Research – Blog about neuroblastoma biology

Congratulations Dr Frawley!

June 9th 2022 – A Big Day for Tom and me. This is the end of the 4th year PhD marathon. A long journey through scattered showers and sunny spells, gale winds and stormy snow with sunshine developing elsewhere, turning chilly under clear skies on some days with temperatures below/above zero. The full spectrum of emotions and hard work spiced up with the COVID19 restrictions’ uncertainty. All these together have moulded into a new high skilled researcher – Dr Thomas Frawley.

The PhD Viva and celebration, June 9th 2022

My greatest thanks to Tom’s examiners Profs Elena Aikawa (Harvard Medical School, USA) and Marc Devocelle (RCSI, Ireland)!!

This work would not be possible without the generous support from the Irish Research Council and National Children’s Research Centre.

Not quite all back to in-person – the EFEM student Symposium 2022

Despite our last blog post celebrating the regained opportunity to meet with other researchers in person and all the benefits that come with it I just had the pleasure of presenting at the first European Federation for Experimental Morphology (EFEM) Student Symposium online.

While it would have been easy for me to attend in person, as the event was hosted and organised here at RCSI, not many others would have had it quite so easy. As the name suggests, researchers from all across Europe attended. Every EFEM associated anatomical society across Europe and RCSI, as the host institution, had the opportunity to select two members to present. I was honoured to be chosen to represent RCSI. Overall, 15 different countries were represented in the student talks which made for a diverse mix that was particularly nice for the bit of organized fun at the end of the first day which encouraged networking.

Especially, because having only begun my PhD this past year I felt the category Preliminary Results and Outlook aimed at Undergrads, Masters and early-stage PhD students perfectly suited the stage of my project. This was also a brilliant way to see what other students at my level were doing in the field of anatomical research all across Europe. Having this chance to see research in progress was refreshing and uplifting contrasted with the usually more rounded later stage presentations. Having studied anatomy in my undergraduate degree I was also delighted to simply engage with more conventional anatomical research than I currently do myself.

*Ronja Struck, 1Yr PhD student at the EFEM Student Symposium 2022*

A wonderful opportunity to gain insights into, for example, the implicit knowledge of academia was the career development part of the conference. Talks about academia, industry and publishing offered a chance to get an inside view of those career paths at different positions within them. Especially the typical day in a research journal’s editor provided a new perspective on what is important when writing papers and will have lasting benefits for me and my scientific writing.

But by far the reason why I’ll remember this conference for the longest time is that being awarded runner up in the category Preliminary Results and Outlook reassured me that I am on the right track and that there is purpose in what I do. Despite the online format of the conference, I had the honour of receiving my prize in person, because Prof. Fabio Quondamatteo, the organiser of the event is based at RCSI.

Overall, the two days were an important step in consolidating my faith in my work and the career path that I have chosen.

Written by Ronja Struck, the IRC-CFNCRF funded PhD student

Return of the in-person conference – IACR2022

In-person conferences are back at last! In March 2021 I attended the IACR conference for the first time, albeit virtually. While there were some great talks at IACR 2021, the virtual experience was lacking in the networking and socialising opportunities that go hand-in-hand with traditional conferences. So I was very excited to be Cork-bound for IACR 2022 in March of this year.

To my surprise, my abstract was selected for a Proffered talk, meaning I had 10 minutes in the limelight of the IACR podium to present my research on immune markers in neuroblastoma. Having gone two years without presenting to a crowd, it was an adrenaline-filled experience, and it was great being surrounded by my colleagues after the talk rather than being at home alone in front of my computer.

Catherine Murphy, PhD student at IACR2022

There were many very memorable research talks and posters at IACR, but some of the best memories came from the moments in between the scientific sessions. From the train down to Cork with my lab group, to buffet dinners, a quick journey into Cork city, going for a swim in the lovely hotel pool, and singing and dancing the night away at the gala dinner on the last day of the conference.

One of the highlights of the conference for me was the awards ceremony at the gala dinner, where to my delight I was awarded the Best Proffered PhD talk! What a fantastic way to end a great few days at IACR 2022.

Written by Catherine Murphy

IACR Meeting 2022: 2 years + a pandemic in between

It was February 2020, just before one of the biggest global pandemics struck, that I attended the IACR as a research assistant. It was my first official conference and it is safe to say ‘Imposter Syndrome’ was my main feeling going down to Galway on the train. Fast forward 2 years and my feelings travelling to IACR 2022 in Cork could not be more different. It is amazing what starting a PhD during a pandemic can do for your confidence and skills as a researcher – a sink or swim moment if there was ever one. My first IACR in Galway was one to remember surrounded by like-minded scientists, all brimming with new ideas and exciting discoveries. As such, I had high hopes for IACR 2022. And it did not disappoint.

Ellen King, PhD student at the IACR Meeting 2022

My PhD project focuses on the development of a vaccine to treat neuroblastoma so I was very excited to hear talks from some of the leading experts in vaccine research, both in industry and academia. I gained so much from hearing these experts discuss their research but also discussing other important topics like career progression and how to keep a work/life balance in research. It was refreshing to hear that as scientists we don’t have to (and shouldn’t) work ourselves to the bone 24/7 to be successful. As a young scientist planning to continue into academic research, this left a lasting impression on me. To top off what was already a hugely beneficial conference for me, my poster was shortlisted for a prize. I was shocked, delighted and excited all-in-one. Starting my PhD during a pandemic was not without challenges. Delays in deliveries, delays getting trained on equipment and multiple lockdowns led to what felt like (for me) quite a disjointed start. For my research to be shortlisted by experts was, to be honest, a relief. To know that my work stood out was extremely important to me and that all the hard work does pay off. When my name was called out at the Gala dinner as a Poster Prize Winner, all the doubts that I had (doubts that we all have as scientists) disappeared. I felt very proud and very grateful that my research was recognised at that level. There is no doubt that in-person conferences give a huge boost to young researchers, and I really look forward to presenting my work at the next IACR meeting.

Written by Ellen King

First Research Meeting For A Medical Student

At the beginning of my career, I worked for two years in a Ukrainian company organizing international industrial conferences. So I have insider knowledge of how the conference works, and that the determining factor for the success is the active communication between the participants. And at the RCSI research day and Cork IACR conference, this component was perfect. At both events, I presented my poster and had a chance to discuss the recent advances in neuroblastoma epigenetic drug research. During RCSI Research day, I was excited to learn about the accomplishments of other undergraduate studies and was thrilled to learn that my classmate is participating in research too. He had developed an online recourse to practice cardiac auscultation, which is extremely useful for my medical studies. But professionally, I enjoyed the cancer research posters and presentations at the IACR conference and was eager to meet the researchers working on medulloblastoma, a paediatric neural cell cancer, and the research team from UCD, the neighbours of our university who worked on breast cancer. It was the most valuable opportunity to take a glimpse into other research, become inspired by the most ingenious methods, and cultivate professional knowledge and personal connections – I am so lucky I have been at RCSI Research day and the IACR conference! I have greatly enjoyed my time, and I am looking forward to (hopefully) going to the next year’s conferences again.

Written by Nadiya Bayeva

RCSI Research Day 2022

Cancer Bioengineering Group thoroughly enjoyed getting back to in-person Research Day at RCSI after 2 years, we’re now very much looking forward to the IACR conference later this month! We will have 2 oral and 5 poster presentations at IACR 2022.

Ronja: My typical day

A typical day for me is difficult to describe because there are many facets to a PhD in the Cancer Bioengineering research group. Some days I spend in the lab sectioning, staining or looking at tumour samples under the microscope. Others I stay at home, read papers and try to figure out how they can help me to achieve my research goals. Some days I take part in the courses and workshops offered in the scope of a structural PhD. Then there are times when I sit here writing up for you guys what it is that I do those other days. The academic environment also provides lots of other opportunities to apply yourself and broaden your horizons or pursue what you enjoy. I, for example, have the chance to partake in weekly dissections for medical teaching which helps to keep my anatomical knowledge fresh and is an always welcome change of scenery (and smell) when I am stuck on other things. Furthermore, I get to see the other side of conferences and what is involved in their planning, because I am part of the local organising committee for the European Federation for Experimental Morphology Symposium 2022.

Figure 1 Working on neuroblastoma cancer the samples I am working with are quite unsurprisingly tumour cells. But these can be grown, for example, in mice (A) or on manmade scaffolds (D). I am moving a staining rack that holds the microscopy slides through staining containers filled with different solutions (C) to stain the slides. After the slides are stained the excess stain is removed by washing in distilled water (B). The resulting images depend on the type of stain. Stains like Alcian Blue can only be viewed with brightfield microscopy (A). But Picrosirius red can also be viewed under polarised light or as seen here (D) with fluorescent microscopy.

Currently, not yet half a year into my PhD, a lot of my time is spent planning. That’s planning which methods to use, which products to order and which experiments, and analyses would result in the most coherent and rounded off story being told by the summation of my research. I also spend a lot of time optimising the methods I will use to assure reproducibility and avoid issues during the analysis later on. For example, the whole tumour sample stained with Alcian blue you can see in Figure 1A clearly shows discernible blue and red regions. However, I have spent about 2 months now trying to get to a point of producing this same outcome reliably rather than having samples show up entirely blue or very only faintly stained. Picrosirius red, the solution I used to stain the sample in Figure 1D stains collagen. But there are many different stains for collagen. After researching most if not all of them I chose this one because it can be viewed with different types of microscopies providing slightly different information. Another step of planning includes how many pictures of which magnification will be required, one image of a whole section for orientation such as in Figure 1A and then more zoomed-in images to investigate the structure of collagen such as in Figure 1D.

Between course work and planning and optimising different aspects of my project, my PhD provides me with plenty of opportunities to focus on something else whenever I get stuck to later return with a fresh set of eyes.

Written by Ronja Struck, a 1st Yr PhD student funded by the IRC-CFNCRF

Welcome to the Cancer Bioengineering Group!

It is time for a full group presentation here at the blog! Throughout the month we shared about our group members and their research focus on Twitter. Now, we would like to share more about the group here and invite you to keep following us on social media.

The Cancer BioEngineering Group is a research group led by Dr Olga Piskareva at the Royal College of Surgeons in Ireland. The group has 6 PhD students developing research projects around neuroblastoma biology.

Our projects address topics related to neuroblastoma microenvironment, cell interactions, tumour resistance and the development of new therapies. To do that we use 3D in vitro models, identify immunotherapeutic targets and evaluate extracellular vesicles.

We are a dynamic group proud to be engaged in research, science communication and patient involvement. We do that through different initiatives.

We support and collaborate with several neuroblastoma charities around Ireland and internationally such as the Conor Foley Neuroblastoma Foundation, the National Children Research Centre, the Children’s Health Foundation Crumlin and the Neuroblastoma UK. Moreover, our projects are funded by the Irish Research Council in partnership with these charities and by RCSI StAR PhD programmes.

We promote neuroblastoma awareness through different activities. For instance, last September at the Childhood Cancer Awareness month we promoted a hiking challenge to raise money and increase awareness of neuroblastoma. We hiked for 30km at Wicklow mountains in a day and raised over € 2,000 for neuroblastoma research charities.

We are also present in social media, creating content in the form of blog posts and tweets to share the science we are doing.

We are always happy to answer questions and interact with the public. Follow us on our social media channels and read our blog to know more about us and our research.

Thanks for reading and we go ahead with neuroblastoma research!

Written by Luiza Erthal

#AskLuiza: How Does The Microenvironment Influence Neuroblastoma Cells?

Understanding how tumour cells interact with the other cells in the body is crucial for an effective treatment. Moreover, it can help to identify patterns that are exclusive of tumour cells to be a target in treatment.

The interactions of tumour cells with the surrounding tissue, the microenvironment, affects chemotherapy sensitivity, immune cells recognition and expression of molecules on the cell surface, to only cite a few interferences.

This is particularly crucial in metastatic cells, which are cells that have spread to other parts of the body coming from the primary tumour location. Specifically, for neuroblastoma half of patients with high-risk disease present a metastatic tumour at the diagnosis. In addition, one of the organs that are mostly populated by metastatic neuroblastoma cells is the bone marrow.

A review paper recently published address some important aspects about the interactions between neuroblastoma cells, bone and bone marrow resident cells¹. This review argues in favour of understanding these interactions to search for new targets for therapy.

However, neuroblastoma cells proved to be difficult to characterise due to dynamic changes induced by external stimuli. Therefore, neuroblastoma cells change upon exposure to the bone marrow microenvironment.

The authors present some studies showing that neuroblastoma cells infiltrating the bone marrow express receptors for small proteins called chemokines that induce cell adhesion in the bone marrow. On the contrary, the cells did not present on their surface molecules that stimulate the immune system recognition. Therefore, they are naturally invisible to the action of this system.

Moreover, it has been shown that metastatic tumour cells release extracellular vesicles expressing GD2. These vesicles have an important role in cell-cell communication and the GD2 is a marker exclusive of neuroblastoma cells. Thus, it facilitates the identification of metastatic cells.

These alterations on neuroblastoma cells surface after they interact with bone marrow cells may facilitate the invasion and spread of the tumour. Thus, looking closely to that may help to develop more effective treatments for neuroblastoma.

At the Cancer Bioengineering Research Group, many of our projects are related to tumour resistance, cell interaction and the tumour microenvironment. These three aspects are very important to understand neuroblastoma at the tissue level. We study them and expand this research to applied projects aiming at the development of new therapeutic modalities.

For instance, we are currently evaluating the effect of extracellular vesicles from different neuroblastoma cell lines in the induction of proliferation and increased viability. Moreover, we are studying the interaction of neuroblastoma cells with immune cells such as macrophages. Finally, we are also identifying targets to develop an anti-tumour nucleic acid-based vaccine against neuroblastoma.

We go from basic to applied research interconnecting the findings and expanding the understanding of neuroblastoma biology. Ultimately, we aim to improve treatment and quality of life for patients.

Written by Luiza Erthal

References

1. Brignole, C. et al. Bone Marrow Environment in Metastatic Neuroblastoma. Cancers 13, 2467 (2021).

#AskLuiza: Is there any vaccine to treat or prevent neuroblastoma relapse?

Anti-cancer vaccines teach the body’s immune system to identify and attack tumour cells. They are a type of immunotherapy and can be used to treat cancer or prevent tumour recurrence. Therefore, they are typically used in patients that have already received other treatments such as surgery, chemotherapy or radiotherapy.

Although anti-cancer vaccines have been gaining more attention over the years, few are being developed for paediatric tumours. From 594 clinical trials in neuroblastoma at clinicaltrials.gov, only 12 active trials are evaluating vaccines. Furthermore, these vaccines are still considered investigational products. They do not have the approval for use granted by health authorities. Therefore, these drugs are available for patients that enter into clinical trials.

An example of these vaccines is the bivalent vaccine for high-risk neuroblastoma developed in the Memorial Sloan Kettering Cancer Center in the US, collaborating with the biopharmaceutical company Y-mAbs Therapeutics. This vaccine is called bivalent because it has two proteins specifically present on the surface of neuroblastoma cells.

The rationale behind the treatment using this vaccine is that the body will be stimulated to produce antibodies against these two proteins. These antibodies will recognise and attach to neuroblastoma cancer cells, thus signalling to the immune system that these cells need to be eliminated.
A phase II trial evaluates vaccine efficacy in 374 patients who received seven subcutaneous injections of the vaccine in combination with an oral intake of an adjuvant, called β-glucan, that boosts the immune system1. The adjuvant intake started either on the first vaccine injection or on the third injection every two weeks until the end of the vaccine schedule. The study aims to analyse the anti-tumour effect of the vaccine and the immune response generated by the vaccine plus β-glucan therapy. The study is estimated to be completed by 2023.
The trials active for neuroblastoma vaccines are phase I or II. After these phases, there are still phases III and IV to complete the evaluation and continue monitoring these therapies. Therefore, in a few more years, we will know if neuroblastoma vaccines will be successful or not.

Written by Luiza Erthal

Reference

1. Memorial Sloan Kettering Cancer Center. Phase I/II Trial of a Bivalent Vaccine With Escalating Doses of the Immunological Adjuvant OPT-821, in Combination With Oral β-glucan for High-Risk Neuroblastoma. https://clinicaltrials.gov/ct2/show/NCT00911560 (2021).