Immunometabolism, Is it under the eye of the clock

Annie Curtis reports

Our Immune-clock laboratory has a real interest in metabolism and how alterations in metabolic pathways termed “metabolic reprogramming” can shape the type of immune response. This area called “Immunometabolism” has exploded in the last 5 years, and the implications are massive. It appears that macrophages use one metabolic pathway to become highly proinflammatory and another metabolic pathway to resolve inflammation and promote wound healing.  So why is our laboratory so interested in this? Well, if you think about daily changes in our environment, the two biggest are the sleep/wake cycle and the other is feeding/fasting. It is now clear that clocks in metabolic tissues like the liver/pancreas/adipose tissue prepare the body to deal with this daily rhythm in feeding/fasting. Based on this, our interest is to figure out if the clock within macrophages is somehow altering its metabolism over the course of the day and is that leading to changes in macrophage function, particularly the inflammatory response.

Jamie Early, my PhD student

Jamie Early, my PhD who “lives” in Prof. Luke O’Neills laboratory at TCD and I were invited to submit this first ever review on circadian immunometabolism, and you can find it here.

Additional reading

  1. Early JO, Curtis AM Immunometabolism: Is it under the eye of the clock?Semin Immunol. 2016 Oct;28(5):478-490

Follow me on Twitter @curtisannie

MCT student, Lisa Dwane, talks about her research and recent achievements

cropped-RCSI-logo-1.jpgFollowing completion of my Pharmacology degree in UCD, I began a PhD in breast cancer research under the supervision of Dr. Darran O’Connor, a career I have always been very determined to follow. My research is focused on endocrine-driven breast cancer and understanding the molecular mechanisms that drive this subtype of cancer. Currently, half of breast cancer patients that receive anti-endocrine therapies will relapse, so there is an urgent need for the identification of novel therapeutic targets. Our research is focused on the deubiquitinating enzyme USP11, which we believe plays a key role in driving endocrine-driven breast cancer. When we silence USP11 in vitro, we see a reduction in estrogen receptor activity and cell viability. During the final year of my PhD, I hope to elucidate the mechanism by which USP11 plays this role, and determine the prognostic relevance of USP11 in breast cancer. This could potentially lead to a better understanding of endocrine-driven breast cancer and with further validation, USP11 may represent a novel therapeutic target.

Lisa Dwane presents her research at the Irish Cancer Society’s Researcher of the Year Award. december, 1st, 2016. TCD
Lisa Dwane presents her research at the Irish Cancer Society’s Researcher of the Year Award. December, 1st, 2016. TCD

As a pharmacologist, I was thrilled to win best oral presentation at the Irish Association of Pharmacologists Annual Meeting! The standard of talks throughout the day were excellent, with a wide range of topics explored. I was also a finalist for the Irish Cancer Society’s Researcher of the Year Award, which took place 1st December at Trinity College Dublin. The purpose of the evening was to communicate our research to a lay audience, which proved more difficult than expected! Although I didn’t take home the award it was a very enjoyable evening, and the experience was invaluable. As scientists it is important for us to share and communicate our research with the general public and this was a skill I gained from the night!

Winners and finalists for the Irish Cancer Society’s Researcher of the Year Award
Winners and finalists for the Irish Cancer Society’s Researcher of the Year Award

Targeting drug resistance in neuroblastoma

MCT Research Talks 5th December 2016  rcsi-logo

Cancer Genetics Group

Neuroblastoma is a childhood cancer caused by the abnormal growth and development of neural crest cells (1). The disease commonly affects children age 5 years or younger. Approximately 50% of children have cancer cells that have migrated to distant sites in the body and formed tumour masses at the time of diagnosis. The main challenge in treating neuroblastoma is to combat tumour metastasis and development of resistance to multiple chemotherapeutic drugs. Despite major advances in available therapies, children with drug resistant and/or recurrent neuroblastoma have a dismal outlook with 5 year survival rates of less than 20%.

Research of Prof. Stallings lab is focused on elucidating the molecular events that contribute to the development and progression of neuroblastoma (2).  A major area of research involves the identification and functional analysis of microRNAs that contribute to chemotherapy resistance in neuroblastoma, along with the development of microRNA-mediated therapeutics.

The main research projects were presented at the Departmental meeting on December, 5th.

Microscopic examination of drug resistant neuroblastoma cells KellyCis83. Cells look healthy and can be kept for another 2-3 days to form a more dense population.
Microscopic examination of drug resistant neuroblastoma cells KellyCis83. Cells look healthy and can be kept for another 2-3 days to form a more dense population.

The first talk by Olga Piskareva has explored how current concepts of development of drug resistant, tumour microenvironment and cell-to-cell communication can be applied to reconstruct relapsed or drug resistant neuroblastoma microenvironment using 3D tumour models.

TEM analysis of exosome fractions. Vesicle sizes range from 30 to 200nm in Kellycis83 (A) and Kelly (B) neuroblastoma cells. (C) EVs which appear larger than the 100 nm upper limit for exosomes (D) Close up of the dried exosome preps identify the typical bowl shaped morphology associated with TEM images of exosomes. (3)
TEM analysis of exosome (EV) fractions. Vesicle sizes range from 30 to 200nm in Kellycis83 (A) and Kelly (B) neuroblastoma cells. (C) EVs which appear larger than the 100 nm upper limit for exosomes (D) Close up of the dried exosome preps identify the typical bowl shaped morphology associated with TEM images of exosomes (3).

The second talk was presented by Ciara Fallon. Ciara is our StAR PhD student. She has selected the project ‘Exosome mediated drug resistance in high-risk neuroblastoma’ as her first choice.  At the moment she is doing her lab placement in Cancer Genetics group as a part of the RCSI StAR PhD Programme. Built upon results of the former BioAt PhD Student Ross Conlon (3), Ciara’s project is focused on the validation of exosomal miR-548d-5p as a regulator of cell viability and proliferation in cisplatin sensitive and resistant neuroblastoma cell lines.

Finally, the last, but not least was a talk by John Nolan. His talk entitled “MiRNA-124-3p Reduces Cell Viability in Cisplatin Resistant Neuroblastoma Cell Models” was focused on the results submitted to the Royal College of Surgeons for the Degree of Doctor of Philosophy. His studies cover the development of cross resistance to other drugs, investigation of common altered proteins and signaling pathways in cisplatin resistant neuroblastoma cell lines and validation of miRNA that can target these proteins and stop cell proliferation. Part of the results was published last year in Cancer Letters (4).

The work carried out in Prof. Stallings lab is supported through the research grant to Prof. Ray Stallings and PhD fellowship to John Nolan by National Children’s Research Centre, Crumlin Hospital. ncrc

References:

  1. Davidoff, A. M. Neuroblastoma. 2012 Semin. Pediatr. Surg. 21, 2–14.
  2. Piskareva, O., Stallings, R. Neuroblastoma. In: Epigenetic Cancer Therapy edited by Grey S., Elsevier 2015.
  3. Conlon, R., Analysis of microRNA bearing exosomes in models of drug resistant neuroblastoma. PhD Thesis. Dublin: Royal College of Surgeons in Ireland; 2015.
  4. Piskareva, O., Harvey, H., Nolan, J., Conlon, R., Alcock. L., Buckley, P., Dowling, P., O’Sullivan, F., Bray, I., Stallings, T.L. The development of cisplatin resistance in neuroblastoma is accompanied by epithelial to mesenchymal transition in vitro. 2015 Cancer Letters, 364:142-55.

Reported by Olga Piskareva

Dr HH Stewart Award to Aya Al-Hasani

MCT is delighted to report that Aya Al-Hasani, one of our undergraduate Medical Students, has come second place in the Biochemistry Section of National Universities of Ireland, Dr HH Stewart Award. The top three students from RCSI are invited to take part in the exams, for each category.  Students are sent the essay title a week in advance, are not allowed to confer with staff, and sit the essay under exam conditions.

 Aya reflects on her award:

Aya AL-Hasani at Royal Hospital Kilmainham, Wednesday 09 November 2016. http://www.nui.ie/images/news/2016/awards2016_Flash/index.asp
Aya AL-Hasani at Royal Hospital Kilmainham, Wednesday 09 November 2016.
http://www.nui.ie/images/news/2016/awards2016_Flash/index.asp

During my first few years at RCSI, my hardest subject was biochemistry. Those complicated signalling pathways seemed absolutely useless to learn at that time. I then started to realise that biochemistry is essentially the platform for understanding all diseases and treatments. Suddenly, biochemistry became my favourite subject! I was so inspired by Prof. Cavalleri, MCT, who was organised and passionate in his teaching. I chose my favourite topic “obesity” after being invited to sit the HH Stewart exam. I was delighted to know that I won the second prize. It meant a lot for me to compete and win an Irish national competition. I just wished my parents were able to see me in the ceremony.

Aya attended the ceremony at Royal Hospital Kilmainham on Wednesday 09 November 2016.

Well done Aya!

HEAD OF DEPARTMENT’S WELCOME

 

Prof. Tracy Robson Head of Molecular & Cellular Therapeutics (MCT), Royal College of Surgeons in Ireland
Prof. Tracy Robson Head of Molecular & Cellular Therapeutics (MCT), Royal College of Surgeons in Ireland

It gives me great pleasure to welcome you to MCT’s blog page. Our department is based within the Royal College of Surgeon’s in Ireland (RCSI) situated on Dublin’s beautiful St Stephen’s Green.  This was one of the initial attractions for my move to Dublin from Queen’s University Belfast in Aug 2016, in addition to the vibrant and innovative environment that RCSI provides, through its achievements in education and research.

Our research focuses on understanding the molecular basis of disease in order to develop and apply our findings to the identification of biomarkers and new drug targets. Our aim is to improve the diagnosis, treatment and, ultimately, prevention of disease; enabling MCT to be at the forefront of personalized medicine. With newly renovated state-of-the-art facilities, strong links with Beaumont Hospital, our clinician-scientist teams are leading therapeutic and biomarker discovery in the areas of autoimmune and inflammatory disease, cancer, cardiovascular disease, infection, platelet biology and neurological and psychiatric disease. This is facilitated by strong collaboration with industry allowing us to translate our findings appropriately, revolutionizing healthcare through discoveries and innovations that improve people’s lives.

I hope that you enjoy reading our blog page which seeks to capture the dynamic nature of the teaching and research environment within MCT and pays testimony to the significant accomplishments of our all of our staff and students.  I hope that we can inspire you ………

Tracy Robson