Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium

Bozóky, Benedek; Moro, Carlos Fernández; Strell, Carina; Geyer, Natalie; Heuchel, Rainer; Löhr, Matthias; Ernberg, Ingemar; Szekeres, L.; Gerling, Marco; Bozóky, Béla

doi:10.1016/j.neo.2021.11.007

Cited by 2 publications

(4 citation statements)

References 27 publications

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“…Here, we further connect tumor phenotypic heterogeneity with specific tissue compartments inside the pancreas. Cancer cells that gradually colonize the pre-existing pancreatic lobules establish direct cell contact with resident epithelial cells, reminiscent of the mode of PDAC growth in the duodenum 34 and similar to the replacement-like growth pattern described in the liver 37,47 . Together, the results support a model where tumor-epithelial cell contacts – such as PDAC-ADM, or PDAC-enterocyte 34 contacts – are associated with a specific tumor cell phenotype.…”

Section: Discussionmentioning

confidence: 77%

“…Cancer cells that gradually colonize the pre-existing pancreatic lobules establish direct cell contact with resident epithelial cells, reminiscent of the mode of PDAC growth in the duodenum 34 and similar to the replacement-like growth pattern described in the liver 37,47 . Together, the results support a model where tumor-epithelial cell contacts – such as PDAC-ADM, or PDAC-enterocyte 34 contacts – are associated with a specific tumor cell phenotype. In addition, they might explain the incongruency observed in tumor phenotypes between primary PDAC and its liver metastasis, considering that tumor-epithelial interactions, for example in tumor-hepatocyte contact in liver metastases, might favor the classical phenotype.…”

Section: Discussionmentioning

confidence: 77%

“…To test whether tumor and stromal phenotypes co-develop gradually or by clonal selection, we first analyzed tumors from a previous experiment 34 , derived from genetically engineered KPC mice ( LSL-Kras G12D/+ ;LSL-Trp53 R172H/+ ;Pdx-1-Cre) , removing some of the inherent heterogeneity of human tumors. KPC mice recapitulate human PDAC histopathology and develop a typical desmoplastic stromal reaction 35 .…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we have shown that PDAC invading the duodenal wall shifts from a basal to a classical phenotype upon translocation from the submucosa (a stroma-rich compartment) to the mucosa (an epithelial compartment) 34 . Here, we further connect tumor phenotypic heterogeneity with specific tissue compartments inside the pancreas.…”

Section: Discussionmentioning

confidence: 99%

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A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

Söderqvist,

Viljamaa,

Geyer

et al. 2024

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type characterized by a particularly extensive stroma. While different types of cancer-associated fibroblasts (CAFs) in this desmoplastic stroma have been described, areas of early invasion and nascent stroma are understudied. Here, we identify a distinctive PDAC niche within the pancreatic lobules, a compartment dominated by pancreatic exocrine cells and slender stroma. Cellular interaction profiling using machine learning on whole slide images of human PDAC reveals that the tumor invasion front in the lobules is dominated by specific interactions of tumor cells and exocrine cells that have undergone acinar-to-ductal metaplasia (ADM). Multiplex protein and mRNA stains confirm that tumor growth in the lobules is closely linked to ADM in the lobules, and reveal stromal protein gradients from the gracile lobular stroma to the characteristic desmoplastic stroma. We identify nascent CAFs (nCAFs), co-expressing expressing nerve growth factor receptor (NGFR) and platelet-derived growth factor receptor alpha (PDGFRa) that are absent in the mature, desmoplastic stroma. Lobular invasion and nCAFs are intertwined with phenotypic changes of the cancer cells, such that tumor cells in lobules express classical subtype markers, while those embedded in the desmoplastic are on the basal end of the phenotypic continuum. In mice, the PDAC subtype – basal or classical – similarly depends on tissue location, suggesting microenvironmental factors rather than clonal selection as important drivers of tumor phenotype identity. Clinically, our results mandate factoring in tumor tissue location when calling PDAC subtypes. Biologically, they identify pancreatic lobules as a distinctive tissue niche associated with nascent stroma, and they suggest that lobular colonization by tumor cells is a significant route of PDAC progression.

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