Lorenzo Manfreda is a PhD student at the Pediatric Research Institute “Città della Speranza” at the University of Padova, Italy who received an EACR Travel Fellowship to visit and work at the Institute of Metabolism and Systems Research at the University of Birmingham, UK between November 2023 and April 2024.

The EACR, with support from Worldwide Cancer Research, provides Travel Fellowships of up to €3,500 to enable early-career cancer researchers to gain new skills through a short-term visit to a lab or research group in another country.

You can read about other Travel Fellows and their experiences here.


Name: Lorenzo Manfreda
Job title: PhD student
Home institute: Pediatric Research Institute “Città della Speranza” at the University of Padova, Italy
Host institute: Institute of Metabolism and Systems Research at the University of Birmingham, UK
Dates of visit: November 2023 – April 2024
Other organisations that funded your trip: Italian Society of Pharmacology
Research:
During my PhD research I’m studying the role of metabolism in sustain drug resistance in a pediatric tumour called medulloblastoma. This tumour is highly aggressive and often, after surgical removal and chemotherapy, undergo recurrence becoming also chemoresistant. As a consequence these patients are untreatable with any drug known. To study this aspect we generated novel models of drug resistance using patient derived cells and we found that a deregulated metabolism appear to be a driving force in sustain this phenomenon. We demonstrated that resistance cells rewire their metabolism sustaining detox system to counteract the damage induced by chemotherapy.


Why did you choose to apply for an EACR Travel Fellowship?

After being in my laboratory for four years, I felt the need to breathe new air, seek new stimuli, and explore new possibilities. So, I began inquiring about the possibility of spending some time abroad. This would allow me to deepen my research project with new techniques and experiments, as well as experience life in a different place and a different research institute. I believed, and now even more so, that seeing new and different places from those we are familiar with is fundamental for growing as individuals and scientists. In the end, I made up my mind. After discovering the opportunity offered by the EACR Travel Fellowship, I decided to write a project and seize this chance, which took me to Birmingham.

How did you choose the host lab?

In October 2022, I attended the EACR Cancer Metabolism Congress in Bilbao, where I met a PhD student from the Tennant Lab at the University of Birmingham, who is also working on brain tumours. Given their strong expertise in metabolomics and isotope tracing, my group and I subsequently decided to start a collaboration with Professor Tennant’s group at the University of Birmingham. Our goal was to enhance our research on metabolism by using mass spectrometry techniques to better characterise the metabolism of our medulloblastoma models.

“Being away from home and the laboratory where I grew up has allowed me to better define my scientific self”

Can you summarise the research you did?

During my visit, using mass spectrometry techniques, we demonstrated that chemotherapy significantly altered the metabolic landscape of resistant cells, decreasing nucleotide catabolism and increasing nucleotide synthesis, as well as enhancing amino acid uptake and utilization. Chemotherapy induction also triggered an NRF2-dependent accumulation of metabolites like GSH and NADPH, promoting redox homeostasis and enabling cells to manage chemotherapy-induced ROS accumulation. This metabolic adaptation involved increased NADPH levels via the pentose phosphate pathway (PPP) for ROS detoxification. Consistent with previous drug screenings, resistant cells showed increased sensitivity to antimetabolites and enhanced sensitivity to chemotherapy and ferroptosis upon NRF2 silencing or inhibition. Moreover, the direct targeting of the PPP with G6PD inhibitor can induce a massive increase in cell death in resistant cells alone, and when coupled with chemotherapy, demonstrating that both cell viability and chemotherapy response in Resistant cells rely on PPP-related NADPH. In this context, our data produced also during my period abroad support the idea that chemotolerant MB cells, through the deregulation of several metabolic pathways, can counteract chemotherapy-induced stress by maintaining high antioxidant capacity and macromolecule biosynthesis.

Lorenzo and friends during his visit

What were you able to do that you could not have achieved in your home lab?

In Prof. Tennant’s laboratory, there are cutting-edge instruments for studying metabolism, including several mass spectrometers. Moreover, the laboratory specialises in the analysis of metabolic fluxes using stable isotopes tracers, which allows them to trace the fate of metabolites in various metabolic pathways—capabilities that are not available in my laboratory in Italy.

Does your lab plan to do any future collaborations with the host lab?

This trip consolidates our collaboration with a couple of papers that will be submitted in the next few months. Moreover, we are currently in the process of writing various research proposals for projects to be performed jointly between our two groups. Specifically, we aim to combine our expertise in patient-derived cell culture and pharmacology with their expertise in the study of metabolism. For these reasons, I have recently submitted a research proposal to spend two years after my PhD in the Tennant lab working on these projects. Fingers crossed!

Is there anything else you’d like to mention?

Sometimes it’s true: when you go abroad, you cry twice—once when you arrive and once when you leave. I believe this sentiment perfectly sum up these wonderful six months. Sometimes it’s not easy to leave, to leave everything and everyone behind, even if only for a short time, but in the end, it’s worth it. During this period, I had the opportunity not only to learn new techniques and explore new fields but most importantly, I learned to know myself, especially as a scientist. Being away from home and the laboratory where I grew up has allowed me to better define my scientific self. This experience proves that periods abroad are not only beneficial for our research and careers but also for our personal growth. Moreover, the chance to meet new people, experience life outside our own country, and form new friendships and relationships helps us build bridges and tear down the walls that many are trying to erect, especially in these challenging times. These bridges will help us remain united in the future, scientifically and otherwise, contributing to build a better world and better science.


Want to find out more?

If you are interested in applying for the Travel Fellowship scheme, please click here for more information: EACR Travel Fellowships.