Periodic Reporting for period 2 - SECRET (Exploitation of the SECRETory pathway for cancer therapy to address European research)
Reporting period: 2021-10-01 to 2023-09-30
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 has been to drive the understanding of the mutual regulation of the secretory pathway and cell signalling in cancer, which together with our current knowledge, would 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 has hindered 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, was 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 investigated how the functional organisation of the secretory pathway affects cell proliferation, migration and invasion as well as cell drug resistance. Emphasis was 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 was 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. Some of this data, together with other published data, has been 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, was to define secretory pathway-linked candidate biomarker genes suitable for cancer diagnosis and prognosis. SECRET thus addressed current unmet needs in the cancer field and has paved the road for the development of novel therapeutic strategies. In WP2 we investigated 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 aimed to provide the rationale for targeting specific secretory pathway components as a therapeutic strategy and worked towards identifying mechanistically-linked biomarkers for prognostic and diagnostic purposes.
The overall research objective of SECRET has been to drive the understanding of the mutual regulation of the secretory pathway and cell signalling in cancer, which together with our current knowledge, would 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 has hindered 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, was 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 investigated how the functional organisation of the secretory pathway affects cell proliferation, migration and invasion as well as cell drug resistance. Emphasis was 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 was 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. Some of this data, together with other published data, has been 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, was to define secretory pathway-linked candidate biomarker genes suitable for cancer diagnosis and prognosis. SECRET thus addressed current unmet needs in the cancer field and has paved the road for the development of novel therapeutic strategies. In WP2 we investigated 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 aimed to provide the rationale for targeting specific secretory pathway components as a therapeutic strategy and worked towards identifying mechanistically-linked biomarkers for prognostic and diagnostic purposes.
All ESRs have worked towards completing their individual tasks and have successfully done so. The SECRET research projects have been investigating disease-relevant signalling networks, their interactions, their pathological perturbations, and their key regulatory genes and proteins in the context of cancer secretion (e.g. RhoGEF/RhoGAP/kinase signalling, EGFR/ErbB and mTOR signalling pathways, MAPK/ERK and PI3K signalling, TGF- signalling, exosome-release pathway, prostaglandin signalling, STAT3-dependent antiapoptotic pathway, etc). In addition, SECRET projects have been studying the effects of these cancer-specific secretion-dependent perturbations on the tumour microenvironment, affecting cancer progression, treatment response and disease outcome. Several biomarkers and putative drug targets have been identified, promising drug combinations for difficult to treat breast and colorectal cancer subtypes have been pointed out, and in silico tools for the identification of relevant biological processes/targets/biomarkers as well as for the simulation of clinical trials have been designed.
In addition, the training program was fully implemented, aiming to prepare the ESRs for successful careers as the next generation of researchers and leaders in their fields.
In addition, the training program was fully implemented, aiming to prepare the ESRs for successful careers as the next generation of researchers and leaders in their fields.
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The SECRET programme aimed to deliver innovative solutions in the form of combinatorial predictive and prognostic biomarker signatures, bioinformatic analytical methods prediction tools based on novel data processing and simulation algorithms, for the identification of new drug targets and biomarkers, and personalized medicine tools to predict drug responsiveness to new targeted therapeutics systems. These outputs are expected to be readily transferred to other cancer types in addition to breast and colorectal cancer. On top of the medical and societal impact, the identification of promising biomarkers to serve as predictive and prognostic tools for the estimation of treatment outcomes and disease progression have great potential to secure a significant share in the market for metastatic and aggressive subtypes of breast and colorectal cancer treatments, probably in the range of several hundred million euros.
In the scientific community, SECRET has and is still expected to make an impact through several publications. So far, five review articles and seven research articles have been published, and one methods paper and one research article are in review process. Several publications are in process of preparation and soon to be submitted.
Last but not least, considerable impact has been reached though outreach activities via the SECRET website and its social media presence. The website has reached thousands of visitors over the past years and has a regular flow of visits from all over the world. Both the website and the SECRET social media channels (Twitter, LinkedIn) are remaining active beyond the end of the programme, and are actively supported by the activities of the consortium members.
The SECRET programme aimed to deliver innovative solutions in the form of combinatorial predictive and prognostic biomarker signatures, bioinformatic analytical methods prediction tools based on novel data processing and simulation algorithms, for the identification of new drug targets and biomarkers, and personalized medicine tools to predict drug responsiveness to new targeted therapeutics systems. These outputs are expected to be readily transferred to other cancer types in addition to breast and colorectal cancer. On top of the medical and societal impact, the identification of promising biomarkers to serve as predictive and prognostic tools for the estimation of treatment outcomes and disease progression have great potential to secure a significant share in the market for metastatic and aggressive subtypes of breast and colorectal cancer treatments, probably in the range of several hundred million euros.
In the scientific community, SECRET has and is still expected to make an impact through several publications. So far, five review articles and seven research articles have been published, and one methods paper and one research article are in review process. Several publications are in process of preparation and soon to be submitted.
Last but not least, considerable impact has been reached though outreach activities via the SECRET website and its social media presence. The website has reached thousands of visitors over the past years and has a regular flow of visits from all over the world. Both the website and the SECRET social media channels (Twitter, LinkedIn) are remaining active beyond the end of the programme, and are actively supported by the activities of the consortium members.