Proposals under this topic should aim to deliver results that are directed and tailored towards and contribute to all of the following expected outcomes:

• Researchers and health professionals gain a deeper understanding of the functional effects of tumour heterogeneity during cancer initiation and progression, supporting the identification of more precise and novel therapeutic targets.
• Researchers, health professionals and innovators benefit from improved knowledge and tools to support the discovery and development of next generation genomically-informed cancer treatments.
• Researchers, innovators, and professionals across disciplines and sectors contribute to the UNCAN.eu research data platform by ensuring data interoperability, and enabling sustainable access to newly developed digital tools and models for the analysis and management of multimodal clinical data.

The proposed topic will contribute to the EU Cancer Mission objective of improving the understanding of cancer initiation and progression. Of particular interest for this topic are paediatric and adolescent cancers^[1] , cancers with limited treatment options, refractory cancers, rare cancers or cancer types with low five-year survival rates. Proposals may include the design of exploratory mechanistic studies using longitudinal patient bio-samples, clinical proof-of-concept studies and/or observational and translational studies involving newly collected or existing data, as appropriate. Applicants are encouraged to leverage technological advances in functional genomics^[2] and structural biology including but not limited to rapid gene sequencing, single-cell studies, spatial gene mapping, spatial transcriptomics, epigenetic profiling, liquid biopsies and functional precision oncology pipelines. The use of causal inference, computational modelling and/or artificial intelligence tools is encouraged for the collection, visualisation, analysis and management of large, complex, and heterogeneous data sets. Collaboration among different scientific disciplines, including healthcare professionals, is envisaged^[3].

Applicants should address all of the following activities:

• To identify and validate new targets for innovative therapeutic approaches, by developing experimental models^[4] and technologies to access the functional effects of tumour temporal heterogeneity on disease initiation, progression and relapse.
• To investigate the mechanisms underlying the interply between the tumor’s dynamic multi-omics characteristics, its microenvironment and patient specific factors^[5] during disease initiation and progression. This includes elucidating the mechanisms of adaptive resistance to therapies, utilizing clinical data where appropriate^[6].
• To apply state-of-the-art approaches, tools and models to integrate and analyse FAIR (Findable, Accessible, Interoperable, Reusable) multimodal longitudinal patient data. These digital assets should be made available through the UNCAN.eu research platform. All datasets produced should be described with metadata records in the EU dataset catalogue of the European Health Data Space. The involvement of existing ESFRI research infrastructures offering life science resources^[7] including biobanking options should be appropriately reflected in the proposal workplan.

Advantage should be taken to the extent possible of data and experience gained under current large-scale initiatives such as: the European 1M+ Genomes^[8] and the European Cancer Imaging initiative^[9] and others as appropriate. Successful proposals are expected to establish appropriate collaborations with the project UNCAN-CONNECT that is implementing the UNCAN.eu research platform^[10].

Successful proposals will be asked to join the 'Understanding' project cluster of the Cancer Mission^[11] and should include a budget for networking, attendance at meetings, and joint activities^[12]. The Commission will facilitate coordination of these activities.

Applicants envisaging to include clinical studies should provide details in the dedicated annex using the template provided in the submission system.

[1] Age at first diagnosis 0-19 years

[2] The use of transcriptomics, proteomics, epigenomics, and metabolomics to understand gene function in a systems biology context

[3] Proposals should include an appropriate mix of stakeholders from various disciplines and sectors, including but not limited to medical doctors, health-IT experts, researchers, AI-experts, solution providers, academia and research institutes, EU research infrastructures and SMEs

[4] Any relevant preclinical or clinical model including but not limited to in silico, in vitro, in vivo or ex vivo models

[5] such as: genetic background, immune status, age, sex, and comorbidities

[6] applicants may build over existing clinically annotated patient cohorts and exploit current EU biobanks for sample access

[7] https://lifescience-ri.eu/home.html

[8] European '1+ Million Genomes' Initiative | Shaping Europe’s digital future

[9] European Cancer Imaging Initiative | Shaping Europe’s digital future

[10] https://cordis.europa.eu/project/id/101215206

[11] In order to address the objectives of the Cancer Mission, participants will collaborate in project clusters to leverage EU-funding, increase networking across sectors and disciplines, and establish a portfolio of Cancer Mission R&I and policy actions

[12] Examples of those activities are organising joint workshops, establishing best practices, joint communication or citizen engagement activities with projects funded under other clusters and pillars of Horizon Europe, or other EU programmes, as appropriate. Proposals are not required to include details of these activities, as they will be defined during the grant agreement preparation and during the life of the project