Pubblicazioni

Autori:

Lloyd, Eloise G; Jihad, Muntadher; Manansala, Judhell S; Li, Wenlong; Cheng, Priscilla S W; Mucciolo, Gianluca; Zaccaria, Marta; Pinto Teles, Sara; Araos Henríquez, Joaquín; Harish, Sneha; Brais, Rebecca; Ashworth, Sally; Luo, Weike; Johnson, Paul M; Veghini, Lisa; Vallespinos, Mireia; Corbo, Vincenzo; Biffi, Giulia

Titolo:

SMAD4 and KRAS Status Shapes Cancer Cell-Stromal Cross-Talk and Therapeutic Response in Pancreatic Cancer

Anno:

2025

Tipologia prodotto:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Lingua:

Inglese

Referee:

No

Nome rivista:

Cancer Research

ISSN Rivista:

0008-5472

N° Volume:

85

Numero o Fascicolo:

8

Intervallo pagine:

1368-1389

Parole chiave:

Animals; Carcinoma, Pancreatic Ductal; Cell Communication; Humans; Mice; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Signal Transduction; Smad4 Protein; Stromal Cells; Tumor Microenvironment; Tumor Suppressor Protein p53

Breve descrizione dei contenuti:

: Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on preclinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase the understanding of malignant cell-stromal cell cross-talk in PDAC. In this study, we used single-cell RNA sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V, in which Smad4 was wild type or deleted. KrasG12DSmad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared with KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype affects cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy. Significance: SMAD4 loss differentially impacts malignant cell-stromal cell signaling and treatment sensitivity of pancreatic tumors driven by KRASG12D or KRASG12V, highlighting the importance of understanding genotype-phenotype relationships for precision therapy.

Id prodotto:

145334

Handle IRIS:

11562/1160403

ultima modifica:

29 maggio 2025

Citazione bibliografica:

Lloyd, Eloise G; Jihad, Muntadher; Manansala, Judhell S; Li, Wenlong; Cheng, Priscilla S W; Mucciolo, Gianluca; Zaccaria, Marta; Pinto Teles, Sara; Araos Henríquez, Joaquín; Harish, Sneha; Brais, Rebecca; Ashworth, Sally; Luo, Weike; Johnson, Paul M; Veghini, Lisa; Vallespinos, Mireia; Corbo, Vincenzo; Biffi, Giulia, SMAD4 and KRAS Status Shapes Cancer Cell-Stromal Cross-Talk and Therapeutic Response in Pancreatic Cancer «Cancer Research» , vol. 85 , n. 8 , 2025 , pp. 1368-1389

Consulta la scheda completa presente nel repository istituzionale della Ricerca di Ateneo