Primary cilia and senescence: a sensitive issue

Primary cilia (PC) are primordial, thin, hair-like organelles that protrude from the surface of vertebrate cells acting as a nexus that sense and transduce various extracellular signals, particularly that of Hedgehog (Hh) signaling. PC have been implicated in development and cancer as well as in a group of genetic disorders termed ciliopathies that affect a diverse range of organs in which the underlying phenomenon is structural or functional abnormalities of cilia. PC have a dual role in cancer as they promote or prevent tumor development depending on whether Hh signaling is activated at receptor level or downstream. Many tumor cells, such as those from pancreatic tumors, often lack cilia, highlighting that PC may be growth-inhibitory. However, the association depends on tumor type, as PC are present in human basal cell carcinomas (BCCs) as well as in distinct molecular subgroups of medulloblastomas. Uncontrolled cell proliferation is a hallmark of cancer. Therefore, senescence, a stable cell cycle arrest induced by replicative exhaustion or in response to stresses such as oncogene activation, is a potent barrier against tumorigenesis. The percentage of PC-containing cells increases in response to quiescence, a transient form of cell cycle arrest, but whether senescence promotes ciliogenesis and if so, what role PC plays in senescence remains to be addressed. The current manuscript by Morrison and colleagues shows that senescent (late passage) human fibroblasts display both increased frequency and length of PC, compared to proliferating (young passage) fibroblasts. Importantly, the expression of Hh signaling components were lower in fibroblasts undergoing replicative senescence in comparison to proliferating cells. Inhibition of Hh signaling decreased cell proliferation and extended the length of PC in proliferating young fibroblasts, suggesting that Hh signaling inhibits ciliogenesis and replicative senescence in human fibroblasts (Fig. 1). Additionally, promoting ciliogenesis by depleting CP110, a negative regulator of ciliogenesis, was sufficient to reduce the proliferative capacity of young cells. However, overexpressing CP110 failed to reinstitute the proliferation of senescent cells. These findings would fit with the growth-inhibitory functions of PC and would suggest that the increase in PC observed in senescent cells could contribute to tumor suppression and that there is a need to suppress PC during cancer progression. However, as it seems to be the case with PC and tumorigenesis, the relation between PC and senescence is not clear-cut. It was previously reported that only a small percentage of primary human mammary epithelial cells (HMECs) exhibited PC and these PC-containing HMECs displayed low levels of p16, a marker of senescence. In addition, depletion of p16 or increased Hh signaling via IHH promoted the formation of PC. In the same direction, cilia were absent both from pancreatic intraepithelial neoplasias (PanINs), which are preneoplastic lesions enriched in senescent cells, and in the resulting pancreatic ductal adenocarcinomas (PDACs). Therefore, an alternative explanation could be that loss of PC is a cancer-related phenotype that is acquired early in tumor progression (at the senescent stage), as it happens with global alterations in DNA methylation.