Sonic Hedgehog Promotes Tumor Cell Survival by Inhibiting CDON Pro-Apoptotic Activity

: CDON is a novel Sonic Hedgehog (SHH) dependence receptor and targeting the SHH-CDON interaction could represent an alternative therapeutic strategy for patients suffering from tumors that express high SHH levels. The Hedgehog signaling is a determinant pathway for tumor progression. However, while inhibition of the Hedgehog canonical pathway—Patched–Smoothened–Gli—has proved efficient in human tumors with activating mutations in this pathway, recent clinical data have failed to show any benefit in other cancers, even though Sonic Hedgehog (SHH) expression is detected in these cancers. Cell-adhesion molecule-related/down-regulated by Oncogenes (CDON), a positive regulator of skeletal muscle development, was recently identified as a receptor for SHH. We show here that CDON behaves as a SHH dependence receptor: it actively triggers apoptosis in the absence of SHH. The pro-apoptotic activity of unbound CDON requires a proteolytic cleavage in its intracellular domain, allowing the recruitment and activation of caspase-9. We show that by inducing apoptosis in settings of SHH limitation, CDON expression constrains tumor progression, and as such, decreased CDON expression observed in a large fraction of human colorectal cancer is associated in mice with intestinal tumor progression. Reciprocally, we propose that the SHH expression, detected in human cancers and previously considered as a mechanism for activation of the canonical pathway in an autocrine or paracrine manner, actually provides a selective tumor growth advantage by blocking CDON-induced apoptosis. In support of this notion, we present the preclinical demonstration that interference with the SHH–CDON interaction triggers a CDON-dependent apoptosis in vitro and tumor growth inhibition in vivo. The latter observation qualifies CDON as a relevant alternative target for anticancer therapy in SHH-expressing tumors.Author Summary: Abnormal activity of the Hedgehog signaling pathway has been linked with tumor progression; deregulation of this pathway can occur in cancers either by mutations in key effectors of the so-called canonical signaling pathway or by aberrant expression of Hedgehog itself. While inhibition of the canonical signaling pathway has proved efficient for treating some cases of human tumors in which the Hedgehog pathway was shown to be overactive, recent clinical data have shown this approach is not often successful. We have identified a new role for the Hedgehog ligand that we propose can explain why inhibiting the canonical signaling pathway generically doesn't always produce the desired therapeutic effect. We show that Hedgehog expression provides a selective growth advantage for tumours. It does so by binding to a novel dependence receptor called Cell adhesion molecule-related, down-regulated by oncogenes (CDON). This type of receptor depends on the presence of its ligand, in the absence of which it induces apoptosis. We show that interfering with the Hedgehog–CDON interaction triggers CDON-dependent apoptosis in vitro, and tumor growth inhibition in vivo. Development of a candidate drug interfering with Hedgehog–CDON interaction could be of potential benefit to the large number of patients suffering from cancers with high SHH levels, but not currently responding to therapies aimed at antagonizing the Hedgehog signaling pathway.