Paracrine Interaction Of Cancer Stem Cell Populations Is Regulated By The Senescence-Associated Secretory Phenotype (Sasp)

Dyskeratosis congenita is a telomere DNA damage syndrome characterized by defective telomere maintenance, bone marrow failure, and increased head and neck cancer risk. The Pot1b(-/-); Terc(+/-) mouse exhibits some features of dyskeratosis congenita, but head and neck cancer was not reported in this model. To model the head and neck cancer phenotype, we created unique Pot1b- and p53-null-mutant models which allow genetic lineage tracing of two distinct stem cell populations. Loss of Pot1b expression depleted stem cells via ATR/Chk1/p53 signaling. Tumorigenesis was inhibited in Pot1b(-/-); p53(+/+) mice due to cellular senescence. Pot1b(-/-); p53(-/-) tumors also exhibited senescence, but proliferated and metastasized with expansion of Lgr6(+) stem cells indicative of senescence-associated secretory phenotype. Selective depletion of the small K15(+) stem cell fraction resulted in reduction of Lgr6(+) cells and inhibition of tumorigenesis via senescence. Gene expression studies revealed that K15(+) cancer stem cells regulate Lgr6(+) cancer stem cell expansion via chemokine signaling. Genetic ablation of the chemokine receptor Cxcr2 inhibited cancer stem cell expansion and tumorigenesis via senescence. The effects of chemokines were primarily mediated by PI3K signaling, which is a therapeutic target in head and neck cancer. Implications: Paracrine interactions of cancer stem cell populations impact therapeutic options and patient outcomes.