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Telomere DNA damage signaling regulates cancer stem cell evolution, epithelial
mesenchymal transition, and metastasis
#MMPMID29113290
Lagunas AM
; Wu J
; Crowe DL
Oncotarget
2017[Oct]; 8
(46
): 80139-80155
PMID29113290
show ga
Chromosome ends are protected by telomeres that prevent DNA damage response and
degradation. When telomeres become critically short, the DNA damage response is
activated at chromosome ends which induces cellular senescence or apoptosis.
Telomeres are protected by the double stranded DNA binding protein TRF2 and
maintained by telomerase or a recombination based mechanism known as alternative
lengthening of telomeres (ALT). Telomerase is expressed in the basal layer of the
epidermis, and stem cells in epidermis have longer telomeres than proliferating
populations. Stem cell expansion has been associated with epithelial-mesenchymal
transition (EMT) in cancer. EMT is a critical process in cancer progression in
which cells acquire spindle morphology, migrate from the primary tumor, and
spread to distant anatomic sites. Our previous study demonstrated that loss of
TRF2 expression observed in human squamous cell carcinomas expanded metastatic
cancer stem cells during mouse skin carcinogenesis. To determine if telomerase
inhibition could block the TRF2-null mediated expansion of metastatic clones, we
characterized skin carcinogenesis in a conditional TRF2/Terc double null mutant
mouse. Loss of TRF2 and Terc expression resulted in telomere DNA damage, severely
depleted CD34 + and Lgr6+ cancer stem cells, and induced terminal differentiation
of metastatic cancer cells. However a novel cancer stem cell population evolved
in primary tumors exhibiting genomic instability, ALT, and EMT. Surprisingly we
discovered that metastatic clones evolved prior to histopathologic onset of
primary tumors. These results have important implications for understanding the
evolution and treatment of metastatic cancer.
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