Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors

Abstract

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in β-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.

Verification of cell cycle-associated cyclin-dependent kinases facilitated prostate cancer progression by integrated bioinformatic analysis and experimental validation

“…ccCDKs are key regulators of cell cycle progression and transcription. Previous studies also provided evidences supporting the oncogenic potential of CDK3 and CDK5 in skin tumorigenesis and pancreatic neuroendocrine tumors, while an increase in CDK7 expression is related to a poorer overall survival and disease-free survival in squamous cell carcinomas of the head and neck [ 21 , 22 , 23 ]. At present, there are no systematic and comprehensive studies on ccCDK family genes.…”

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

“…Carter A.M. et al developed a bi-transgenic mouse line in which the aberrant activation of the cyclin-dependent kinase 5 (Cdk5) pathway can selectively induce the growth of pancreatic β-cells with consequent generation of heterogeneous population of NETs [ 106 ]. The utility of this model is enhanced by the ability to form tumor-derived allografts in a large cohort of animals.…”

“…It may represent the starting point for the development of innovative transgenic mouse models of midgut and bronchial NETs with CS, for example, through the transgenic overexpression of TPH-1 promoter mediated by the activation of Cdk5 pathway. Indeed, this pathway seems to be involved in the tumorigenesis of several NETs [ 106 , 107 ].…”

FABP5 regulates lipid metabolism to facilitate pancreatic neuroendocrine neoplasms progression via FASN mediated Wnt/β‐catenin pathway

“…The incidence of pNENs has risen considerably in recent decades, accounting for over 3% of pancreatic malignancies, due to advancements in diagnostic methods 2 . Notably, recent research has revealed several potential novel biomarkers, such as INSM1 and CDK5, and implicated some new signaling pathways, including TGF‐beta and the NOTCH pathway, as being relevant to the tumorigenesis of pNENs 3–6 . Despite these advances, current treatment options for the medical management of pNENs remain limited in their sensitivity and specificity.…”