GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming

Duan, Suzann; Sawyer, Travis W.; Sontz, Ricky; Wieland, Bradley A.; Diaz, Andres F.; Merchant, Juanita L.

doi:10.1016/j.jcmgh.2022.06.009

Cited by 9 publications

(23 citation statements)

References 75 publications

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“…While homologous recombination resulted in embryonic lethality, heterozygous Men1 mice developed tumors in endocrine tissues including the pancreas, parathyroid, and pituitary; however, no gastrinomas were reported in this model 131 . Although Bertolino et al 132 reported gastrinomas in their Men1 +/T mice, careful review of the figure showing the histology from these mice reveals only a hyperplastic mouse antrum and G‐cell hyperplasia, as we also reported 29,34 . The pancreatic islets, pituitary, parathyroid, adrenal, and thyroid glands all displayed significant endocrine tumors in the heterozygous Men1 mice that were like those found in human MEN1 patients.…”

Section: Men1 Gastrinomas: Current Understanding From Animal Modelssupporting

confidence: 66%

“…131 Although Bertolino et al 132 reported gastrinomas in their Men1 +/T mice, careful review of the figure showing the histology from these mice reveals only a hyperplastic mouse antrum and G-cell hyperplasia, as we also reported. 29,34 The pancreatic islets, pituitary, parathyroid, adrenal, and thyroid glands all displayed significant endocrine tumors in the heterozygous Men1 mice that were like those found in human MEN1 patients. In their model, both benign and malignant tumors from diverse tissues all lacked the wild-type Men1 allele.…”

Section: Current Understanding From Animal Modelsmentioning

confidence: 86%

“…It has long been hypothesized that gastrointestinal neuroendocrine cells arise from epithelial‐derived Lgr5+ stem cells. However, we have raised the possibility that non‐epithelial cells may also be a cell of origin for these tumors 34 . Sundaresan et al 36 used immunohistochemistry to demonstrate that compared to pancreatic gastrinomas, human DGASTs and associated lymph node metastases display enteric glial cell (EGC) markers.…”

Section: Men1 Gastrinomas: Current Understanding From Animal Modelsmentioning

confidence: 99%

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MENIN‐mediated regulation of gastrin gene expression and its role in gastrinoma development

2023

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The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues.Gastrinomas are neuroendocrine neoplasms that overproduce the hormone gastrin and can arise sporadically or as part of the MEN1 syndrome, in which mutations in the MEN1 gene lead to loss or inactivation of MENIN protein. Gastrin is a peptide hormone that is primarily synthesized in the gastric antrum and stimulates the secretion of histamine from enterochromaffin-like (ECL) cells and subsequently acid from parietal cells in the gastric corpus. In addition, gastrin exerts a mitogenic function primarily on ECL cells and progenitor cells in the gastric isthmus. Current studies seek to understand how MEN1 mutations generate a mutant MENIN protein that abrogates its tumor suppressor function. Mutations in the MEN1 gene are broadly distributed throughout its nine protein-coding exons, making it difficult to correlate protein structure with its function. Although disruption of the Men1 locus in mice causes functional neuroendocrine tumors in the pituitary and pancreas, gastrinomas do not develop in these transgenic animal models. Prior studies of human gastrinomas suggest that tissue-specific microenvironmental cues in the submucosal foregut may contribute to tumorigenesis by reprogramming of epithelial cells toward the neuroendocrine phenotype. Accordingly, recent studies suggest that neural crest-derived cells are also sensitive to reprogramming when MEN1 is deleted or mutated. Thus, the goal of this report is to review our current understanding of how MENIN modulates gastrin gene expression while highlighting its role in the prevention/suppression of neuroendocrine cell transformation.

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Section: Men1 Gastrinomas: Current Understanding From Animal Modelssupporting

confidence: 66%

Section: Current Understanding From Animal Modelsmentioning

confidence: 86%

Section: Men1 Gastrinomas: Current Understanding From Animal Modelsmentioning

confidence: 99%

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MENIN‐mediated regulation of gastrin gene expression and its role in gastrinoma development

2023

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“…In conclusion, Duan et al 7 have shown that deletion of Men1 from GFAP-expressing glial cells led to loss of this cell lineage, its reprogramming to an endocrine phenotype, and NET development in the pancreas and pituitary. These findings raise the possibility that some NENs arise from the reprogramming of neural crest–derived cells rather than from enteroendocrine cells.…”

mentioning

confidence: 83%

“…In the current issue of Cellular and Molecular Gastroenterology and Hepatology , Duan et al 7 have built on preliminary findings from their lab that were described in the paper by Sundaresan et al 6 to investigate whether some GEP-NENs develop from reprogrammed neural crest–derived cells rather than from endoderm-derived enteroendocrine cells. They conditionally deleted Men1 from glial fibrillary acid protein (GFAP)-expressing glial cells in mice and showed a phenotype closely resembling human MEN1.…”

mentioning

confidence: 99%

New Mouse Model Suggests That Some Neuroendocrine Tumors May Originate From Neural Crest–Derived Cells

Pritchard

2022

Cellular and Molecular Gastroenterology and Hepatology

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Spatial profiling reveals tissue‐specific neuro‐immune interactions in gastroenteropancreatic neuroendocrine tumors

Duan,

Sawyer,

Witten

et al. 2024

The Journal of Pathology

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Gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor‐derived signals from the surrounding microenvironment by applying digital spatial profiling (DSP) to hormone‐secreting and non‐functional GEP‐NETs. By combining this approach with in vitro studies of human‐derived organoids, we demonstrated the convergence of cell autonomous immune and pro‐inflammatory proteins that suggests their role in neuroendocrine differentiation and tumorigenesis. DSP was used to evaluate the expression of 40 neural‐ and immune‐related proteins in surgically resected duodenal and pancreatic NETs (n = 20) primarily consisting of gastrinomas (18/20). A total of 279 regions of interest were examined between tumors, adjacent normal and abnormal‐appearing epithelium, and the surrounding stroma. The results were stratified by tissue type and multiple endocrine neoplasia I (MEN1) status, whereas protein expression was validated by immunohistochemistry (IHC). A tumor immune cell autonomous inflammatory signature was further evaluated by IHC and RNAscope, while functional pro‐inflammatory signaling was confirmed using patient‐derived duodenal organoids. Gastrin‐secreting and non‐functional pancreatic NETs showed a higher abundance of immune cell markers and immune infiltrate compared with duodenal gastrinomas. Compared with non‐MEN1 tumors, MEN1 gastrinomas and preneoplastic lesions showed strong immune exclusion and upregulated expression of neuropathological proteins. Despite a paucity of immune cells, duodenal gastrinomas expressed the pro‐inflammatory and pro‐neural factor IL‐17B. Treatment of human duodenal organoids with IL‐17B activated NF‐κB and STAT3 signaling and induced the expression of neuroendocrine markers. In conclusion, multiplexed spatial protein analysis identified tissue‐specific neuro‐immune signatures in GEP‐NETs. Duodenal gastrinomas are characterized by an immunologically cold microenvironment that permits cellular reprogramming and neoplastic transformation of the preneoplastic epithelium. Moreover, duodenal gastrinomas cell autonomously express immune and pro‐inflammatory factors, including tumor‐derived IL‐17B, that stimulate the neuroendocrine phenotype. © 2024 The Pathological Society of Great Britain and Ireland.

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GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming

Cited by 9 publications

References 75 publications

MENIN‐mediated regulation of gastrin gene expression and its role in gastrinoma development

MENIN‐mediated regulation of gastrin gene expression and its role in gastrinoma development

New Mouse Model Suggests That Some Neuroendocrine Tumors May Originate From Neural Crest–Derived Cells

Spatial profiling reveals tissue‐specific neuro‐immune interactions in gastroenteropancreatic neuroendocrine tumors

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