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Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
Published on: January 31, 2025
Sonic Hedgehog promotes tumor cell survival by inhibiting CDON pro-apoptotic activity
Céline Delloye-Bourgeois1, Benjamin Gibert, Nicolas Rama
1Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, Institut National de la Santé et de la Recherche Médicale (INSERM) U1052- Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR5286), Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
Abstract:
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.
Insights
Cell-adhesion molecule-related/down-regulated by Oncogenes (CDON) acts as a dependence receptor, inducing apoptosis when Sonic Hedgehog (SHH) is absent. SHH signaling can block this, promoting tumor growth, making CDON a potential cancer therapy target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- The Hedgehog signaling pathway regulates tumor progression, but its inhibition is only effective in tumors with specific mutations.
- Sonic Hedgehog (SHH) expression is found in various cancers, yet canonical pathway inhibition shows limited clinical benefit.
- Cell-adhesion molecule-related/down-regulated by Oncogenes (CDON) is a newly identified receptor for SHH.
Purpose of the Study:
- To investigate the role of CDON as a Sonic Hedgehog (SHH) dependence receptor.
- To elucidate the mechanism of CDON-induced apoptosis and its regulation by SHH.
- To evaluate CDON as a potential therapeutic target in SHH-expressing tumors.
Main Methods:
- Investigated CDON's function as a dependence receptor in apoptosis.
- Analyzed the requirement of proteolytic cleavage and caspase-9 activation for CDON's pro-apoptotic activity.
- Assessed the impact of CDON expression on tumor progression in preclinical models.
- Examined the effect of interfering with the SHH-CDON interaction on tumor growth.
Main Results:
- CDON functions as a dependence receptor, inducing apoptosis in the absence of SHH via caspase-9 activation.
- Decreased CDON expression correlates with intestinal tumor progression in mice.
- SHH signaling provides a tumor growth advantage by inhibiting CDON-induced apoptosis.
- Interference with SHH-CDON interaction triggers apoptosis and inhibits tumor growth in vivo.
Conclusions:
- CDON actively induces apoptosis when SHH is not bound, acting as a tumor suppressor.
- SHH signaling in tumors may promote growth by suppressing CDON-mediated apoptosis.
- Targeting the SHH-CDON interaction offers a promising therapeutic strategy for SHH-expressing cancers.
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