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

Informazioni relative al progetto

FINDR

ID dell’accordo di sovvenzione: 101152080

DOI

10.3030/101152080

Progetto chiuso

Data della firma CE 11 Marzo 2024

Data di avvio 1 Aprile 2024

Data di completamento 31 Marzo 2026

Finanziato da

• Marie Skłodowska-Curie Actions (MSCA)

Costo totale

Nessun dato

Contributo UE

€ 187 624,32

Coordinato da

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)

Periodo di rendicontazione: 2024-04-01 al 2026-03-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.