Development of clinically representative patient-derived organoid models for diverse G1/G2 gastroenteropancreatic neuroendocrine tumors

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Introduction: While gastroenteropancreatic neuroendocrine tumors (GEP-NETs) grow slowly, they are incurable when reaching advanced stages. The characteristic slow growth of GEP-NETs results in the scarcity of clinically relevant models that has hindered our comprehension of GEP-NET biology and pathology, leading to limited progress in systemic therapies of GEP-NET treatment.

Aim(s): This project aims to generate patient-derived organoid models (PDOs) from diverse G1/G2 GEP-NETs that faithfully recapitulate the genetic and biological characteristics of their original tumors.

Materials and methods: The doxycycline (Dox)-inducible/controlled TP53R273H and SV40LT lentiviruses, marked with EGFP, were generated and characterized. Single cells digested from 22 surgically resected G1/G2 GEP-NET tissues (pancreatic NET [pNET, n= 9]; intestinal NETs [n=12]; gastrinoma [n=1]) were transduced with these lentiviruses and cultured to produce Dox-controlled genetically modified PDOs (GM PDOs). The GM PDOs under Dox-on and Dox-off culture conditions were characterized by measuring cell proliferation rates and expression of NET markers (e.g., CHGA, SYP, CD56) and Ki67, and conducting whole genome sequencing (WGS) in comparison to the original tumor cells.

Conference:

Presenting Author:

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

Keywords: gastroenteropancreatic neuroendocrine tumors, patient-derived organoids, Dox-controlled genetic modifications, characterization,