Integrated Multiomics Unravels Hedgehog (HH) Signaling Characteristics in Pancreatic Cancer (PC) and DCBLD2 Regulates HH Signaling to Drive PC Progression.

Hedgehog (HH) signaling plays a crucial role in cancer development. However, HH signaling-related molecular characteristics have not been comprehensively evaluated in pancreatic cancer (PC). This study dissected the characteristics of HH signaling in PC using integrated bulk and single-cell profiling. GSEA indicated that HH signaling is significantly enriched in PC tissue. Consensus clustering was utilized to classify PC samples into two HH signaling-related subtypes: HRGcluster A and HRGcluster B. In contrast with HRGcluster A, HRGcluster B has an earlier clinical stage, better outcome, less active level of HH signaling, higher infiltration level of CD8+ T cells and B cells, and a greater likelihood of benefiting from immunotherapy and gemcitabine chemotherapy. Moreover, an HH signaling-related prognostic model (including ANLN, SERPINB3, LY6D, and DCBLD2) with excellent prediction performance was established and validated. Further analysis indicated that ANLN, SERPINB3, LY6D, and DCBLD2 were significantly upregulated in PC and associated with poor prognosis. Single-cell analysis revealed that HH signaling is relatively more active in PC cells, and PC cells with DCBLD2 high expression had significantly higher HH signaling scores. In vitro assays further indicated that DCBLD2 knockdown downregulates HH signaling and inhibits the proliferation, migration, and invasion of PC cells. In conclusion, this study reveals that HH signaling characteristics in PC and DCBLD2 regulate HH signaling to drive PC progression, providing new perspectives and theories for the diagnosis and treatment of PC.