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  • The Hedgehog Hh pathway is linked to the development

    2022-05-13

    The Hedgehog (Hh) pathway is linked to the development of several types of epithelial cancers (Rubin and de Sauvage, 2006). A paracrine mechanism has been implicated in CAF activation, with Hh ligands secreted by cancer cells activating the glioma-associated transcription factors (Gli) in surrounding stromal cells (Junttila and de Sauvage, 2013, Theunissen and de Sauvage, 2009). Interestingly, while this chain of events should enhance tumor formation (Theunissen and de Sauvage, 2009), an opposite restraining function of stromal Hh activation in pancreatic and Pifithrin-α cancer has also been reported (Özdemir et al., 2014, Rhim et al., 2014, Shin et al., 2014). Mammalian cells express three GLI proteins (Aberger and Ruiz i Altaba, 2014). Under basal conditions, glioma-associated transcription factor 2 (GLI2) is cleaved into a transcriptional repressor, with Hh stimulation blocking this process and converting it into an activator. Expression of glioma-associated transcription factor 1 (GLI1) is then induced as a signal amplifier. In Drosophila, the activation of GLI homolog Cubitus interruptus (Ci) is well established (Ruel et al., 2003, Wang et al., 2000), with a kinase (Fused) releasing it from an inhibitory complex (Costal2/SuFu) and promoting its nuclear translocation. In mammalian cells, the mechanisms responsible for GLI activation are less understood. Recently, the unc-51-like-kinase 3 (ULK3), an inducer in human fibroblasts of autophagy (Young et al., 2009), has been proposed to fulfill the role of Fused through association and phosphorylation of GLI2 (Maloverjan et al., 2010, Rubin and de Sauvage, 2006). Importantly, in cancer cells, GLI proteins can also be activated by Hh-receptor-independent mechanisms involving phosphatidylinositol 3-kinase (PI3K)/AKT (Metcalfe and de Sauvage, 2011), mitogen-activated protein kinase (MAPK)/ERK (Seto et al., 2009), S6K (Wang et al., 2012), and KRAS activation (Nolan-Stevaux et al., 2009, Stecca et al., 2007). Recent evidence suggests that altered metabolic properties of CAFs, resulting from increased autophagy/mitophagy and associated shift to aerobic glycolysis, can contribute to their tumor-enhancing properties (Kalluri, 2016, Martinez-Outschoorn et al., 2017). How these processes relate to CAFs activation remains to be determined. We report here an as-yet-unexpected link between the CSL and GLI signaling pathways, with the ULK3 kinase as an attractive target for stroma-focused anti-cancer intervention, controlling the CAF effector gene expression program separately from the autophagy/mitophagy processes.
    Results
    Discussion Genes with critical cell- and tissue-regulatory functions are tightly controlled by the convergence of multiple positive and negative signals. While a large number of CAF-effector genes have been identified, an unanswered question is in regard to the integration of different signaling pathways involved in their control. In stromal fibroblasts, CSL represses senescence- and CAF-effector genes, with induction of the first class of genes occurring as the result of loss of CSL repression and increased p53 activity (Procopio et al., 2015). We show here that relief of CSL repression of CAF-effector genes is not sufficient for induction of their expression, for which activation of GLI1/2 transcription factors is also required. Increased expression of the ULK3 kinase, which occurs in CAFs from various cancer types, provides a link between compromised CSL function and GLI activation, which can occur in concert with other previously reported Hh-receptor-dependent and -independent mechanisms (Metcalfe and de Sauvage, 2011, Seto et al., 2009, Wang et al., 2012, Nolan-Stevaux et al., 2009, Stecca et al., 2007). Autophagy can create a pro-tumorigenic microenvironment rich in metabolic precursors directed from CAFs to tumors (Lisanti et al., 2010, Zhao et al., 2013). As ULK3 is also an inducer of this process, it provides an attractive target for stroma-focused anti-cancer intervention to suppress combined aspects of CAF activation.