Metastatic pancreatic neuroendocrine tumors have decreased somatostatin expression and increased Akt signaling

Tran, Catherine; Scott, Aaron; Li, Guiying; Sherman, Scott K.; Ear, Po Hien; Howe, James R.

doi:10.1016/j.surg.2020.04.034

Cited by 8 publications

(5 citation statements)

References 23 publications

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“…This hypothesis was further supported by the transcriptomic data which denoted that the pathways involved in cell proliferation (like E2F targets, G2M checkpoint, MYC targets, and mitotic spindle) were more enriched in metastases. Similarly, another transcriptomic study found metastatic panNETs had decreased somatostatin expression and increased Akt Signaling which further corroborated our hypothesis [ 21 ]. However, one interesting finding is the “KRAS signaling up” was more enriched in primary sites which conflicted with the higher mutation rates of KRAS in metastases.…”

Section: Discussionsupporting

confidence: 88%

Molecular and Functional Heterogeneity of Primary Pancreatic Neuroendocrine Tumors and Metastases

Guo¹,

Tian²,

Cheng³

et al. 2023

Neuroendocrinology

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Introduction: Treatment response to the standard therapy is low for metastatic pancreatic neuroendocrine tumors (PanNETs) mainly due to the tumor heterogeneity. We investigated the heterogeneity between primary PanNETs and metastases to improve the precise treatment. Methods: The genomic and transcriptomic data of PanNETs were retrieved from the Genomics, Evidence, Neoplasia, Information, Exchange (GENIE), and Gene Expression Omnibus (GEO) database, respectively. Potential prognostic effects of gene mutations enriched in metastases were investigated. Gene set enrichment analysis was performed to investigate the functional difference. Oncology Knowledge Base was interrogated for identifying the targetable gene alterations. Results: Twenty-one genes had significantly higher mutation rates in metastases which included TP53 (10.3% vs. 16.9%, p = 0.035) and KRAS (3.7% vs. 9.1%, p = 0.016). Signaling pathways related to cell proliferation and metabolism were enriched in metastases, whereas epithelial-mesenchymal transition (EMT) and TGF-β signaling were enriched in primaries. Gene mutations were highly enriched in metastases that had significant unfavorable prognostic effects included mutation of TP53 (p < 0.001), KRAS (p = 0.001), ATM (p = 0.032), KMT2D (p = 0.001), RB1 (p < 0.001), and FAT1 (p < 0.001). Targetable alterations enriched in metastases included mutation of TSC2 (15.5%), ARID1A (9.7%), KRAS (9.1%), PTEN (8.7%), ATM (6.4%), amplification of EGFR (6.0%), MET (5.5%), CDK4 (5.5%), MDM2 (5.0%), and deletion of SMARCB1 (5.0%). Conclusion: Metastases exhibited a certain extent of genomic and transcriptomic diversity from primary PanNETs. TP53 and KRAS mutation in primary samples might associate with metastasis and contribute to a poorer prognosis. A high fraction of novel targetable alterations enriched in metastases deserves to be validated in advanced PanNETs.

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Section: Discussionsupporting

confidence: 88%

Molecular and Functional Heterogeneity of Primary Pancreatic Neuroendocrine Tumors and Metastases

Guo¹,

Tian²,

Cheng³

et al. 2023

Neuroendocrinology

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“…Notably, SSTR2 expression has prognostic significance in GEPNETs. Nodal and hepatic metastases were found to exhibit significantly lower SSTR2 expression compared to the primary pNETs [235]. Conversely, higher SSTR2 expression is a predictor of better patient overall survival and correlates with longer PFS following SSA therapy [229,[236][237][238].…”

Section: Somatostatin Receptor Signalingmentioning

confidence: 93%

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Maharjan

Ear

Tran

et al. 2021

Cancers

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Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

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“…A molecular profiling study of liver metastases from SI-NENs showed that the mTOR signalling pathway was overexpressed in liver metastases from SI-NENs in comparison to the primary tumour, demonstrating that during the metastatic process there is progressive epigenetic dysregulation of this pathway [ 43 ]. Similarly, another study on 43 resected pancreatic NENs showed that liver metastases showed overexpression of the mTOR pathway in comparison to the primary tumour [ 177 ]. High mTOR expression is a prognostic factor and is linked to a worse prognosis in pancreatic NENs [ 179 ].…”

Section: Cell Signalling Pathway Heterogeneity: the Mtor Pathwaymentioning

confidence: 99%

Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms

Reccia

Pai

Jayant

et al. 2023

Cancers

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Tumour heterogeneity is a common phenomenon in neuroendocrine neoplasms (NENs) and a significant cause of treatment failure and disease progression. Genetic and epigenetic instability, along with proliferation of cancer stem cells and alterations in the tumour microenvironment, manifest as intra-tumoural variability in tumour biology in primary tumours and metastases. This may change over time, especially under selective pressure during treatment. The gastroenteropancreatic (GEP) tract is the most common site for NENs, and their diagnosis and treatment depends on the specific characteristics of the disease, in particular proliferation activity, expression of somatostatin receptors and grading. Somatostatin receptor expression has a major role in the diagnosis and treatment of GEP-NENs, while Ki-67 is also a valuable prognostic marker. Intra- and inter-tumour heterogeneity in GEP-NENS, however, may lead to inaccurate assessment of the disease and affect the reliability of the available diagnostic, prognostic and predictive tests. In this review, we summarise the current available evidence of the impact of tumour heterogeneity on tumour diagnosis and treatment of GEP-NENs. Understanding and accurately measuring tumour heterogeneity could better inform clinical decision making in NENs.

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Metastatic pancreatic neuroendocrine tumors have decreased somatostatin expression and increased Akt signaling

Cited by 8 publications

References 23 publications

Molecular and Functional Heterogeneity of Primary Pancreatic Neuroendocrine Tumors and Metastases

Molecular and Functional Heterogeneity of Primary Pancreatic Neuroendocrine Tumors and Metastases

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms

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