| First Author | Sozzi S | Year | 2024 |
| Journal | J Exp Clin Cancer Res | Volume | 43 |
| Issue | 1 | Pages | 265 |
| PubMed ID | 39342278 | Mgi Jnum | J:357744 |
| Mgi Id | MGI:7764590 | Doi | 10.1186/s13046-024-03189-3 |
| Citation | Sozzi S, et al. (2024) Inactivation of HIPK2 attenuates KRAS(G12D) activity and prevents pancreatic tumorigenesis. J Exp Clin Cancer Res 43(1):265 |
| abstractText | BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) features KRAS mutations in approximately 90% of human cases and excessive stromal response, termed desmoplastic reaction. Oncogenic KRAS drives pancreatic carcinogenesis by acting on both epithelial cells and tumor microenvironment (TME). We have previously shown that Homeodomain-Interacting Protein Kinase 2 (HIPK2) cooperates with KRAS in sustaining ERK1/2 phosphorylation in human colorectal cancers. Here, we investigated whether HIPK2 contributes to oncogenic KRAS-driven tumorigenesis in vivo, in the onset of pancreatic cancer. METHODS: We employed an extensively characterized model of KRAS(G12D)-dependent preinvasive PDAC, the Pdx1-Cre;LSL-KRas(G12D/+) (KC) mice. In these mice, HIPK2 was inhibited by genetic knockout in the pancreatic epithelial cells (KCH(-/-)) or by pharmacologic inactivation with the small molecule 5-IodoTubercidin (5-ITu). The development of preneoplastic acinar-to-ductal metaplasia (ADM), intraepithelial neoplasia (PanIN), and their associated desmoplastic reaction were analyzed. RESULTS: In Hipk2-KO mice (KCH(-/-)), ERK phosphorylation was lowered, the appearance of ADM was slowed down, and both the number and pathologic grade of PanIN were reduced compared to Hipk2-WT KC mice. The pancreatic lesion phenotype in KCH(-/-) mice was characterized by abundant collagen fibers and reduced number of alphaSMA(+) and pSTAT3(+) desmoplastic cells. These features were reminiscent of the recently described human "deserted" sub-TME, poor in cells, rich in matrix, and associated with tumor differentiation. In contrast, the desmoplastic reaction of KC mice resembled the "reactive" sub-TME, rich in stromal cells and associated with tumor progression. These observations were confirmed by the pharmacologic inhibition of HIPK2 in KC mice. CONCLUSION: This study demonstrates that HIPK2 inhibition weakens oncogenic KRAS activity and pancreatic tumorigenesis providing a rationale for testing HIPK2 inhibitors to mitigate the incidence of PDAC development in high-risk individuals. |
