New surprises from an old favourite: The emergence of telomerase as a key player in the regulation of cancer stemness.

It has been well established that the upregulation/reactivation of telomerase is a prerequisite for cellular immortalisation and malignant transformation. More significantly, perhaps, telomerase stands at the crossroads of multiple signalling pathways and its upregulation/reactivation leads to the modulation of critical cellular processes, including gene expression and metabolism. In recent years, this multifaceted ribonucleoprotein particle has become increasingly associated with the cancer stem cell (CSC) phenotype in various human cancers. Cancer stemness is a major contributor to therapy resistance and hence tumour recurrence. Here, we discuss new findings about the telomere-independent tumour-promoting functions of telomerase and provide a mechanistic explanation for its regulatory role in CSC biology. It is striking that there is a positive feedback loop between a number of gene products targeting telomerase's reverse transcriptase subunit (TERT) and TERT expression itself. This plausibly amplifies the effects of central oncogenes and oncogenic pathways related to cancer stemness in a cell-autonomous fashion. A more complete elucidation of these regulatory mechanisms affords the opportunity to develop telomerase-focused therapies that differentiate or kill CSCs effectively.