Esophageal 3D Organoids of Mouse Model of Mitochondrial DNA Depletion Show Epithelial Cell Plasticity and Telomere Attrition

Overview

Journal Oncotarget

Specialty Oncology

Date 2019 Nov 7

PMID 31692873

Citations 2

Authors

Manti Guha

Satish Srinivasan

Maura M Sheehan

Takashi Kijima

Gordon Ruthel

Kelly Whelan

Koji Tanaka

Andres Klein-Szanto

Prasanna M Chandramouleeswaran

Hiroshi Nakagawa

Narayan G Avadhani

Affiliations

Soon will be listed here.

Abstract

Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with late-stage detection and poor prognosis. This emphasizes the need to identify new markers for early diagnosis and treatment. Altered mitochondrial genome (mtDNA) content in primary tumors correlates with poor patient prognosis. Here we used three-dimensional (3D) organoids of esophageal epithelial cells (EECs) from the mouse model of mtDNA depletion to investigate the contribution of reduced mtDNA content in ESCC oncogenicity. To test if mtDNA defects are a contributing factor in ESCC, we used oncogenic stimuli such as ESCC carcinogen 4-nitroquinoline oxide (4-NQO) treatment, or expressing p53 oncogenic driver mutation. We observed that EECs and 3D-organoids with mtDNA depletion had cellular, morphological and genetic alterations typical of an oncogenic transition. Furthermore, mitochondrial dysfunction induced cellular transformation is accompanied by elevated mitochondrial fission protein, DRP1 and pharmacologic inhibition of mitochondrial fission by mDivi-1 in the organoids reversed the phenotype to that of normal EEC organoids. Our studies show that mtDNA copy number depletion, activates a mitochondrial retrograde response, potentiates telomere defects, and increases the oncogenic susceptibility towards ESCC. Furthermore, mtDNA depletion driven cellular plasticity is mediated via altered mitochondrial fission-fusion dynamics.

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