Differential impact of the ERBB receptors EGFR and ERBB2 on the initiation of precursor lesions of pancreatic ductal adenocarcinoma

Meyers, Nora; Gérard, Claude; Lemaigre, Frédéric P.; Jacquemin, Patrick

doi:10.1038/s41598-020-62106-8

Cited by 18 publications

(13 citation statements)

References 38 publications

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“…While repression of “basalness/squamousness” seems an intrinsic feature of FGFR4, we also showed that its silencing in FGFR4 low basal-like models increases malignant behaviour suggesting a bona fide tumour suppressive role for endogenous levels of FGFR4 in PDAC. Others have recently suggested that RTKs in PDAC might exert an oncogenic role only when overexpressed [ 54 ]. In keeping with this, acceleration of cell proliferation could be observed in established and primary cell lines regardless of their background and upon either transient or stable knockdown of FGFR4 .…”

Section: Discussionmentioning

confidence: 99%

Loss of FGFR4 promotes the malignant phenotype of PDAC

D’Agosto

Pezzini²,

Veghini³

et al. 2022

Oncogene

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Transcriptomic analyses of pancreatic ductal adenocarcinoma (PDAC) have identified two major epithelial subtypes with distinct biology and clinical behaviours. Here, we aimed to clarify the role of FGFR1 and FGFR4 in the definition of aggressive PDAC phenotypes. We found that the expression of FGFR4 is exclusively detected in epithelial cells, significantly elevated in the classical PDAC subtype, and associates with better outcomes. In highly aggressive basal-like/squamous PDAC, reduced FGFR4 expression aligns with hypermethylation of the gene and lower levels of histone marks associated with active transcription in its regulatory regions. Conversely, FGFR1 has more promiscuous expression in both normal and malignant pancreatic tissues and is strongly associated with the EMT phenotype but not with the basal-like cell lineage. Regardless of the genetic background, the increased proliferation of FGFR4-depleted PDAC cells correlates with hyperactivation of the mTORC1 pathway both in vitro and in vivo. Downregulation of FGFR4 in classical cell lines invariably leads to the enrichment of basal-like/squamous gene programs and is associated with either partial or full switch of phenotype. In sum, we show that endogenous levels of FGFR4 limit the malignant phenotype of PDAC cells. Finally, we propose FGFR4 as a valuable marker for the stratification of PDAC patients.

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Section: Discussionmentioning

confidence: 99%

Loss of FGFR4 promotes the malignant phenotype of PDAC

D’Agosto

Pezzini²,

Veghini³

et al. 2022

Oncogene

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“…High-grade IPMN can progress to invasive PDAC, which can be indistinguishable from conventional PDAC, with the exception of colloid carcinoma, a distinct PDAC subtype producing abundant extracellular mucin, which originates from intestinal-type IPMN 26-28 . From a genetic point of view, the most important alterations in IPMN include KRAS and GNAS mutations, and microsatellite instability, which is more common in the intestinal subtype 16 , 22 , 29 .…”

Section: Pancreatic Ductal Adenocarcinomamentioning

confidence: 99%

Malignant epithelial/exocrine tumors of the pancreas

et al. 2020

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Summary Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.

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“…130,131 More importantly, the release of cytokines TNF-α and RANTES by macrophages stimulates the activation of NF-κB in acinar cells to induce acinar cell transdifferentiation into a duct-like progenitor cell types, which is termed acinar-to-ductal metaplasia (ADM). 131,132 Notch receptors 133,134 and EGFR 135,136 have also been shown to induce ADM in acinar cells. M2 macrophages are recruited to help the cells revert back to acinar cells and initiate tissue remodeling and repair.…”

Section: Pancreatitismentioning

confidence: 99%

Macrophages in the pancreas: Villains by circumstances, not necessarily by actions

Cruz

Rohban

Esni

2020

Immunity Inflam & Disease

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Introduction Mounting evidence suggest that macrophages play crucial roles in disease and tissue regeneration. However, despite much efforts during the past decade, our knowledge about the extent of macrophages' contribution to adult pancreatic regeneration after injury or during pancreatic disease progression is still limited. Nevertheless, it is generally accepted that some macrophage features that normally would contribute to healing and regeneration may be detrimental in pancreatic cancer. Altogether, the current literature contains conflicting reports on whether macrophages act as friends or foe in these conditions. Methods and Results In this review, we briefly review the origins of tissue resident and infiltrating macrophages and the importance of cellular crosstalking between macrophages and other resident cells in tissue regeneration. The primary objective of this review is to summarize our knowledge of the distinct roles of tissue resident and infiltrating macrophages, the impact of M1 and M2 macrophage phenotypes, and emerging evidence on macrophage crosstalking in pancreatic injury, regeneration, and disease. Conclusion Macrophages are involved with various stages of pancreatic cancer development, pancreatitis, and diabetes. Elucidating their role in these conditions will aid the development of targeted therapeutic treatments.

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Differential impact of the ERBB receptors EGFR and ERBB2 on the initiation of precursor lesions of pancreatic ductal adenocarcinoma

Cited by 18 publications

References 38 publications

Loss of FGFR4 promotes the malignant phenotype of PDAC

Loss of FGFR4 promotes the malignant phenotype of PDAC

Malignant epithelial/exocrine tumors of the pancreas

Macrophages in the pancreas: Villains by circumstances, not necessarily by actions

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