Characterization of cell line with dedifferentiated GIST-like features established from cecal GIST of familial GIST model mice

by Selleckchem | Jun 21 2023

Approximately 40 families with multiple gastrointestinal stromal tumors (GISTs) and germline c-kit gene mutations have been reported. Three knock-in mouse models have been generated, and all the models showed a cecal GIST. In the present study, we established a cell line derived from cecal GIST in a familial GIST model mouse with KIT-Asp818Tyr. Since the established cells showed spindle-shaped morphology with atypical nuclei, and since immunohistochemistry revealed that they were positive for α-SMA but negative for KIT, CD34 and desmin, the phenotypes of the cells were reminiscent of dedifferentiated GIST-like ones but not the usual GIST-like ones. Gene expression analysis showed that the cell line, designated as DeGISTL1 cell, did not express c-kit gene apparently, but highly expressed HSP90 families and glutaminase 1. Pathway analysis of the cells revealed that metabolic pathway might promote their survival and growth. Pimitespib, a heat shock protein 90α/β inhibitor, and Telaglenastat, a selective glutaminase 1 inhibitor, inhibited proliferation of DeGISTL1 cells and the combination of these showed an additive effect. DeGISTL1 cells might be a good model of dedifferentiated GISTs, and combination of Pimitespib and Telaglenastat could be a possible candidate for treatment strategy for them.

Comments:

The given information describes a study involving a cell line derived from cecal gastrointestinal stromal tumors (GISTs) in a familial GIST mouse model with a specific gene mutation (KIT-Asp818Tyr). The cell line, named DeGISTL1, exhibited spindle-shaped morphology with atypical nuclei and showed characteristics reminiscent of dedifferentiated GIST-like cells, rather than the usual GIST-like cells. Immunohistochemistry revealed that the cells were positive for α-SMA (alpha-smooth muscle actin) but negative for KIT, CD34, and desmin.

Gene expression analysis demonstrated that the DeGISTL1 cells did not express the c-kit gene prominently but exhibited high expression levels of HSP90 (heat shock protein 90) families and glutaminase 1. Pathway analysis indicated that the metabolic pathway might play a role in promoting the survival and growth of these cells.

In terms of potential therapeutic strategies, the study found that Pimitespib, an inhibitor of heat shock protein 90α/β, and Telaglenastat, a selective glutaminase 1 inhibitor, both inhibited the proliferation of DeGISTL1 cells. Moreover, combining these inhibitors showed an additive effect in inhibiting cell proliferation. This suggests that a combination of Pimitespib and Telaglenastat could be a possible treatment strategy for dedifferentiated GISTs.

Overall, the study established the DeGISTL1 cell line as a valuable model for dedifferentiated GISTs and identified potential therapeutic targets, HSP90 and glutaminase 1, as well as the combination of Pimitespib and Telaglenastat, for further exploration in the treatment of this subtype of GISTs.