György Marko-Varga, Sweden

Focusing on Patient-Relative-Friend Aspects in the 2018 Summit

Photo by Karl Melin.

The European Cancer Moonshot Symposium was held in Lund May 23rd. The primary goal of the meeting was to invite and discuss cancer research from the perspective of patients, relatives, and friends. Patients and relatives from the US and different parts of Europe told their stories and about their experiences from treatment of various cancer forms (https://www.facebook.com/europencancermoonshotlund/ ).

Honest and emotional lectures were given on the factual circumstances that a patient and a close relative face when dealing with tough messages, treatments, and decisions. The mental trainer, Igor Ardoris, shared his experience of how to deal with these situations, controlling the mind and imaginational part, that can be trained to overcome and ease pain and disease pressure.

The former athlete and world record holder in high jump Patrik Sjöberg gave a deeply touching talk about a child’s perception of having cancer. Mr Sjöberg is now working part time advocating for children with cancer, through the Tuva’s Day Foundation (Varberg för Liv/Tuvas Dag). Martin Bekken from BEWi, has been a strong support to the European Cancer Moonshot Lund Center, by getting the word out on the build of the PRF-group-that was the focus of our meeting this year.

With the patient in focus the meeting also engaged the hospital management of the southern health care district of Sweden, experts and medical doctors from cancer treatment clinics, and prominent cancer researches in the cancer diagnostic field. The Cancer Moonshot research team in Lund hosting the Symposium also had reporting from the Cancer Moonshot Australia activities, was presented by Professor Mark Baker, where major funding and investments for future Cancer research and developments have been made recently, expanding on the US/Australia Cancer Moonshot collaboration. Dr. Henry Rodriguez, from the NIH/NCI (National Instituts of Health/National Cancer Institute), presented the overall progress and activities of the Cancer Moonshot program in the US, and Dr. Thomas Conrads, showed the latest cancer studies within the Cancer Moonshot & US/Apollo developments, which were very impressive.

Statement from professor Johan Malm “When working with front-line clinical research at the European Cancer Moonshot Lund Center, as we are doing, it is very stimulating and inspiring to listen to all the different stories from patient and their relatives. Then you realize that what matters is not you. It is what you are working for, namely a better life for the people facing the consequences of cancer”.

Statement from Ken Miller, Thermo Fisher Scientific “Thermo Fisher is a partner to many global Cancer Moonshot laboratories and we consider the program in Lund to be an exemplar of clinical excellence, biobanking, and analytical expertise. We are confident that this team will help the cancer research field make progress toward the dream of patient phenotyping and precision medicine.”

The Cancer Moonshot was initiated in 2016 by the 47th vice president Joe Biden.

The project team in Lund hosting this year’s international European Cancer Moonshot summit built the theme on Joe Biden’s vision;

“Break down the silos and start to collaborate, involve all disciplines, with one common aim, to defeat cancer.”

Related links:

Watch all 5 sessions of the European Cancer Moonshot Symposium in Lund

Session 1: https://www.youtube.com/watch?v=nsvPAvvqCLA&t=4s

Session 2: https://www.youtube.com/watch?v=ihxSd820lNo

Session 3: https://www.youtube.com/watch?v=Gfp6Ic8pe5U&t=3s

Session 4: https://www.youtube.com/watch?v=vcV5rcnLT7I&t=4s

Session 5: https://www.youtube.com/watch?v=MJe56CHUw_k

Follow the European Cancer Moonshot Lund Center here: http://www.cancermoonshotlund.com/ 

Hear about Eve Kelly's story here: https://www.youtube.com/watch?v=9euomHlFqnY

Michelle Hill, QIMR Berghofer Medical Research Institute, and The University of Queensland, Australia

Post-translational modifications (PTMs) on proteins can play a critical role in function by regulating protein structure, function and/or localization. Although consensus sites for some of the more well-studied PTMs have been established, PTMs are not predictable from the genetic code. Furthermore, PTMs can be either stably attached through the life of a protein, or reversibly added depending on stimulation. Hence, direct interrogation at the protein level is required to fully characterize PTM function in health and disease.

Several B/D-HPP teams have been investigating the biological roles of PTMs and their disease associations, with two recent publications in leading interdisciplinary journals.

Neil Kelleher and his team at Northwestern University used top-down proteomics to characterize proteoforms of KRAS, a gene frequently mutated in human cancer. The novel mass spectrometry-based whole protein assay enabled the team to investigate the effect of genetic mutations in KRAS on PTMs of the protein that are important for proper KRAS regulation. In collaboration with National Cancer Institute, the study, recently published in Proceedings of the National Academy of Science USA, quantified the percentage of mutant KRAS4b present in colorectal cancer tissue, and identified differences in the level of C-terminal carboxymethylation, which is critical for KRAS function. Such detailed characterization and quantification of KRAS proteoforms was only possible with the novel top down mass spectrometry-based assay. In the future, targeted assays such as this will be extended to characterize proteoforms within specific cell types to increase their sensitivity and selectivity and inform cancer prognosis and personalized therapy selection.

A collaboration between Jenny Van Eyk’s team at Cedars-Sinai Medical Center and Shengbing Wang and David Kass at Johns Hopkins University School of Medicine, determined the functional consequences of a redox-regulated PTM on glycogen synthase kinase 3b (GSK3b). S-nitrosylation is the attachment of nitric oxide to sulfhydryl residues of proteins, and is involved in redox-based cell signaling. The study, published in Circulation Research, reported the novel finding that GSK3b can be modified by S-nitrosylation at specific sites in models of heart failure and sudden cardiac death. S-nitrosylation of GSK3b overrides the classical phospho-regulation and sends it to the nucleus, away from its usual cytoplasmic location. The result is that the S-nitrosylated GSK3b now phosphorylates a completely different repertoire of proteins in the nucleus compared to its known cytoplasmic substrates, implying that drugs meant to target cytoplasmic GSK3b may inhibit complete different nuclear pathways if the GSK3b is S-nitrosylated. “Knowing the PTM status of drug targets and the functional effect is key to next generation therapies.” Says Jenny.

Together, these studies exemplify the work of B/D-HPP teams and clinical collaborators on apply and developing advanced proteomics methods to understanding disease. Future work of the B/D-HPP teams will be to translate the findings into the pathology or clinical chemistry laboratories, to make an impact on patients lives.

Péter Horvatovich, University of Groningen, Netherlands

The Chromosome-Centric Human Proteome Project (C-HPP) plans to identify all elements of the human proteome, their proteoforms and determine their functions. C-HPP efforts are summarized as protein evidence status and functional and other annotations of human protein coding genes by neXtProt. The C-HPP is organized as an international consortium based currently on a per chromosome basis and is open to the entire scientific community for contribution. Besides individual publications, other scientific contributions are summarized in the C-HPP special issues appearing each year in the Journal of Proteome Research. On an ongoing basis, the main C-HPP achievements are highlighted in C-HPP Newsletters published every year. The C-HPP has initiated a community information sharing Wiki page, to enable sharing C-HPP–related information directly by member teams. The C-HPP Wiki includes the following sections:

- Representation of team members information, resources, expertise, projects and results on a chromosome basis

- Protocols, guidelines and central resources of the C-HPP project

- The program of C-HPP workshops organized each year at HUPO congresses and at C-HPP workshops, which includes presentations with authors permission and other workshop related information

- C-HPP news items, which includes announcement of new achievements, new guidelines and yearly appearing C-HPP Newsletters

C-HPP Wiki is a live non-centralized information sharing platform of C-HPP members and has as its goal to share as much information as possible for C-HPP members, for the proteomics scientific community and for interested readers. The web page for C-HPP Wiki is at https://c-hpp.webhosting.rug.nl/tiki-index.php?page=HomePage

Péter Horvatovich, University of Groningen, Netherlands

On February 21, 2018 the new release of neXtProt was published, which serves as the definitive reference database of the human proteome and is used by the Human Proteome Project (HPP) to assess the progress of completing the map of Human Proteome. The new version of neXtProt updated the human proteome evidence using the latest data from PeptideAtlas (release Human 2018-01) and resulted in 17,470 validated human proteins (PE1), 393 more compared to the previous version of January 17, 2017, leaving 2,186 missing proteins with status PE2+PE3+PE4 and 574 uncertain proteins (PE5). In this new release a total of 51 PeptideAtlas data sets was included from cancer tissues and cell lines, with over 1.4 million peptides detected by mass spectrometry. Data from UniProtKB, Ensembl, IntAct, GOA, and GeneIDs, have been also updated. The data have been complemented with GO molecular function, biological process and cellular component annotations for most of the human protein kinases, as well as expression information, mutagenesis and variant phenotype data. The number of validated proteins with unknown function (uPE1) is now 2,271 which can be obtained with SPARQL query NXQ_00022.

Two new rules have been implemented to reflect protein existence:

- proteins with PE2, PE3 or PE4 status have been upgraded to evidence at protein level (PE1) status if the entry has GOLD binary interaction data from neXtProt.

- As a consequence of UniProtKB demerging entries encoded by multiple genes, some neXtProt entries now have exactly the same protein sequence and are indistinguishable at protein level. The list can be retrieved using SPARQL query NXQ_00231. Peptides matching uniquely on such indistinguishable entries are now labeled “pseudo-unique” rather than "Found in other entries" and were used to validate protein existence if they complied with the HPP guidelines.

The Proteomics view for entries has been revamped and now loads faster. In addition, it is now possible to search the positional annotations listed in the feature table for a specific category or for text found in the feature description. For instance, searching for "SRM" returns the number of SRM peptides mapping to the isoform and allows to the users to rapidly browse the data for all SRM peptides.

New advanced search SPARQL queries have been added, such as to identify proteins with high proline content in the SnorQL interface (NXQ_00225), to list proteins with at least 2 uniquely mapping peptides larger than 9 amino acid lengths found in blood plasma, urine or cerebrospinal fluid to support markers research (NXQ_00226) and to identify proteins with experimentally determined lengthy alpha-helices (length larger than 75 amino acids) illustrating query of proteins with specific secondary structure (NXQ_00230).

New letter format of Journal of Proteome Research to report missing proteins

Discovery of a missing protein or new proteins can now be published in the Journal of Proteome Research December 2018 Special Issue as a short definitive report, submitted in the Letters format. To be considered for publication as a Letter, the missing protein(s) must meet the HUPO Data Interpretation Guidelines version 2.1 and be cast in the context of both the HPP and biological setting in which they were discovered. We anticipate this format will encourage many teams, particularly of the B/D-HPP and the general proteomics community, to highlight such protein discoveries when found in disease and biological sample analyses. Such side findings in a more biological focused analysis may otherwise may be lost or not further detailed as they were an incidental finding.

Letters have a maximum length of four journal pages and should contain sufficient experiment detail for the research to be reproduced. There should be no more than 3 figures, 2 tables and 20 references. A separate Table of Contents Graphic is required, but does not count toward the 4-page or Figure limit. Reporting of missing proteins must meet both the Journal of Proteome Research technical and the HUPO Data Interpretation Guidelines (see further details in Deutsch et al. PMID 27490519) including figure(s) of the annotated spectra and the data uploaded to ProteomeXchange with a PXD number included in the abstract. To be reviewed the HPP Checklist items must be fulfilled and submitted.

Michelle Hill, QIMR Berghofer Medical Research Institute, and The University of Queensland, Australia

The last decades saw a steady increase in the incidence of rheumatic and autoimmune diseases such as osteoarthritis (OA) rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel diseases (IBD) and systemic lupus erythematosus (SLE). Rheumatic and autoimmune diseases (RAD) are characterised by inflammation of joints, muscles, and connective tissues around joints and bones. Apart from the debilitating mobility and pain, RAD patients are also at increased risk of cardiovascular and neurodegenerative diseases. Given the huge socioeconomic impact of RAD, broad research efforts have been dedicated these diseases worldwide.

The RAD B/D-HPP initiative was launched in 2017 by Francisco J. Blanco (Rheumatology Department, INIBIC-Complejo Hospitalario Universitario A Coruña in Spain) with co-chair Paul J. Utz from Stanford Department of Medicine, USA). Currently, 6 research groups from 5 countries participate in RAD-HPP, but the collaborative network has already extended to Cardiovascular-HPP and Chromosome 16-HPP .

After establishing the networks and promoting visibility of the new initiative, the immediate scientific goals of RAD-HPP are to define the proteome of human joint tissues (cartilage, synovial membrane, subchondral bone), and to assemble prioritized lists of proteins clinically relevant in RAD using the ‘popular proteins’ strategy with text mining tools. Collaborations within the RAD-HPP have already resulted in several publications in 2017, including circulating biomarkers for knee radiographic osteoarthritis , use of protein array to discover and validate biomarkers for Osteoarticular Pathologies , and anti-citrullinated protein antibodies in rheumatoid arthritis.

To spread the word outside of proteomics research circles, RAD-HPP members presented their proteomics work at key RAD clinical meetings around the globe in 2017. These included Osteoarthritis Research Society International (OARSI) World Congress in Las Vegas (USA), the Annual European Congress of Rheumatology-EULAR in Madrid (Spain), Annual Meeting of the American College of Rheumatology in San Diego (USA), and XLIII Congress of the Spanish Rheumatology Society in Bilbao (Spain).

To boost the development and utility of quantitative proteomics assays, RAD-HPP members conducted focused proteomics training sessions in 2017, with highlights being sessions at “Cutting Edge Osteoarthritis” Symposium at Pembroke College, Oxford, and “Proteomics in rheumatic diseases” lecture at a Summer School on Platform Technologies and Big Data applications in Precision Medicine, in Santander, Spain.

With the synergistic international effort and strong clinical translational focus, the RAD-HPP initiative is poised to realise the utility of proteomics in RAD diagnosis and management.

Péter Horvatovich, University of Groningen, Netherlands

The 19th Chromosome Centric Human Proteome Project workshop will be held in Santiago de Compostela (Spain) on June 16-17, 2018 as a companion event of the XII EuPA Congress 2018. We are cordially inviting all scientists and partners interested in discussing the status and future directions of the Chromosome Centric Human Proteome Project. The workshop has the aim to discuss the most pertinent questions of the (chromosome centric) human proteome project, which includes the following topics:

-Completeness of the human proteome and new developments to identify missing proteins, highlights on next-MP50 (50 next missing proteins) program

-Start of the uPE1 project aiming to find function(s) for human proteins identified with high confidence (PE1 category in neXtProt) without any known function

-Discussion on the future directions of the Human Proteome Project focusing on bright (know, HPP PE1 proteome) and dark proteome (unknown, “Missing” proteins, uPE1 proteins and dark structural proteins)

-Inclusion of translated small open reading frames and long non-coding RNAs, sequence variants, splice isoforms and proteins peptides with post-translation modifications

-Bioinformatics infrastructure of the (C-)HPP project

-Recent results and future directions of B/D-HPP and joint actions with C-HPP teams

To follow the status and future paths of C-HPP, the reader is referred to a recent review of the C-HPP Executive Committee members in Expert Review of Proteomics entitled “Advances in the Chromosome-Centric Human Proteome Project: looking to the future”. Questions and suggestions for the workshop can be addressed to the organizer of the workshop, Fernando Corrales (fcorrales@cnb.csic.es, Spanish National Centre for Biotechnology, Madrid, Spain). The continuously updated workshop program is available at C-HPP Wiki. We are looking forward to meet all interested persons at this event.

Michelle Hill, QIMR Berghofer Medical Research Institute, and The University of Queensland, Australia

More than 20 investigators across the globe are working together to unveil the proteins that allow us to see. The B/D-HPP EyeOME initiative began in 2013, under the leadership of Prof Richard Semba (Johns Hopkins University School of Medicine). As for other HPP initiatives, the first task is to identify all of the eye proteins. For this arguably the most complex of organs, this task is far from simple; the human eye consists of diverse specialised tissues and biofluids.

Thanks to the collective efforts of proteomics researchers, the eye proteome database now contains a total of 9,782 non-redundant proteins for 11 eye tissues and biofluids, with the highest number (6,538 proteins) from vitreous humor and the lowest number (827) from aqueous humor. The database was curated under rigorous standards as highlighted in the recent article from the EyeOME team, which also outlined recommendations for human eye proteome studies.

The team is currently preparing a website to facilitate broader dissemination and usage. The international effort in EyeOME will provide a proteomic knowledgebase to increase our understanding of how the eye works at a molecular level. This knowledge will ultimately contribute to improved treatments for disorders of the eye.

The human eye proteome database is available for download here: Supplemental Table S2 xlsx.

Lennart Martens, Ghent University, Dept of Biochemistry, Belgium

Proteomics bioinformatics was recently accepted as a formal Community in the European ELIXIR Bioinformatics Research Infrastructure, and currently consists of thirteen members: Germany, Belgium, Czech Republic, Denmark, France, Italy, Netherlands, Sweden, Switzerland, Ireland, UK and EMBL-EBI.

To learn more about what this means for the field, HUPOST spoke with Dr. Juan Antonio Vizcaíno (EMBL-EBI), Prof. Oliver Kohlbacher (University of Tuebingen), and Prof. Lennart Martens (Ghent University and VIB), three of the founders of the newly minted ELIXIR Community, about what this means for proteomics.

HUPOST: What exactly is ELIXIR?

JAV: ELIXIR is a recently created European Research Infrastructure (ESFRI) for life sciences data. It was founded in 2014 as a way to raise awareness in the research community about the importance of European data resources and bioinformatics tools, which increasingly act as basic building blocks for research in the field.

OK: In that vein, ELIXIR aims to establish standards, bring researchers together, and enable international collaboration on these topics. And to enable all this, there is some funding available as well.

LM: ELIXIR is organized around the central ELIXIR Hub at EMBL-EBI, which is connected to a network of national nodes in 21 European countries at present, with in turn act as liaisons to 180 research organizations. So ELIXIR is in its essence a large-scale European research network for bioinformatics research infrastructure.

HUPOST: Why is a Proteomics Community within ELIXIR important?

JAV: The creation of formal Communities (formerly known as ‘use cases’) within ELIXIR is meant to highlight special interest subgroups that focus on a mature application domain within the life sciences.

LM: So having a Proteomics Community brings three benefits: first, it recognizes the importance of proteomics, and of proteomics bioinformatics in the life sciences in general; second, it provides a means for the European proteomics bioinformatics community to interact between the various nations; and third, it also provides a formal framework to integrate proteomics bioinformatics with other Communities (see here).

HUPOST: What was needed to establish the Proteomics Community in ELIXIR?

JAV: First, the ELIXIR Hub asked prominent members in the community to organize a workshop, which served as the catalyst to write a white paper to establish the needs of the community, their contributions and links to other Communities, and their priorities related to the five core ELIXIR platforms: data, tools, compute resources, training, and interoperability.

OK: The Proteomics Community white paper has been published as open access in F1000Research, and you can find it here. It is worth noting that the same workshop also sparked off similar activities for a separate, but closely connected, metabolomics community in ELIXIR.

LM: Once the white paper had been published, a formal Community application was submitted, which was then reviewed and approved by the Heads of Node of the different ELIXIR members.

HUPOST: What has the ELIXIR Proteomics Community already accomplished?

JAV: We have recently been granted a first Implementation study application, and a second one has been applied for. These Implementation Studies are small-scale collaborative projects in which several national ELIXIR nodes work together towards a common goal, again focused primarily on one of the five ELIXIR platforms.

LM: And let’s not forget that the PRIDE database has also been named an ELIXIR core data resource, which are European resources deemed to be of fundamental importance to the wider life science community, and for the long-term preservation of biological data (see here). This decision thus recognizes the efforts that the community has been investing in making proteomics data available, as well as the widespread adoption of data sharing practices in the field.

HUPOST: Seems like you’re off to a good start! What are the next steps for the Proteomics Community?

JAV: We identified three areas of future activities: improved data processing and analysis pipeline; elucidation of the deep proteome and its integration with multi-omics data; and of course, throughout we need data management and annotation! The details are set out in our the white paper. Of course, these goals are directly relevant to HUPO, and this is no coincidence. European proteomics bioinformatics researchers have after all been very actively involved in several related HUPO initiatives, such as HUPO-PSI and the HPP.

LM: It’s also relevant to point out that the ELIXIR Proteomics Community is happy to liaise with similar proteomics and proteomics informatics communities outside of Europe. And we really do need to invest some time in the near future to make a nice Community webpage on the ELIXIR website, with our vision, contact details, and plans!

HUPOST: Thank you for your time, and good luck with the ELIXIR Proteomics Community!

Lennart Martens, Ghent University, Dept of Biochemistry, Belgium

Spring is just around the corner in the Northern Hemisphere, which probably has something to do with a forward looking issue of HUPOST.

A first forward look concerns the 2018 HUPO World Congress at Orlando, Florida, which will take place from September 30 until October 4th, and for which registration has now been opened! All information can be found on the 2018 HUPO Congress website.

A second forward look brings us to the newly minted Proteomics Community in the ELIXIR European Bioinformatics Research Infrastructure. If this does not automatically make a lot of sense to you, you should definitely read the HUPOST interview with a few of the founders in this issue!

And as a third forward look, you will also find the announcement of the 19th Chromosome Centric Human Proteome Project workshop in this issue, which will be held in Santiago de Compostela in Spain in the weekend of June 16-17, 2018 as a companion event to the XII EuPA Congress 2018.

And in closing, I leave you with this bit of interesting information: Santiago de Compostela has a 1000-year history as one of the main pilgrimage sites in Europe, and remains extremely popular today. So if you see some weary travellers while you’re there, keep in mind that they have just walked hundreds or even thousands of kilometers to get there!

Cheers, Lennart Martens, HUPOST Editor.

Péter Horvatovich, University of Groningen, Netherlands

Proteins are biologically active biomolecules encoded by genes, which realize the key molecular events of life. The Chromosome-Centric Human Proteome Project (C-HPP), together with the proteomic scientific community, had a successful five years of research progress to identify missing proteins in the human proteome. Missing proteins are those encoded by human genes but with limited or no protein evidence (PE) of translation. The official human proteome database for HUPO is neXtProt, which has collected protein evidences on 87% of human protein coding genes.

The attention of C-HPP community is starting to pivot towards other aims, including the functional characterization of proteins that have been identified with strong evidences (PE1), but have completely unknown functions. These human protein coding genes are termed uncharacterized (u)PE1 proteins. NeXtProt contains 1200 uPE1 proteins-See complete list in neXtProt here. The C-HPP executive committee encourages C-HPP members and the proteomics community to develop functional analysis of these proteins, with the aim to complete the picture of the function of the human proteome.