MCT research seminar
The way we act very much depends on our surroundings; not the least on the weather conditions. In a similar way, cells in our body very much depend on what is going on around them. It has been known for a long time that the specific niches in which cells reside impact on the cellular phenotype. While most researchers have looked at chemical signals – either released into the environment or reflecting the composition of the extracellular matrix – it is becoming increasingly clear that also physical properties, such as stiffness and topography, are sensed by a wide variety of cells and influences their decisions.
It is our pleasure to welcome Prof Viola Vogel this Monday at RCSI for the MCT research seminar.
July 16th, 4.00 pm, Albert Lecture Theatre “How does the mechanobiology of extracellular matrix steer cancer progression?”
Prof Vogel and her laboratory at ETH Zurich have pioneered the field of mechanobiology. Her earlier work focused on how proteins act as mechanochemical switches to transduce mechanical signals from the ECM into the cell. More recent work addresses the importance of tissue strain in the development of tumours. Prof Vogel will also share her latest results on how physical constraints affect decision making of macrophages.
Anyone who is interested in getting a different viewing angle on cancer and immunity is heartily invited! To steer your personal decision making towards attending the talk, refreshments will be served from 3.30 pm on in the Atrium.
Pathological blood vessel formation (angiogenesis), or the inability of endothelial cells to perform their physiological function (endothelial dysfunction), are defining features of disease. The endothelium actively controls vessel integrity, vascular growth and remodelling, tissue growth and metabolism, immune responses, cell adhesion, angiogenesis, haemostasis and vascular permeability. It is, therefore, a vital and largely unexploited target for novel therapies.
Prof Tracy Robson’s team have identified and characterised a novel anti-angiogenic protein, FK506 binding protein like – FKBPL, significantly advancing our understanding of the anti-angiogenic process, in particular, how tumours recruit blood vessels to support their growth. This led to a collaborative study with Almac Discovery to develop therapeutic peptides based on FKBPL’s active domain to explore their potential in cancer by targeting the ability of tumours to recruit blood vessels to grow, invade and metastasise beyond the site of the primary tumour. The team are also testing the ability of these peptides to sensitise tumours to current therapies and to target cancer stem cells that lead to the onset of resistance and/or recurrent disease. Importantly, these studies led to a ‘first in man’ phase I clinical in cancer patients where the clinical candidate drug, ALM201, was very well tolerated over a wide range of doses. Prof Robson’s team (Dr Stephanie Annett and Dr Gillian Moore) will discuss this data together with new data suggesting a strong role for FKBPL in vascular endothelial dysfunction and possible implications therefore in other diseases associated with vascular disease.
On Friday, March 23rd, MCT and the Department of Physiology hosted a Spinathon for Daffodil Day, the Irish Cancer Society’s biggest fundraising day of the year. The aim of the Spinathon was to cycle the same distance as the Ring of Kerry, a total of 170 km on each bike. A number of willing participants took part on the day, including Sudipto, Lisa, George and Tony from MCT. A total of €1966 between the JustGiving.ie fundraising page and bucket collections on the day.
Well done to everyone involved!
MCT Research Talks
Neuroblastoma is a cancer of the nervous system that primarily affects children aged 5 and younger. Although neuroblastoma accounts for only 5% of childhood cancers, it is responsible for approximately 15% of childhood cancer deaths. For children with high-risk neuroblastoma – children in which cancer has spread significantly – the outlook is extremely poor. Approximately 1 in 5 of these children will not respond to treatment, and of those that do, 50% will develop drug resistance leading, in many cases, to death.
Dr Olga Piskareva, an NCRC supported scientist and Honorary Lecturer at RCSI, has recently published a study describing a new way to grow cancer cells in the lab. Traditionally, researchers grow cancer cells in the flasks on the flat surface. This is not the way cells grow in the human body. Dr Piskareva in collaboration with Dr Curtin and Prof O’Brien has designed a new way to grow cancer cells that recreate their growth in 3 dimensions as in the human or mice body. They used special cotton wool like sponges as a new home for cancer cells and populated them with cancer cells. At the next step, they gave cells the drug at the different amount and checked what happened. In this system, cells responded only to the drug at doses used in the clinic or mice models.
This new strategy to grow cells on sponges should help to understand cancer cell behaviour better and accelerate the discovery and development of new effective drugs for neuroblastoma and other cancers. This, in turn, will make the outlook for little patients better and improve their quality of life.
More details about our research can be found in Dr Piskareva’s blog!
Reported by Olga Piskareva
MCT Research Talks
Our group is a drug discovery lab currently working on the development of a novel Fc gamma receptor IIa inhibitors. FcgRIIa is a low affinity receptor for Fc portion of immunoglobulin G (IgG) and is implicated in a variety of conditions that are still mainly untreatable, such as rheumatoid arthritis, lupus, immune thrombocytopenia, sepsis. FcgRIIa is widely expressed by human innate immune cells, and is the only Fc gamma receptor found on human platelets.
Mainly over-stimulation of the FcgRIIa receptor in these conditions that leads to the progression of the disease. For example, in sepsis the platelets get activated via FcgRIIa in response to bacteria present in the blood, which results in thrombocytopenia and disseminated immune coagulopathy. This causes, not only internal haemorrhage but also formation of blood clots that block peripheral blood vessels leading to sepsis-associated limb loss, heart attacks and/or strokes. Using a targeted approach, such as pharmacophore modelling, our group has developed a small molecule compound that effectively blocks FcgRIIa-mediated platelet aggregation in vitro. In agreement with the chosen targeted approach, this compound was shown to bind to the FcgRIIa directly and possesses specificity for the FcgRII subgroup of the Fcg receptors.
Ultimately, this compound has a great potential to be used for treatment of other FcgRIIa-mediated auto-immune conditions, such as rheumatoid arthritis, lupus and an array of immune thrombocytopenia conditions.
Prof Dermot Cox, Dr Tatiana Devine and Padraig Norton
Please join me in offering congratulations to ‘Drs’ Shane O’Grady and Brian Mooney who successfully defended their PhD thesis yesterday:
Shane’s: Investigation of the functional roles of calcium channels, inflammatory cytokines and tumour micro-environmental factors in a human in vitro model of breast cancer calcification
Supervisor: Maria Morgan
Brian’s: The role of the anorectic neuropeptide CART in breast cancer. Supervisor: Darran O’Connor
Well done to all.
Many MCTers presented their research at the 54th Irish Association for Cancer Research Meeting on February 22-23, 2018. The annual IACR meetings bring together the Irish cancer research community and distinguished international speakers. 260 attendees registered for the meeting with 150 abstracts accepted for oral and poster presentations. Notably, the IACR meeting committee creatively shapes the way this conference run. This year, the most dynamic session – Oral Poster Presentations (Prof. John Fitzpatrick Medal, 5 min talk+1 min Q&A) was set for the lay audience with the judging panel consisting of patients, patient advocates and researchers. Very interesting experience, have to say. Two MCT research studies were selected for this session: Olga Piskareva presented the collaborative project between her team and Prof Fergal O’Brien (TERG) “3D Tissue-Engineered Cell Model Of Neuroblastoma For Evaluating Cytotoxic and miRNA-Targeted Therapeutics” and O’Connor’s collaborative project on “RNA Sequencing Identifies BRD3 As A Novel Therapeutic Target In Invasive Lobular Carcinoma Breast Cancer” was presented by Kathryn Haley. Darran O’Connor himself was an invited plenary speaker. He talked about “The Power Of 1: What Can We Learn From Molecular Case Studies?” at the plenary session Emerging Techniques In Biomarker Discovery, Drug Development And Patient Stratification. MCT had a spot at the Proffered Paper Session with John Nolan presented the first data of the NCRC funded project “Modulation of Drug Resistance in High-Risk Neuroblastoma Through Exosomal miRNA”. Many other MCTers had Posters. For Shane O’Grady and Lisa Dwane, it was the last conference in the PhD status and for Olga Piskareva – in her role of Honorary Treasurer f0r the IACR!
Well done to all!
The 55th Irish Association for Cancer Research Meeting will be taking place in Belfast.
Reported by Olga Piskareva
Dr Justyna Surowka, Medical University of Lublin, Lublin, Poland
(Current Erasmus Post-doc with the O’Connor group) presented “Assessment of chosen immune cell populations in patients with ovarian cancer”
Despite the decades of studies on developing new therapeutic strategies, ovarian cancer remains one of the malignancies with the highest mortality rate. Therefore, new therapies, among them immunotherapy, are in demand. Recently, Kurman and Shih proposed a new classification of ovarian cancer. It is based on molecular and histopathological differences between tumors and divides them into two subtypes: type I and type II ovarian cancer. However, there are no studies exploring functions of an immune system in those types of ovarian cancer. We demonstrated that each type of ovarian cancer can induce a unique phenotype of dendritic cells and differentiation of Tregs, both associated with immunosuppressive function, which may be an obstacle while developing effective anticancer dendritic cell vaccination.
Dr Sudipto Das presented “Dissecting the epigenome of metastatic colorectal cancer”
The talk highlighted the experimental and analytical pipelines that have been established in the lab in order to develop single-base pair resolution DNA methylation maps derived from difficult-to-handle FFPE (Formalin Fixed Paraffin Embedded) tissue. We next applied these optimized approaches to primary tumour samples derived from 58 metastatic colorectal cancer (mCRC) patients and 10 matched normal samples, with an aim to unravel the methylation alterations across both conventional gene regulatory regions such as promoters as well as alternative regulatory elements such as enhancers of protein-coding and non-coding genes. Intriguingly, we have now identified a DNA methylation specific signature consisting of 377 differentially methylated loci that differentiates tumour and normal and in parallel provides us with three distinctive clinical clusters, which show a significant overlap with prognostically relevant consensus molecular sub-types of CRC. However, further work is warranted to ascertain the precise function of the signature as well as their role in predicting patient response to treatment.
The second part of the talk detailed about the ongoing genomics focused on “n-of-1” genomic studies which essentially involves atypical cancer presentation in patients, with the idea of understanding the biology of such unusual clinical phenotypes and moreover to identify any potential therapeutic targets.