that the depletion of iRhoms totally abrogates tumour growth in xenografts. In the end, the project grew in scale from what we had envisioned but, although this added some stress, we are thrilled with the outcome.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

B.S.: Definitely the xenograft assay! To be honest, we were hoping that deleting iRhoms by CRISPR-Cas9 would lead to some defect in tumour growth but not to that extent – cancer cells lacking iRhoms completely fail to grow in xenograft tumours. That was a very interesting and encouraging finding in our study.

F.L.: When I first tested TOC mutant iRhom2 with oncogenic KRAS, I saw a big effect in ADAM17 activity, which was the ‘eureka’ moment for me. TOC mutations are all single amino acid mutations, so it is exciting to see how much effect a single amino acid mutation can bring to the protein (iRhom2) and its binding partner (ADAM17)!

Why did you choose Journal of Cell Science for your paper?

B.S. and F.L.: We particularly like the quality of data and the general philosophy of Journal of Cell Science (e.g. the ‘At a Glance’ poster articles), and the sense of a community that the journal represents. JCS is the perfect fit for our story on the requirement of iRhoms in KRAS-induced lung cancer, which will reach a broad audience – cell biologists studying Rhomboid-like proteins and ADAM17, as well as cancer biologists investigating the crosstalk between growth factor and KRAS signalling in lung cancer.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

B.S.: I am fascinated by how protein–protein interactions are regulated to drive complex cell signalling responses. I have had the chance to work with multiple systems and the ones that stuck with me are the simultaneous divisions of centrioles in the Drosophila syncytium (during my Masters), and formation of spheroids by lung cancer cells as a system to investigate potential therapeutic targets of EGFR dysregulation.

F.L.: The control of cell signalling is complex but so interesting and has significance in health and disease. I have always been intrigued by how sophisticated the signalling network could be and always wanted to understand more about it!

iRhoms are required for KRAS-driven tumorigenesis. Loss of iRhoms in lung cancer A549 cells abolishes xenograft tumour growth. Insets show representative tumours. Scale bars: 5 mm.

iRhoms are required for KRAS-driven tumorigenesis. Loss of iRhoms in lung cancer A549 cells abolishes xenograft tumour growth. Insets show representative tumours. Scale bars: 5 mm.

What's next for you?

B.S.: This project actually happened at the end of my PhD and I was very lucky that Fangfang took over the project and finished it beautifully. I am now working with fission yeast (stunning microscopy!) on the Ras-driven signalling pathway of pheromone signalling in the laboratory of Sophie Martin. I aim to build a path on which I will lead my own lab on Ras signalling across evolution.

F.L.: I will graduate soon from my PhD and hope to wrap up another paper (which is exciting!) in the Freeman lab. After that, I plan to do a postdoc in the US and pursue my research interest in signalling control in health and disease!

Tell us something interesting about yourself that wouldn't be on your CV

B.S.: I have found that, contrary to experiments, baking does always work! I really like making multi-layered cakes with chocolate decorations – Black Forest cake, Mozart cake or Opéra cake.

F.L.: I have been interested in running and would like to run the Sierre-Zinal (30 km): the race of the five 4000s in 2023!

Boris Sieber's contact details: University of Lausanne, 1015 Lausanne, Switzerland.

Fangfang Lu's contact details: Sir William Dunn School of Pathology, University of Oxford, South Park Road, Oxford, OX1 3RE, UK.


S. M.
A. G.
A. J.
iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells
J. Cell Sci.