Publications

Authors:

Fiorini, Elena; Malinova, Antonia; Schreyer, Daniel; Pasini, Davide; Bevere, Michele; Alessio, Giorgia; Rosa, Diego; D'Agosto, Sabrina; Azzolin, Luca; Milite, Salvatore; Andreani, Silvia; Lupo, Francesca; Veghini, Lisa; Grimaldi, Sonia; Pedron, Serena; Castellucci, Monica; Nourse, Craig; Salvia, Roberto; Malleo, Giuseppe; Ruzzenente, Andrea; Guglielmi, Alfredo; Milella, Michele; Lawlor, Rita T; Luchini, Claudio; Agostini, Antonio; Carbone, Carmine; Pilarsky, Christian; Sottoriva, Andrea; Scarpa, Aldo; Tuveson, David A; Bailey, Peter; Corbo, Vincenzo

Title:

MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC

Year:

2025

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Referee:

No

Name of journal:

Nature

ISSN of journal:

0028-0836

N° Volume:

640

Number or Folder:

8059

Page numbers:

811-820

Keyword:

DOUBLE MINUTE CHROMOSOME,SEXTRACHROMOSOMAL DNA, TUMOR, AMPLIFICATION, HYDROXYUREA, EVOLUTION, SUBTYPES, TOOLKIT, GENES

Short description of contents:

: Intratumour heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance1,2. Oncogene dosage variation contributes to cell-state transitions and phenotypic heterogeneity3, thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor of MYC heterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNAs drive varying levels of MYC dosage, depending on their regulatory landscape, enabling cancer cells to rapidly and reversibly adapt to microenvironmental changes. In the absence of selective pressure, a high ecDNA copy number imposes a substantial fitness cost on PDAC cells. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors. Our work provides a detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC.

Note:

These authors contributed equally: Elena Fiorini, Antonia Malinova,Daniel Schreyer. Epub 2025 Mar 12

Product ID:

144729

Handle IRIS:

11562/1157632

Last Modified:

April 24, 2025

Bibliographic citation:

Fiorini, Elena; Malinova, Antonia; Schreyer, Daniel; Pasini, Davide; Bevere, Michele; Alessio, Giorgia; Rosa, Diego; D'Agosto, Sabrina; Azzolin, Luca; Milite, Salvatore; Andreani, Silvia; Lupo, Francesca; Veghini, Lisa; Grimaldi, Sonia; Pedron, Serena; Castellucci, Monica; Nourse, Craig; Salvia, Roberto; Malleo, Giuseppe; Ruzzenente, Andrea; Guglielmi, Alfredo; Milella, Michele; Lawlor, Rita T; Luchini, Claudio; Agostini, Antonio; Carbone, Carmine; Pilarsky, Christian; Sottoriva, Andrea; Scarpa, Aldo; Tuveson, David A; Bailey, Peter; Corbo, Vincenzo, MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC «Nature» , vol. 640 , n. 8059 , 2025 , pp. 811-820

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