First person – Mira Kuzmić

Mira Kuzmić

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

Cells have a skeleton that determines their shape, and its deformation enables them to move and multiply. The building blocks of the cytoskeleton include tubular structures called microtubules and cable-like structures called actin fibers. Septins form filaments, and their functions in the cytoskeleton are still ill defined, but they are known to play a role in cell multiplication and movement. One of the human septins, SEPT9, has been identified as a factor potentially contributing to the growth of solid tumors and their spreading (metastasis). In this publication, we show precisely how SEPT9 associates with septins and stabilizes microtubules in cancer cells. When this association with microtubules is disrupted, septins shift to associate with actin fibers. In contrast, a mutant of SEPT9 solely associating with microtubules depletes actin fibers from septins. Finally, we show that the distribution and mechanical properties of actin fibers are dependent on this balance between the association of septin with microtubules and actin fibers. These findings will add to our understanding of the role of septins in human biology and pathologies.

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

Of course, there were challenges throughout this project. Some of them were overcome, some of them not. For example, how to show that all SEPT9 isoforms are unable to bind microtubules, even in what appeared to be the most favorable conditions for this interaction, i.e. acetylated microtubule bundles? I treated U20S cell lines that express different SEPT9 isoforms with paclitaxel (PTX), a cancer chemotherapeutic agent that stabilizes microtubules and induces microtubule bundling and acetylation in cells. Upon treatment with PTX, leading to bundling and acetylation of microtubules, we observed that SEPT9 isoforms or mutants associating only with actin fibers were still unable to bind microtubules, whereas the septin isoforms SEPT9_i1 and SEPT9_i1-i5 bound to microtubules even more.

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

I had the question in my head, what happens with SEPT9_i1 or the mutant SEPT9_i1-i5 in the absence of microtubules? Do septins lose any specific localization or degrade? Or do they bind by default to the actin cytoskeleton or membranes when microtubules are absent? For this reason, I treated the cells with nocodazole, a drug that specifically depolymerizes microtubules. And there it was; SEPT9_i1 and SEPT9 i_1-i5 associating with actin in the absence of microtubules. I also did the video microscopy to see what it looked like, and it was a ‘wow’ moment! This is why I am very passionate about being a scientist: it is more than a job, it is an endless learning experience with great challenges but also with the rewarding moments discoveries, even if they are small.

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

We have chosen Journal of Cell Science for our venue of publication because this journal has a very good reputation for fundamental research on cells and the publications from this journal are of a great quality. We are confident that our publication in this journal will have an impact in the field of septin research and be a reference for numerous future studies.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

Luckily, I had two very significant mentors who guided me beyond words. Namely, after my PhD, I wanted to change the field of research, which is not at all easy. My everlasting aim was cancer research. On one hand, Dr Ali Badache accepted me in his team and told me that his door is always open for science. And it was literally like that; I could stop by his office at any time to ask him for his point of view, advice, etc. He was always there, was very kind, and had such patience and understanding for every question or problem I faced during my post-doc. On the other hand, Dr Pascal Verdier-Pinard taught me how to work in cancer cell biology. He spent countless number of hours with me, explaining the rational of experimental work in a project, the experimental design and strategical choices, including methodological ones, aiming at answering present questions and those raised by results. There are no words to explain how much that has shaped me and improved my skills. Finally, I am very grateful for the opportunity they both gave me to work in such a supportive environment.

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?

Owing to my family history, I have wanted to work in cancer research since my childhood, to contribute to better treatments and diagnosis of these diseases. During my undergraduate biochemistry studies in Ljubljana, there was a subject named ‘Biochemistry of cancer’. It inspired me even more to be part of the cancer research community. The present article reflects perfectly this angle as a point of entry into cancer research.

Who are your role models in science? Why?

One of my role models in science is Marie Salomea Skłodowska Curie, a pioneer in radioactivity research who discovered polonium and radium. She dedicated her life to science. Notably, she initiated the clinical trials of cancer treatments with radioactive isotopes. Finally, she made fundamental discoveries in human science and medicine that scientists and medical doctors are still building on.

What's next for you?

I am searching for a second postdoc position. My aim is to work in cancer immunology.

What are, in your view, the roots of difficulties encountered by young but experienced scientists in finding a first stable researcher job?

I think there is huge competition for a stable researcher job because there are too many qualified people. However, I do not understand why this is not regulated from the beginning, which means that there should be fewer positions for PhD and postdocs available, proportional to the quantity of the stable positions as a researcher. There is a problem here because people invest at least 11 years after high school into their education and work hard (university, PhD and postdoc), but they have no stable job as a researcher afterwards. Subsequently, most of those people leave the research they love and join industry because they need the salary to live and to support their family. It should not be forgotten that science is the basis of most medical treatments and preventions that we know, e.g. vaccines. Finally, it seems to me that scientists are not respected, not even close enough, for the work they do. I would like to hear your opinion on this subject!