Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.

Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer / P. Di Chiaro, L. Nacci, F. Arco, S. Brandini, S. Polletti, A. Palamidessi, B. Donati, C. Soriani, F. Gualdrini, G. Frigè, L. Mazzarella, A. Ciarrocchi, A. Zerbi, P. Spaggiari, G. Scita, S. Rodighiero, I. Barozzi, G.R. Diaferia, G. Natoli. - In: CANCER CELL. - ISSN 1535-6108. - 42:4(2024 Mar 18), pp. 662-681.e10. [10.1016/j.ccell.2024.02.017]

Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer

F. Arco;S. Polletti;A. Palamidessi;B. Donati;L. Mazzarella;G. Scita;S. Rodighiero;I. Barozzi;
2024

Abstract

Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.
PDAC; extracellular matrix; histology; laser microdissection; pancreatic cancer; perineural invasion; spatial transcriptomics; tumor heterogeneity; tumor microenvironment
Settore MED/04 - Patologia Generale
18-mar-2024
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S1535610824000795-main.pdf

accesso riservato

Descrizione: Article
Tipologia: Publisher's version/PDF
Dimensione 11.67 MB
Formato Adobe PDF
11.67 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
1-s2.0-S1535610824000795-main_compressed.pdf

accesso riservato

Descrizione: File compresso
Tipologia: Publisher's version/PDF
Dimensione 5.33 MB
Formato Adobe PDF
5.33 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1044189
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 1
  • ???jsp.display-item.citation.isi??? ND
social impact