Sara Sigismund is an Associate Professor at the Department of Oncology and Hemato-Oncology at the University of Milan, and a Researcher in the Department of Experimental Oncology at the European Institute of Oncology (IEO) in Milan, Italy. Her research aims to understand the role of endocytosis in the regulation of EGFR signalling, focusing on non-clathrin endocytosis and its role in health and disease. In addition to running a research group, Sara is the current President of the Italian Association of Cell Biology and Differentiation (Associazione di Biologia Cellulare e del Differenziamento; ABCD). We spoke to Sara about her career path, her advice for early career researchers and her role as President of the ABCD.

Sara Sigismund

How did you first become interested in science?

It took me quite a while to realise that my true passion lay in science. I initially started studying Classical Studies at high school, so the time I had allocated for science and maths was limited. But I really looked forward to those few hours every week. When it came time to choose what to study at university, I opted for biology because I was impressed by the professor who introduced the course; he managed to transmit his passion for biology to me.

I have to admit that I didn't really know what working in a lab would be like. It was only when I did my undergraduate thesis that I figured this out – and it was a bit of a shock! On a typical university day, I would spend my time going to classes and studying but still had time for leisure activities. But on lab days, I would spend 10 h working solidly in the lab. However, it was during that time that I realised that I loved it – I loved it so much I was happy to stay there all day. I think this is also when I really fell in love with cell biology. I realised you can study something that no one else is investigating and could make real discoveries. I couldn't imagine any other job or profession that could offer such a possibility.

How did you then decide that you wanted to do a PhD?

After my undergraduate degree, I knew immediately that I wanted to do a PhD – I wanted to give it a try. At the time, I was at the University of Milan and there weren't many options there. So, I spoke with one of my Professors and he told me about an institute that was quite new – the European Institute of Oncology – that was looking for scientists. I had an interview with Pier Paolo Di Fiore, who was one of the scientists there. Again, I could really feel his passion for what he was doing, and I also liked the topic he was working on. After speaking with people in his lab, I decided to join his team.

Following your early work as part of your PhD, on EGFR ubiquitylation and endocytosis, you were involved in the discovery of a clathrin-independent mode of EGFR internalization. Can you tell us more about this work?

At that time, we discovered that ubiquitylation was driving another type of endocytic mechanism – the so-called ‘non-clathrin endocytosis’. It really was an important moment in my career because it was when I learned one of the most important lessons in science: you must remain open minded and not stuck on your initial hypothesis. We were investigating the role of ubiquitylation in EGFR endocytosis, and we thought that it was driving clathrin-mediated endocytosis. Despite efforts to demonstrate this, the results were just not convincing, and seemed to point in another direction. I was very disappointed, but I recalled the words of my mentor, Pier Paolo Di Fiore, “when a result does not align with your expectation, this is an opportunity to discover something entirely new.” He was right! We discovered that ubiquitylation was actually driving a novel clathrin-independent endocytic mechanism. It was a very exciting moment in my scientific career.

And how was the discovery received by the field at the time?

It was actually very challenging to gain acceptance of our results. The prevailing view at that time was that the major mechanism of endocytosis was clathrin mediated, and that ubiquitylation was driving clathrin-mediated endocytosis. There were only a few papers that hinted at a clathrin-independent pathway. It took more than two years to publish our findings. So, after the initial excitement, it was hard work. We tried a few journals, but the reviews were negative. Finally, we managed to publish our paper and it has now been cited more than 600 times – it was the starting point of a new direction in the field.

Now, the existence of a clathrin-independent pathway is well accepted. In fact, I remember when I went to my first Gordon conference, every talk was about clathrin-mediated endocytosis but now there are many talks on clathrin-independent mechanisms.

What is the main focus of your lab's research at the moment?

Our main focus is to understand how the non-clathrin endocytic mechanism is integrated with clathrin-mediated endocytosis to regulate EGFR signalling, and the relevance of these mechanisms to physiology and pathology. We know that the non-clathrin endocytic mechanism is important for restricting EGFR signalling, so it could be a way to protect cells from overstimulation. It might also be important in cancer, where excessive receptor signalling often occurs. For this reason, we are investigating whether endocytic proteins involved in the non-clathrin endocytic mechanism are altered or mutated in cancer. We are using different cell models, such as cell lines, organoids and patient-derived cells, to answer this question. Only by studying the basic biological mechanisms will we get a broad perspective on how these endocytic mechanisms might be implicated in tumours.

…now I know there is not a predetermined path to becoming a scientist; each individual must find their own way.

Scientists often get told to move around and change fields, but you've been based in Milan for much of your education and career and yet have managed to be productive and lead a successful research programme. What would be your advice for people who are contemplating career moves?

A lot of people told me that I had to move to have a successful scientific career, but now I know there is not a predetermined path to becoming a scientist; each individual must find their own way. In fact, there are no set rules in this world that guarantee you'll become a PI, even if you change labs and go abroad. Certainly, there are more traditional paths that you can follow, and these might increase your chances of success. They might broaden your perspective and open your mind to different views and so on. But I feel that staying in the same country, in some cases, also has its advantages. For example, I received a lot of support from my family, especially my parents, and this has allowed me to balance a career in science with having a family. I have three kids, so pursuing a scientific career would have been much more challenging if I were far away from my parents. I have lots to thank them for.

Staying in the same place also meant that I had the opportunity to start my own field of research while I was a postdoc in Pier Paolo Di Fiores' lab, and with his mentoring and support. This was a big advantage because I could, for example, start training scientists in my group while still having an active mentor myself. Training new scientists, in my opinion, is the most demanding aspect of being a PI. But because I started training people while I still had a mentor, I had a lot of support.

I also think funding agencies are changing and reconsidering some aspects of which people and what they fund. It used to be that you had to be very international, moving around between different countries. But they are now starting to consider that such movement isn't always possible, particularly for some countries and also for people with family commitments. So, I think we should be looking at people's achievements and not how they reached them, because not everybody has the same access to opportunities.

You've also seemed to have a constant stream of collaborators. What is your advice for establishing good collaborations?

Finding good collaborators is difficult because they have to share, at least in part, your aims and objectives. But I do think that productive collaborations are fundamental if you want to make significant progress. I would say it's been especially important for my career in Italy, where the amount of funding we get is not very high. Because of this, we have to find ways of doing research at the same level as other countries but with less funding. One way to do this is by growing our network and collaborations – it's crucial for remaining competitive. Additionally, I think that if you can collaborate with other people with different areas of expertise, you can open your mind and look at your problem from a different perspective.

Collaborating is also so much easier to do now – we're in a digital world where you can have collaborators anywhere across the world! Societies, like the ABCD, really help in this regard; I established most of my collaborations through the ABCD.

Is there any advice you would give to early-career researchers who aspire to become PIs?

One piece of advice is the lesson that I learned early in my career, which is to stay open minded to unexpected results as they might lead to a ground-breaking discovery. I also think you need to be receptive to using new technologies. This is where collaborations can really help you.

It is also very important to not be afraid of sharing your findings. If someone else is working on similar research, it's better to be aware and share your findings. You can reach out to them and explore opportunities to collaborate and even redirect your work to make it complementary and avoid overlap. There are so many things we can do, questions that we can ask and interesting things to be discovered that there is no reason for people to work on exactly the same topic. This is something that, again, my mentors taught me. So, go to the meeting and show your data, even if they're not published – it's important to share with the community.

One piece of advice is the lesson that I learned early in my career, which is to stay open minded to unexpected results as they might lead to a ground-breaking discovery

You are currently President of the Italian Association of Cell Biology and Differentiation (Associazione di Biologia Cellulare e del Differenziamento; ABCD) – how, when and why did you first become involved with the society?

My first meeting as a student was an ABCD meeting, so I've known about the society since then. I realised from the beginning that scientific societies, like the ABCD, are very important for junior scientists because they give you the opportunity to present your findings and discuss science with colleagues, usually at a very low cost. My involvement in ABCD started off as a council member and helping to organise a meeting on membrane trafficking. I was then appointed treasurer and now I'm very happy and proud to be the President.

What are the main aims/the mission of the society?

Firstly, we hold a meeting every 2 years to bring the Italian scientific community together and to foster collaborations amongst them. We also, in the alternate years, hold our national PhD meeting, which is a meeting that is dedicated to PhD students. We usually have one or two international speakers, but all the other talks are delivered by PhD students and there is a committee of PhD students that selects the talks. This means they get experience of presenting and talking to other colleagues in a friendly and informal environment. It's a meeting that I always attend.

We also hold smaller more focussed meetings, based on topics that are proposed by our community. Even during the pandemic, when it was not possible to bring people together in-person, we organised a series of online lectures that were delivered by experts in different fields from across the world.

Thankfully, we managed to get the PhD students back together after the pandemic for an in-person meeting. They were so happy because some of them had never had the occasion to give a talk since starting their PhD. It was such an important experience for them. They also saw the benefits of the society early on in their career and hopefully will stay engaged. We have quite a large membership, but I think this is because we engage with students right from the beginning.

If you could change one thing in academia, what would it be?

I think we need to do more to improve the situation for women in science/academia, although I can only speak about this from an Italian perspective. The situation is slowly starting to change, as we see more and more women in academia, but I still think things can and must be improved. Firstly, institutions should recognise, reward and incentivize diversity, equity and inclusion. Based on my own experience, I think it is also important to provide mentorship for young female scientists in order to help them achieve their full potential and to give them the confidence that they can have a successful career in science.

I also think that the general support for women in science can be improved, for example by allowing more flexible working schedules, by providing childcare support and by giving better maternity leave. I had the advantage of having my family around to help me, but if someone does not have this possibility, I think that society – the university, the institution – should provide this. And of course, we have to change and challenge our mentalities and our biases, to really help from the bottom up.

Finally, I think it is very important to ensure we recognise and award women who are doing good work, and to give them important positions in our system. For example, I'm really proud to be the President of the ABCD society because I think this sets a good role model for other women, so that that they can say, “Okay, it is possible for me too”.

Finally, is there anything that our readers would be surprised to find out about you?

I have been thinking about this, but I don't have anything to say – I'm really just an ordinary person!

Sara Sigismund's contact details: IEO, European Institute of Oncology IRCCS, Building 13 Floor 3rd Via Adamello 16, Milano, Italy.

E-mail: sara.sigismund@ieo.it

Sara Sigismund was interviewed by Seema Grewal, Executive Editor for Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.