Developing innovative, genetically modified, proliferation-regulated patient-derived models representing human well-differentiated GEP-NETs for drug screening

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Introduction: The slow-growing nature of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) has limited the development of clinically relevant models, hindering the discovery in the field.

Aim(s): To generate patient-derived cancer models from diverse GEP-NETs that reflect the original tumours and evaluate their drug response.

Materials and methods: Doxycycline (Dox)-inducible TP53R273H and SV40LT lentiviruses, marked with EGFP, were generated. Cells digested from 21 surgically resected primary or metastasis G1/G2 GEP-NETs were transduced with these lentiviruses to create Dox-inducible genetically modified PDOs (GM PDOs). GM PDOs from 2 pancreatic NETs transduced with a luciferase lentivirus were injected into the pancreata of NSG mice to generate orthotopic GM PDO-derived xenografts (GM PDXs). The GM PDOs and GM PDXs were comprehensively characterised by phenotypic assessment, WGS, and RNA-seq. The drug testing was conducted on 4 GM PDOs. Growth rates were monitored and quantified using EGFP fluorescence for GM PDOs and bioluminescence for GM PDXs.

Conference:

Presenting Author: Zuo X

Authors: Zuo X, Liu Y, Maxwell J, Halperin D, Dasari A,

Keywords: Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumour, Patient-Derived Cancer Model, Doxycycline-Controlled Genetic Modification, Drug Screening,