Characterization of signaling pathways and molecular mechanisms underlying kisspeptin response in pancreatic neuroendocrine tumor (panNETs) cells

Temporal and spatial tumor heterogeneity can be observed in pancreatic neuroendocrine tumor. We report the case of a young woman with long term stabilization of a G2 metastatic pancreatic NET that, after pregnancy, suddenly progressed into one single liver metastasis corresponding to a transformation into G3 large-cell neuroendocrine cancer. The patient underwent liver resection (the progressive and one dormant metastasis). With a 45 months follow-up the patient is without evolutive disease. Exome sequencing of the two metastases revealed completely different genomic signatures and gene alterations: the dormant metastasis was MSS without any gene alteration; the poorly differentiated tumor was MSI, with gain of many mutations including MEN1, BCL2, MLH1 and TP53 corresponding to a mutational signature 11. Could temozolomide play a role in this transformation?

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Growth factor signaling in pancreatic neuroendocrine tumor metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.256 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 256-256

Author(s):

Brenna Rheinheimer ◽

Ronald Heimark ◽

Tun Jie

Keyword(s):

Liver Metastases ◽

Neuroendocrine Tumor ◽

Signaling Pathways ◽

Surgical Resection ◽

Metastatic Disease ◽

Genetic Variants ◽

Genomic Analysis ◽

Pancreatic Neuroendocrine Tumor ◽

Proliferation Index ◽

Who Grade

256 Background: Pancreatic neuroendocrine tumors (PanNETs) are among one of the fastest growing cancer diagnoses, yet clinical management for patients with metastatic disease is largely empirically based. Currently, surgical resection remains the only curative option; however, surgical resection of metastatic disease may not be feasible. Preliminary genomic analysis of primary PanNETs revealed a complex mutational landscape with four common oncogenic events; but, critical activation pathways of metastatic lesions have yet to be elucidated. Therefore, pan-genomic analysis of metastatic PanNETs is necessary to understand which genes/pathways are deregulated in PanNET metastases for potential therapeutic exploitation. Methods: We initiated a preliminary genomic sequencing study to evaluate mutations in a set of matched primary and metastatic PanNETs to determine genetic variants involved in metastasis to the liver. De-identified FFPE tumor samples were analyzed from patients who underwent surgical resection without receiving preoperative therapy. DNA was isolated and whole exome sequencing was performed using the Nextera Rapid Capture Exome Kit by Illumina on an Illumina HiSeq 2000/2500. The following criteria were used to define genetic variants: bidirectional, non-synonymous, clean mapping in IGV, ≥ 15X coverage, and an alternate allele frequency of 0.3 ≤ x ≤ 0.7. Results: All metastatic PanNETs were classified as WHO grade G2/G3 based on their KI-67 proliferation index. Each primary PanNET contained an average of 102 genetic variants while liver metastases showed an average of 124 genetic variants. MUFFINN and string analysis revealed that primary PanNETs contained enrichment for mutations involved in the PI3K/Akt and Ras signaling pathways while liver metastases showed enrichment for mutations involved in the MAPK and ErbB signaling pathways. Additionally, two-thirds of liver metastases contained somatic mutations in FGFR3. Conclusions: We have discovered novel pathways that have the potential to regulate pancreatic neuroendocrine tumor metastasis along with an innovative signaling pathway that may sustain metastatic growth and survival as well as exploitation for therapeutic potential.

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The V369M Gcgr knock-in mice are a precision medicine model of mild Mahvash disease

Biochemical Journal ◽

10.1042/bcj20200522 ◽

2020 ◽

Vol 477 (15) ◽

pp. 2873-2874

Author(s):

Run Yu

Keyword(s):

Neuroendocrine Tumor ◽

Precision Medicine ◽

Metabolic Profile ◽

Pancreatic Neuroendocrine Tumor ◽

Mutant Mice ◽

Glucagon Receptor ◽

Biochemical Journal ◽

Pancreas Morphology ◽

Inactivating Mutations

The detailed metabolic characterization of the glucagon receptor (Gcgr)V369M+/+ mutant mice described in Lin et al. in the Biochemical Journal is of interest and resulting in the expected metabolic profile. We would like to point out that these mice might also be extremely useful as a precision medicine model of mild Mahvash disease, a rare hereditary pancreatic neuroendocrine tumor syndrome characterized by inactivating mutations in the glucagon receptor. Further characterization of pancreas morphology and histology in the GcgrV369M+/+ mice at more advanced ages will be critically important to understand mild Mahvash disease in humans.

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Dual Inhibition of PI3K and mTOR Signaling Pathways Decreases Human Pancreatic Neuroendocrine Tumor Metastatic Progression

Pancreas ◽

10.1097/mpa.0b013e3182a44ab4 ◽

2014 ◽

Vol 43 (1) ◽

pp. 88-92 ◽

Cited By ~ 11

Author(s):

Clarisse Djukom ◽

Laura J. Porro ◽

Amy Mrazek ◽

Courtney M. Townsend ◽

Mark R. Hellmich ◽

...

Keyword(s):

Neuroendocrine Tumor ◽

Signaling Pathways ◽

Pancreatic Neuroendocrine Tumor ◽

Mtor Signaling ◽

Metastatic Progression ◽

Dual Inhibition

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18F-FDG PETCT and 68Ga-DOTA PETCT mismatch with in vivo histopathological characterization of low-grade neuroendocrine pancreatic tumor

European Journal of Hybrid Imaging ◽

10.1186/s41824-021-00103-4 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Marcello Moro Queiroz ◽

Carlos Diego Holanda Lopes ◽

Alessandra Corte Real Salgues ◽

Felipe de Galiza Barbosa ◽

Emerson Shigueaki Abe ◽

...

Keyword(s):

Neuroendocrine Tumor ◽

Neuroendocrine Tumors ◽

Pancreatic Neuroendocrine Tumor ◽

Standard Uptake Value ◽

Histopathological Analysis ◽

Low Grade ◽

High Grade ◽

Ki 67

Abstract Background Pancreatic neuroendocrine tumor (PNET) is a subgroup of neuroendocrine tumor (NET) that has unique biology and natural history. The histological classification has a major role in the management of this pathology, but in recent years Gallium 68 dotatate (68Ga-DOTA) scanning is at the center of a discussion about how these imaging technologies can modify clinical management of neuroendocrine tumors and how their results are correlated to Ki67 index. Method We hereby describe a case of a patient that investigated an unspecific stable pancreatic nodule suspected of high-grade NET after evaluation with 68Ga-DOTATOC positron emission tomography—computed tomography (PETCT) and 18F-Fluorodeoxyglucose (18F-FDG) PETCT. Results The images corroborate the hypothesis of high-grade NET based on the standard uptake value (SUV) described in both image exams (16.4 in 18FDG PETCT and 9.2 in 68Ga-DOTATOC PETCT). After surgery, the histopathological analyses revealed a localized grade 2 well-differentiated NET, Ki-67 of 4.7, glucose transport proteins 1 (GLUT1) negative by immunohistochemistry, evidencing a rare case of mismatch between the functional image and the in vivo characterization of the neoplasm. Conclusion Functional imaging of neuroendocrine tumors with different modalities of PETCT is a well-described strategy for evaluating PNET and can dictate conducts in some cases. However, histopathological analysis is crucial to confirm the grade and prognosis related to this disease.

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18F-FDG PETCT and 68Ga-DOTA PETCT Mismatch With in Vivo Histopathological Characterization of Low Grade Neuroendocrine Pancreatic Tumor

10.21203/rs.3.rs-143517/v1 ◽

2021 ◽

Author(s):

Marcello Moro Queiroz ◽

Carlos Diego Holanda Lopes ◽

Alessandra Corte Real Salgues ◽

Felipe de Galiza Barbosa ◽

Emerson Shigueaki Abe ◽

...

Keyword(s):

Neuroendocrine Tumor ◽

Neuroendocrine Tumors ◽

Pancreatic Neuroendocrine Tumor ◽

Standard Uptake Value ◽

Histopathological Analysis ◽

Low Grade ◽

High Grade ◽

Ki 67

Abstract BackgroundPancreatic neuroendocrine tumor (PNET) is a subgroup of neuroendocrine tumor (NET) that has unique biology and natural history. The histological classification has a major role in the management of this pathology, but in recent years Gallium 68 dotatate (68Ga-DOTA) scanning is at the center of a discussion about how these imaging technologies can modify clinical management of neuroendocrine tumors and how their results are correlated to Ki67 index.MethodWe hereby describe a case of a patient that investigated an unspecific stable pancreatic nodule suspected of high-grade NET after evaluation with 68Ga-DOTATOC positron emission tomography - computed tomography (PETCT) and 18F-Fluorodeoxyglucose (18F-FDG) PETCT. ResultsThe images corroborate the hypothesis of high-grade NET based on the standard uptake value (SUV) described in both image exams (16.4 in 18FDG PETCT and 9.2 in 68Ga-DOTATOC PETCT). After surgery, the histopathological analyses revealed a localized grade 2 well differentiated NET, Ki-67 of 4.7, evidencing a rare case of mismatch between the functional image and the in vivo characterization of the neoplasm.ConclusionFunctional imaging of neuroendocrine tumors with different modalities of PETCT is a well-described strategy for evaluating PNET and can dictate conducts in some cases. However, histopathological analysis is crucial to confirm the grade and prognosis related to this disease. Besides the rarity of this case, our patient presented a mismatch between imaging and histopathological analysis, with the former one allowing active surveillance based on a low-grade neuroendocrine tumor.

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Added Value of Tomoelastography for Characterization of Pancreatic Neuroendocrine Tumor Aggressiveness Based on Stiffness

Cancers ◽

10.3390/cancers13205185 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5185

Author(s):

Emin Gültekin ◽

Christoph Wetz ◽

Jürgen Braun ◽

Dominik Geisel ◽

Christian Furth ◽

...

Keyword(s):

Neuroendocrine Tumor ◽

Diagnostic Performance ◽

Quantitative Imaging ◽

Pancreatic Neuroendocrine Tumor ◽

Pancreatic Tissue ◽

Added Value ◽

Tumor Aggressiveness ◽

Shear Wave Speed ◽

Imaging Markers

Purpose: To evaluate the diagnostic performance of tomoelastography in differentiating pancreatic neuroendocrine tumors (PNETs) from healthy pancreatic tissue and to assess the prediction of tumor aggressiveness by correlating PNET stiffness with PET derived asphericity. Methods: 13 patients with PNET were prospectively compared to 13 age-/sex-matched heathy volunteers (CTR). Multifrequency MR elastography was combined with tomoelastography-postprocessing to provide high-resolution maps of shear wave speed (SWS in m/s). SWS of pancreatic neuroendocrine tumor (PNET-T) were compared with nontumorous pancreatic tissue in patients with PNET (PNET-NT) and heathy pancreatic tissue (CTR). The diagnostic performance of tomoelastography was evaluated by ROC-AUC analysis. PNET-SWS correlations were calculated with Pearson’s r. Results: SWS was higher in PNET-T (2.02 ± 0.61 m/s) compared to PNET-NT (1.31 ± 0.18 m/s, p < 0.01) and CTR (1.26 ± 0.09 m/s, p < 0.01). An SWS-cutoff of 1.46 m/s distinguished PNET-T from PNET-NT (AUC = 0.89; sensitivity = 0.85; specificity = 0.92) and a cutoff of 1.49 m/s differentiated pancreatic tissue of CTR from PNET-T (AUC = 0.96; sensitivity = 0.92; specificity = 1.00). The SWS of PNET-T was positively correlated with PET derived asphericity (r = 0.81; p = 0.01). Conclusions: Tomoelastography provides quantitative imaging markers for the detection of PNET and the prediction of greater tumor aggressiveness by increased stiffness.

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