RABL6A Promotes Pancreatic Neuroendocrine Tumor Angiogenesis and Progression In Vivo.

Chandra K Maharjan,David K Meyerholz,Dawn E Quelle,Casey Bauchle,Benjamin W Darbro,Viviane P Muniz,Sarah L Mott,Shaikamjad Umesalma,Patrick Breheny,K D Zamba,Courtney A Kaemmer,Mariah R Leidinger,Samuel B Stephens

doi:10.3390/biomedicines9060633

Chandra K Maharjan, David K Meyerholz + Show 11 more

Open Access

https://doi.org/10.3390/biomedicines9060633

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Journal: Biomedicines	Publication Date: Jun 2, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: University of Iowa, Fraternal Order of Eagles

Abstract

Pancreatic neuroendocrine tumors (pNETs) are difficult-to-treat neoplasms whose incidence is rising. Greater understanding of pNET pathogenesis is needed to identify new biomarkers and targets for improved therapy. RABL6A, a novel oncogenic GTPase, is highly expressed in patient pNETs and required for pNET cell proliferation and survival in vitro. Here, we investigated the role of RABL6A in pNET progression in vivo using a well-established model of the disease. RIP-Tag2 (RT2) mice develop functional pNETs (insulinomas) due to SV40 large T-antigen expression in pancreatic islet β cells. RABL6A loss in RT2 mice significantly delayed pancreatic tumor formation, reduced tumor angiogenesis and mitoses, and extended survival. Those effects correlated with upregulation of anti-angiogenic p19ARF and downregulation of proangiogenic c-Myc in RABL6A-deficient islets and tumors. Our findings demonstrate that RABL6A is a bona fide oncogenic driver of pNET angiogenesis and development in vivo.

Highlights

Pancreatic neuroendocrine tumors are incurable, typically indolent neoplasms originating from multiple neuroendocrine cell types, β cells, within the islets of Langerhans [1]
We explored the in vivo oncogenic role of RABL6A in Pancreatic neuroendocrine tumors (pNETs) development and progression
About one-fifth undergo an angiogenic switch and become vascularized angiogenic islets by 7–9 weeks, with one-fourth of those progressing into enlarged pNETs starting at 10–12 weeks [20,21,32]

Summary

Introduction

Pancreatic neuroendocrine tumors (pNETs) are incurable, typically indolent neoplasms originating from multiple neuroendocrine cell types, β cells, within the islets of Langerhans [1]. Pancreatic β cells maintain proper blood glucose levels via insulin production and release. Β cell dysfunction leads to diabetes while their neoplastic transformation results in pNET formation. PNETs are uncommon, their incidence has risen more than 4-fold over the past four decades [2,3,4]. This is alarming because the molecular etiology of pNET development is only partly understood and current therapies have little to no impact on improving overall patient survival [5].

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