Inactivation of HIPK2 attenuates KRASG12D activity and prevents pancreatic tumorigenesis.

IF 11.4 1区 医学 Q1 ONCOLOGY Journal of Experimental & Clinical Cancer Research Pub Date : 2024-09-28 DOI:10.1186/s13046-024-03189-3
Silvia Sozzi, Isabella Manni, Cristiana Ercolani, Maria Grazia Diodoro, Armando Bartolazzi, Francesco Spallotta, Giulia Piaggio, Laura Monteonofrio, Silvia Soddu, Cinzia Rinaldo, Davide Valente
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引用次数: 0

Abstract

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 KRASG12D-dependent preinvasive PDAC, the Pdx1-Cre;LSL-KRasG12D/+ (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 αSMA+ 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.

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HIPK2 失活可减轻 KRASG12D 的活性并防止胰腺肿瘤发生。
背景:约 90% 的人类胰腺导管腺癌 (PDAC) 具有 KRAS 突变和过度基质反应(脱瘤反应)的特征。致癌 KRAS 通过作用于上皮细胞和肿瘤微环境 (TME) 推动胰腺癌的发生。我们之前研究发现,同源多聚酶域相互作用蛋白激酶 2(HIPK2)与 KRAS 相互合作,维持人类结直肠癌中 ERK1/2 的磷酸化。在此,我们研究了在胰腺癌发病过程中,HIPK2 是否有助于体内 KRAS 驱动的肿瘤发生:我们采用了一种具有广泛特征的 KRASG12D 依赖性浸润前 PDAC 模型--Pdx1-Cre;LSL-KRasG12D/+(KC)小鼠。在这些小鼠中,通过基因敲除胰腺上皮细胞(KCH-/-)或使用小分子 5-ITu 抑制 HIPK2。结果分析了肿瘤前针尖至导管化生(ADM)、上皮内瘤变(PanIN)的发展及其相关的去瘤反应:结果:与Hipk2-WT KC小鼠相比,Hipk2-KO小鼠(KCH-/-)的ERK磷酸化程度降低,ADM的出现速度减慢,PanIN的数量和病理级别降低。KCH-/- 小鼠胰腺病变表型的特点是胶原纤维丰富,αSMA+ 和 pSTAT3+ 去增生细胞数量减少。这些特征让人联想到最近描述的人类 "荒废的 "亚 TME,细胞少,基质丰富,与肿瘤分化有关。相反,KC 小鼠的脱鳞反应类似于 "反应性 "亚 TME,富含基质细胞,与肿瘤进展有关。在 KC 小鼠体内对 HIPK2 进行药物抑制证实了这些观察结果:本研究表明,抑制 HIPK2 可减弱致癌 KRAS 的活性和胰腺肿瘤的发生,为测试 HIPK2 抑制剂以降低高危人群 PDAC 的发病率提供了理论依据。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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