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Exploitation of the SECRETory pathway for cancer therapy to address European research

Periodic Reporting for period 1 - SECRET (Exploitation of the SECRETory pathway for cancer therapy to address European research)

Reporting period: 2019-10-01 to 2021-09-30

In 2020, 19.3 million new cancer cases were diagnosed worldwide, with 4.2 million represented by breast and colorectal cancer (BC and CRC), estimated to represent the most frequent types of cancer in Europe in 2020. Despite strong efforts, BC and CRC are still estimated to account for 13.1% and 12.4%, respectively, of all deaths from cancer in Europe in both sexes. In the case of triple-negative BC (TNBC, lacking hormone and HER2 receptor expression) accounting for 15% of all BC cases, there are no targeted therapies available and non-selective chemotherapy is the only treatment option. TNBC and CRC patients are prone to develop metastases and have an especially poor prognosis underpinning the need for new targeted and broadly applicable therapeutic strategies.

The overall research objective of SECRET is to drive the understanding of the mutual regulation of the secretory pathway and cell signalling in cancer, which together with our current knowledge, will serve as a platform to identify and interrogate novel diagnostic and therapeutic strategies for application in TNBC and CRC.

While it is intuitively clear that tumour growth and metastasis are linked to secretion, strategies for therapeutic exploitation of the secretory pathway are still in their infancy. This can be explained by the incomplete understanding of how the secretory pathway is disregulated by aberrant signalling in cancer cells. This lack of knowledge hinders efforts to exploit the secretory pathway for therapeutic and diagnostic purposes.

One of the main research objectives of the SECRET programme, outlined in WP1 – SECRET- MECHANISMS, is to obtain a mechanistic and quantitative understanding of the mutual regulation of the secretory pathway through signalling and delineate its contribution to cancer progression. In WP1 we investigate how the functional organisation of the secretory pathway affects cell proliferation, migration and invasion as well as cell drug resistance. Emphasis is given to analyse structural proteins of the secretory pathway, signalling molecules at the endomembranes as well as the architecture of the secretory pathway using inducible gene expression, RNA interference, and genome editing techniques. This is combined with testing how drugs used in targeted cancer therapy impact the secretory pathway using quantitative molecular cell biology and proteomics, state-of the art imaging, and 3D cell culture models. These data are planned to be used as a basis to build a mathematical network that will help us to identify druggable nodes/regulators and mechanistically-linked candidate biomarkers.

The second main research objective of SECRET, outlined in WP2 – SECRET- BIOMARKERS, is to define secretory pathway-linked candidate biomarker genes suitable for cancer diagnosis and prognosis. SECRET will thus address current unmet needs in the cancer field and pave the road for the development of novel therapeutic strategies. In WP2 we investigate on a systems level whether and how the secretome of cancer is deregulated and how this secretome shapes the ability of cancer cells to communicate with their environment and to modulate tumour inflammation using state of the art “omics”, bioinformatics, systems biology approaches, 3D organotypic cell culture models, and PDX models. WP2 aims to provide the rationale for targeting specific secretory pathway components as a therapeutic strategy and aims in identifying mechanistically-linked biomarkers for prognostic and diagnostic purposes.
All ESRs have worked towards reaching Milestone 5 - SECRET-Mechanisms and SECRET Biomarkers, which entailed setting up of 3D cell culture, multi-omics, as well as establishing of computational modelling and translational strategies. Specifically, computational prototypes were expected to be available, 3D cell culture model defined, candidate pathways identified, candidate biomarkers available, translational models established, and strategies defined. Each ESR has worked towards these goals, and by now, assays and computational pipelines have been set up, and targets or biomarkers of interest, or relevant pathways have been identified. Students are currently channeling their efforts to narrow down the project focus towards the most relevant hits or pathways to follow up during the remaining course of their projects. In the case of all the individual projects, progress is evident and promising preliminary results raise expectations of relevant discoveries and novel exploitation avenues to arise. However, most of the results are not yet published and require more time until becoming open to the general public.

In case of ESR15, Lorenzo Signorini, a first completed project has been published recently. In the team of Prof Roded Sharan at the Tel Aviv University, Lorenzo has built upon and upgraded an algorithmic framework for studying proteome-wide protein-protein interactions and uncovering signalling pathways in cancer. The work has been published in BMC Bioinformatics in October 2021. The framework (ANAT 3.0) has a wide application potential, and as a result, Lorenzo is collaborating with other ESRs to apply the developed pipeline to improve biomarker prediction on their datasets.
The SECRET research projects are currently investigating disease-relevant signalling networks, their interactions, their pathological perturbations, and their key regulatory genes and proteins in the context of cancer secretion. In addition, SECRET projects are studying the effects of these cancer-specific secretion-dependent perturbations on the tumour microenvironment, affecting cancer progression, treatment response and disease outcome. It is expected that the consortium research outputs will contribute to the field by addressing unmet needs and providing innovative solutions that promote the rational design of optimal patient surveillance and treatment strategies. The exploitation potential of the projects is, although in early stages, developing according to expectations.

Significant impact of the SECRET project has already been achieved. During the recruitment period, after a broad international advertisement of the open positions, SECRET ITN attracted the interest of over 600 young scientists keen to participate in its doctoral training. Although still early, two review articles have been published by SECRET members, while three scientific papers have been published/or are in review process by SECRET beneficiaries. SECRET outreach activities included several external reports in the press/social media, advertisement of the program on member's websites, the distribution of the SECRET brochure within the collaboration networks and the participation of both beneficiaries and ESRs in several international meetings and conferences, in some cases with poster presentations or talks. The SECRET ITN website has been a striking success, bringing forth progress into the projects, such as breakthrough moments, publications or secondment updates, as well as news on organised training events and meetings. Since the beginning of the project, the website has had thousands of visitors from all over the world.

All in all, the impact of SECRET ITN has been visible through the successful promotion of the first results, focus and objectives of the programme.
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