3rd Chromosomal Instability as a Driver of Human Disease Conference
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Insights by Amy Mandigo (Jefferson University)
Hi everyone! I am a senior graduate student in the laboratory of Dr. Karen Knudsen at the Sidney Kimmel Cancer Center at Jefferson University in Philadelphia, PA. My primary research work focuses on the consequences of retinoblastoma (RB) tumor suppressor loss on prostate cancer progression to castration-resistant prostate cancer (CRPC). I study crosstalk between the E2F1 transcription factor and the androgen receptor (AR) after RB depletion and the mechanism by which these two proteins cooperate to regulate transcription and downstream signaling. I was granted the incredible opportunity to write this blog from a student’s perspective about the 2nd Fusion Nuclear Receptor Meeting, at which I was honored to attend and present my research.
The 2nd Fusion Nuclear Receptors Meetings focusing on new roles for nuclear receptors in development, health and disease took place at the Melia Nassau Beach Resort in Nassau, Bahamas from Feb 24th to Feb 27th 2020. The meeting was organized by Drs. Wayne Tilley, Charlotte Bevan and Karen Knudsen. This intimate meeting consisted of over thirty talks by leaders of the nuclear receptor field including Wayne Tilley, Charlotte Bevan, Donald McDonnell, Benita Katzenellenbogen, Geoff Greene, John Cidlowski, and David Moore with the keynote delivered by Ronald Evans. Other speakers included Ciara Metcalfe from Genentech and Mehrad Tavallai from Foundation Medicine providing a wide variety of talks from multiple perspectives. The talks were presented by both invited speakers and trainee abstracts selected by the organizers which included postdoctoral fellows and graduate students adding more diversity to those presenting their data.
Overall, the program of the meeting was extremely well put-together, allotting time for breaks in the middle of the sessions along with free afternoons for time at the beach. The refreshment breaks were held next door to the conference room and included soft drinks and light snacks. This was also the room where the poster session occurred. The posters were displayed throughout the duration of the meeting and provided many opportunities for attendees to present their own work and see the work presented by others. As a trainee presenting a poster, this was extremely helpful as often, posters are only displayed during the designated poster sessions which does not provide enough to interact with other presenters. I had the opportunity to present my research during multiple breaks and was able to utilize this time to discuss not only my research, but my career goals and available postdoc positions with leaders in the field. The program was divided into six sessions by topic with a 30-minute panel discussion at the end. The panel discussions provided an excellent opportunity for conversations on controversial issues between the speakers and attendees along with new perspectives on the current hurdles in the field. A group dinner was held each evening of the meeting which afforded students and trainees the opportunity to interact with successful scientists in the field to gain both research and career advice.
The Melia resort is an all-inclusive beach front resort with five on-site restaurants, multiple bars, three pools, many land and water activities, and a conference area on the lower level. This casual and relaxing location provided an excellent environment for early career scientists to meet well-established investigators and other early trainees in the field. Activities on the resort were available during the afternoon and evening free time and were well utilized by conference attendees.
The first day of the meeting started with opening comments from both Wayne and Charlotte followed by the first session titled “Nuclear Receptors and Cancer”. The first half of this session was heavily focused on breast cancer with talks from Carol Sartoius (University of Colorado Anschutz Medical Campus) and Mohammed Bentires-Alj (University of Basel) discussing breast tumor heterogeneity; and Isabella Goldsbrough (Imperial College London) introducing varying mutations in the estrogen receptor A gene in metastatic, endocrine-resistant breast cancer. Wayne Tilley also discussed ER in response to androgen stimulation which was further expanded on by Ayesha Shafi (Jefferson University) who switched the conversation to prostate cancer and the novel androgen receptor (AR) regulated DNA repair protein, CRY1. These five talks were followed by a 30-minute refreshment break in the room with the posters displayed.
Following the break, the session continued with ER-focused talks from Geoff Greene (University of Chicago) discussing novel treatments for ER-positive breast cancer and Cecillia Williams (KTH Royal Institute of Technology/Karolinska Institute) introducing novel ERb functions in colorectal cancer. Hisham Mohammed (Knight Cancer Institute, OHSU) picked back up on tumor heterogeneity presenting a multi-omic single-cell approach to highlight areas of heterogeneous signaling within a tumor. The session ended with a talk from Moray Campbell (Ohio State University) who discussed crosstalk between RARg and AR signaling in response to DHT stimulation. The following panel discussion was one of the best of the meeting. It included questions regarding the sequence of breast cancer treatment and patient quality of life, the need for better models to examine drug response, and the role of ERa in driving proliferation. The discussion for this session included valuable insight from leaders of the field including Donald McDonnell, Gary Hammer, Jason Carroll, and David Moore along with the speakers of the session. As a trainee early in my career, I appreciated the opportunity to listen and engage in critical discussions of broad, “big picture” topics and issues within the field beyond nuclear receptor functions, extending to the larger questions that have yet to be answered.
After the panel discussion, the poster presenters (including myself) had the opportunity to introduce themselves and their research to the rest of the meeting attendees. This was extremely helpful to not only get people excited about the posters but to also introduce myself to the entire group. Additionally, it allowed trainees to meet other trainees and compare research interests.
Following the poster introductions was the keynote by Ron Evans (Salk Institute/HHMI) who gave a detailed history of the last 35 years of nuclear receptors and a new way to think about cancer risk. He also discussed his work on the bile acid receptor, FXR and Tauro-beta-muricholic acid (T-bMCA) function in disease progression.
The second day began with the session titled, “Nuclear Receptors in Reproduction, Development and Metabolism,” moving away from a cancer focus and into additional functions of nuclear receptors in disease. The session started with work on glucocorticoid and progesterone receptors (GR, PR) with talks form Sarah Cunningham (Duke University) discussing GR cell cycle control in fetal membranes and Darryl Russell (University of Adelaide) examining the distinct functions of PRA and PRB isoforms in the uterus and ovaries. These talks were followed by a refreshment break, again allowing for time viewing and presenting posters.
After the refreshment break, the session continued with novel functions of targets regulated by nuclear receptors: Vincent Giguere (McGill University) discussed novel functions of AR-regulated mTOR after DHT treatment, and Gary Hammer (University of Michigan) introduced the mechanism of SF1 regulation of endocrine and paracrine signaling. Charlotte Bevan (Imperial College London) then turned the conversation to lipid metabolism, discussing the LXR regulation of glycerophospholipid metabolism. The session closed with a panel discussion followed by a break for lunch and free time.
During the free time, I had the opportunity to have lunch and catch up with other trainees at the meeting. This extra time was truly important for forming long lasting relationships with peers who will eventually be my future colleagues in the field. This was a time where future career directions were discussed as well as the hurdles early career scientists face both in the laboratory and when publishing papers. Discussions continued on the beach and in the ocean allowing time to interact with colleagues in a much more casual setting.
After the break was the session titled, “Nuclear Receptors in Central Systems.” This session included an array of talks on various topics beginning with John Cidlowski (National Institute of Environmental Health Sciences) and a discussion on crosstalk between the mineralocorticoid receptor (MR) and GR in cardio systems. Moving on into adipose and skeletal muscle, Natasha Kralli (Johns Hopkins Medical School) spoke about the estrogen related orphan receptors, alpha, beta and gamma and their distinct functions in metabolic control. Saskia van Mil (UMC Utrecht) continued the metabolic discussion with novel functions of FXR in regulating mitochondria respiratory capacity through MPC1 and lipogenesis SHP. This was followed by Andrew Holding (University of York) who discussed a novel interaction between ER and GRHL2 identified by the new method, VirtUaL ChIP-seq Analysis through Networks (VULCAN) which combines publicly available tumor expression data with ChIP-seq data. To close this session, Holly Ingraham (UCSF) presented her work on estrogen signaling in the hypothalamus and the implications on bone density and women’s health.
The third day started off with the session, “Translating Nuclear Receptors to the Clinic.” This session included multiple talks on endocrine therapy and endocrine resistance. Ciara Metcalfe (Genetech) started off discussing targeting ER in breast cancer and introducing the differences between the mechanism of action of ER antagonists and ER modulators. This talk was of particular interest to me as a trainee, as it gave an industry perspective on targeting disease. Keeping on the topic of endocrine resistance, Donald McDonnell (Duke University) spoke about the role of ERa on T-cell function and the tumor microenvironment, explaining why endocrine therapy for melanoma is more successful in males. Benita Katzenellenbogen (University of Illinois) linked FOXM1 and 12-3-3z protein kinase signaling to tamoxifen resistance driving a metastatic phenotype. Beyond endocrine therapy, Claire Fletcher (Imperial College London) discussed a novel role for miR346 in regulating DNA damage response through the long noncoding RNA, NORAD, sensitizing prostate cancer cells to PARP inhibition. Continuing on the topic of DNA damage response, Dan Gioeli (University of Virginia) presented his work on crosstalk between cell cycle checkpoint protein, CHK2, and AR, promoting downstream DNA repair. Changing the focus to glucocorticoid therapeutics, Onno Meijer (Leiden University Medical Center) introduced the downstream metabolic effects of the selective GR modulator, CORT118335. Also focused on GR function, Inez Rogatsky (HSS Research Institute) discussed the function of GRIP1 in inflammatory response through regulation of GR transcription. Lastly, Mehrad Tavallai (Foundation Medicine) provided a broad genomic landscape of male breast cancer highlighting targetable alterations. The panel discussion of this section was primarily focused on understanding the full clinical potential of targeting ER in breast cancer and how important it is to individually study ER targeting by asking separate questions and bring the conclusions together as a field. This discussion really highlighted the importance of sharing scientific data and collaborating across the field.
After the generous lunch and leisure break, the meeting continued with the “Nuclear Receptors in Non-Malignant Disorders” session. David Moore (Baylor College of Medicine) began the session discussing targeting LRH-1 with dilauroyl phosphatidycho-line (DLPC) and utilizing CAR to treat inflammatory bowel disease. This was followed by Jessica Tollkuhn (Cold Spring Harbor Laboratory) who spoke about her work identifying a role for ERa in regulating neuro specific pathways in the brain. Stephan Herzig (Helmholtz Zentrum Munich) then spoke of his work on PPARa and GR regulation in hepatocytes and targeting GR or the fatty acid oxidizing enzyme, Pla2g7, in diabetes. Following the break, Eric Kalkhoven (UMC Utrecht) presented his work on the distinct gain-of-function and loss-of-function activity of mutant LXRb in hepatic metabolic control. Ending the session, David Mangelsdorf (University of Texas) gave a very interesting talk on his work in parasitic disease introducing the role of nuclear receptor DAF-12 in regulating reproduction of S. stercoralis and how to target parasitic infection, demonstrating the breadth of nuclear receptor function across species.
The third evening was the presentation of awards and the gala dinner. This was one of my favorite nights. The dinner was brightly decorated and took place outside by the pool. The evening started with a cocktail hour followed by a sit-down dinner providing excellent time to continue networking and discuss previous talks or studies of interest. After dinner there were two different types of awards presented. The first were for the posters which were awarded to myself, Sue Powell (Imperial College London), Aysegul Ors (The Knight Cancer Institute-OHSU) and Linnea Petterson Hases (Karolinkska Institute). The second award was for trainee participation. To promote participation and discussion throughout the talks, the organizers decided to award the trainee who was the most involved in discussions and asked the most questions. This was awarded to Isabella Goldsbrough (Imperial College London). I think this was an excellent idea. Many early career trainees are intimidated at meetings and tend not to participate in discussions much. This award really encouraged more participation. After the awards, there was a singer and dancing which is always the best part of any meeting. Investigators and trainees dancing together and having a great time is such a great way to end such an intimate conference.
After all the dancing and singing the night before, the final morning started off with a talk from Lee Kraus (University of Texas) discussing the differential functions of the micropeptide, TSP1 in HER2 positive and triple negative breast cancers. Cyrille de Joussineau (Université Clermont Auvergne) then discussed ecdysone signaling in Drosophila and how it regulates tumor invasiveness and heterogeneity. Switching over to LXRa, Irina Bochkis (University of Virginia) presented her work showing LXRa dependence on Foxa2 for recruitment to chromatin after ligand activation. Touching on AR and GR, Eva Estebanz-Perpina (University of Barcelona) presented her work on GR and AR oligomerization complexes. The last talk of the meeting was by Iain McEwan (University of Aberdeen) who presented his work on N-terminal targeting of AR and the splice variants with EPI compound derivatives.
This was the second Fusion Nuclear Receptors Meeting I have had the opportunity to attend. Fusion never disappoints. The meetings are always very well organized with a lot of attendee interaction. The casual environment and generous amounts of free time really fosters an ideal environment for networking and building long term relationships with both established advisors as well as early-career trainees/peers in the field. I would highly recommend this meeting to other trainees as it is an excellent place to gain quality feedback on your research, to meet lead investigators in the field (many of which remembered me from the previous meeting), and to learn about career positions available. Communication with the Fusion team is always very easy. The meeting this year was managed by Amy Johnson who was always available via email to answer any questions and kept everything moving smoothly. I truly enjoy these meetings and look forward to the 3rd Fusion Meeting on Nuclear Receptors.
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