Spatiotemporal characterization of extrachromosomal DNA transcription and its key regulators in cancer cells

Project Information

FINDR

Grant agreement ID: 101152080

DOI

10.3030/101152080

Project closed

EC signature date 11 March 2024

Start date 1 April 2024

End date 31 March 2026

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 187 624,32

Coordinated by

PRINSES MAXIMA CENTRUM VOOR KINDERONCOLOGIE BV
Netherlands

Periodic Reporting for period 1 - FINDR (Spatiotemporal characterization of extrachromosomal DNA transcription and its key regulators in cancer cells)

Reporting period: 2024-04-01 to 2026-03-31

Summary of the context and overall objectives of the project

Cancer cells can amplify cancer-promoting genes on small DNA elements outside normal chromosomes, known as extrachromosomal DNA or double minutes. These elements are found in aggressive cancers and are linked to tumour evolution, therapy resistance, and poor patient outcomes. The FINDR project addressed the need for better tools to understand how these DNA elements behave inside cancer cells. Its overall objective was to establish new single-cell approaches to study how extrachromosomal DNA is positioned in the nucleus, how active it is, and how it may be regulated by its cellular environment. By creating such tools, FINDR aimed to provide an enabling framework for future studies into how extrachromosomal DNA contributes to cancer progression and treatment resistance. In the longer term, this knowledge may support the discovery of new vulnerabilities in cancers driven by amplified cancer-promoting genes.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project established new experimental approaches to study extrachromosomal DNA organization and activity in individual cancer cells. These tools were applied in selected cancer models to gain first quantitative insights into how amplified DNA elements behave in their nuclear environment. The work showed that different extrachromosomal DNA species can display distinct nuclear behaviours and transcriptional states. It also provided initial evidence that genes amplified outside chromosomes may be regulated differently from their corresponding chromosomal copies. These findings point to important biological questions that can now be investigated more systematically.The project also advanced complementary strategies to identify cellular factors that may regulate extrachromosomal DNA. In parallel, selected regulatory processes were explored, revealing promising starting points for future mechanistic studies. Overall, FINDR delivered new tools and first biological insights that together provide a foundation for broader investigation of extrachromosomal DNA regulation in cancer.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

FINDR advanced the state of the art by moving beyond the detection of extrachromosomal DNA towards functional analysis of how these elements behave in intact single cells. The project established approaches that make it possible to connect nuclear organization with gene activity, opening new opportunities to study cancer-driving gene amplification in its cellular context. The results provide initial evidence that extrachromosomal DNA activity is influenced by nuclear organization. Importantly, the project generated methods, proof-of-concept results, and candidate mechanisms for larger and more systematic studies.The workflows and concepts developed in FINDR are expected to be transferable to other cancer models and related questions in gene regulation and nuclear organization. Further uptake will be supported by publication of the results, deposition of relevant datasets and analysis resources in public repositories, and follow-up studies to validate candidate regulatory factors.