Open AccessMitochondrial Haplotype of the Host Stromal Microenvironment Alters Metastasis in a Non-cell Autonomous Manner
Author(s) -
Amanda E. Brinker,
Carolyn J. Vivian,
Thomas C. Beadnell,
Devin C. Koestler,
Shao Thing Teoh,
Sophia Y. Lunt,
Danny R. Welch
Publication year - 2020
Publication title -
cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.103
H-Index - 449
eISSN - 1538-7445
pISSN - 0008-5472
DOI - 10.1158/0008-5472.can-19-2481
Subject(s) - biology , mitochondrial dna , mitochondrion , stromal cell , metastasis , cancer research , nuclear dna , melanoma , cancer , microbiology and biotechnology , genetics , gene
Mitochondria contribute to tumor growth through multiple metabolic pathways, regulation of extracellular pH, calcium signaling, and apoptosis. Using the Mitochondrial Nuclear Exchange (MNX) mouse models, which pair nuclear genomes with different mitochondrial genomes, we previously showed that mitochondrial SNPs regulate mammary carcinoma tumorigenicity and metastatic potential in genetic crosses. Here, we tested the hypothesis that polymorphisms in stroma significantly affect tumorigenicity and experimental lung metastasis. Using syngeneic cancer cells (EO771 mammary carcinoma and B16-F10 melanoma cells) injected into wild-type and MNX mice (i.e., same nuclear DNA but different mitochondrial DNA), we showed mt-SNP-dependent increases (C3H/HeN) or decreases (C57BL/6J) in experimental metastasis. Superoxide scavenging reduced experimental metastasis. In addition, expression of lung nuclear-encoded genes changed specifically with mt-SNP. Thus, mitochondrial-nuclear cross-talk alters nuclear-encoded signaling pathways that mediate metastasis via both intrinsic and extrinsic mechanisms. SIGNIFICANCE: Stromal mitochondrial polymorphisms affect metastatic colonization through reactive oxygen species and mitochondrial-nuclear cross-talk.