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Myeloid-derived macrophages and secreted HSP90? induce pancreatic ductal adenocarcinoma development.

ABSTRACT: We detected a significant elevation of serum HSP90? levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90? levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90? levels occurred early during PDAC development, we used LSL-KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90? levels were detected before PDAC formation and an extracellular HSP90? (eHSP90?) inhibitor effectively prevented PDAC development. Both serum HSP90? level and pancreatic lesion were suppressed when the mice were administered a CD11b-antagonizing antibody, suggesting that CD11b⁺-myeloid cells were associated with eHSP90? levels and pancreatic carcinogenesis. Consistently, in CD11b-DTR-EGFP transgenic mouse model with CD11b⁺-myeloid cells depletion, serum HSP90? levels were suppressed and Panc-02 cell grafts failed to develop tumors. Macrophages and granulocytes are two common tissue-infiltrating CD11b⁺-myeloid cells. Duplex in situ hybridization assays suggested that macrophages were predominant HSP90?-expressing CD11b⁺-myeloid cells during PDAC development. Immunohistochemical and immunohistofluorescent staining results revealed that HSP90?-expressing cells included not only macrophages but also pancreatic ductal epithelial (PDE) cells. Cell culture studies also indicated that eHSP90? could be produced by macrophages and macrophage-stimulated PDE cells. Macrophages not only secreted significant amount of HSP90?, but also secreted interleukin-6 and interleukin-8 to induce a JAK2-STAT3 signaling axis in PDE cells, stimulating them to express and secrete HSP90?. eHSP90? further promoted cellular epithelial-mesenchymal transition, migration, and invasion in PDE cells. Besides myeloid cells, eHSP90? can be potentially taken as a target to suppress PDAC pathogenesis.

SUBMITTER: Chen CC

PROVIDER: S-EPMC5927518 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Myeloid-derived macrophages and secreted HSP90α induce pancreatic ductal adenocarcinoma development.

Chen Chia-Chi CC Chen Li-Li LL Li Chung-Pin CP Hsu Yu-Ting YT Jiang Shih-Sheng SS Fan Chi-Shuan CS Chua Kee Voon KV Huang Sheng-Xiang SX Shyr Yi-Ming YM Chen Li-Tzong LT Huang Tze-Sing TS

Oncoimmunology 20180201 5

We detected a significant elevation of serum HSP90α levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90α levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90α levels occurred early during PDAC development, we used LSL-KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90α levels were detected before PDAC formation ...[more]

PMID: 29721383

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Project description:Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), but it is not clear how obesity contributes to pancreatic carcinogenesis. The oncogenic form of KRAS is expressed during early stages of PDAC development and is detected in almost all of these tumors. However, there is evidence that mutant KRAS requires an additional stimulus to activate its full oncogenic activity and that this stimulus involves the inflammatory response. We investigated whether the inflammation induced by a high-fat diet, and the accompanying up-regulation of cyclooxygenase-2 (COX2), increases Kras activity during pancreatic carcinogenesis in mice.We studied mice with acinar cell-specific expression of KrasG12D (LSL-Kras/Ela-CreERT mice) alone or crossed with COX2 conditional knockout mice (COXKO/LSL-Kras/Ela-CreERT). We also studied LSL-Kras/PDX1-Cre mice. All mice were fed isocaloric diets with different amounts of fat, and a COX2 inhibitor was administered to some LSL-Kras/Ela-CreERT mice. Pancreata were collected from mice and analyzed for Kras activity, levels of phosphorylated extracellular-regulated kinase, inflammation, fibrosis, pancreatic intraepithelial neoplasia (PanIN), and PDACs.Pancreatic tissues from LSL-Kras/Ela-CreERT mice fed high-fat diets (HFDs) had increased Kras activity, fibrotic stroma, and numbers of PanINs and PDACs than LSL-Kras/Ela-CreERT mice fed control diets; the mice fed the HFDs also had shorter survival times than mice fed control diets. Administration of a COX2 inhibitor to LSL-Kras/Ela-CreERT mice prevented these effects of HFDs. We also observed a significant reduction in survival times of mice fed HFDs. COXKO/LSL-Kras/Ela-CreERT mice fed HFDs had no evidence for increased numbers of PanIN lesions, inflammation, or fibrosis, as opposed to the increases observed in LSL-Kras/Ela-CreERT mice fed HFDs.In mice, an HFD can activate oncogenic Kras via COX2, leading to pancreatic inflammation and fibrosis and development of PanINs and PDAC. This mechanism might be involved in the association between risk for PDAC and HFDs.

Project description:BackgroundIncreasing evidence supports that infiltration M2 Macrophages act as pivotal player in tumor progression of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, comprehensive analysis of M2 Macrophage infiltration and biological roles of hub genes (FAM53B) in clinical outcome and immunotherapy was lack.MethodThe multiomic data of PDAC samples were downloaded from distinct datasets. CIBERSORT algorithm was performed to uncover the landscape of TIME. Weighted gene co-expression network analysis (WGCNA) was performed to identify candidate module and significant genes associated with M2 Macrophages. Kaplan-Meier curve and receiver operating characteristic (ROC) curves were applied for prognosis value validation. Mutation data was analyzed by using "maftools" R package. Gene set variation analysis (GSVA) was employed to assign pathway activity estimates to individual sample. Immunophenoscore (IPS) was implemented to estimate immunotherapeutic significance of risk score. The half-maximal inhibitory concentration (IC50) of chemotherapeutic drugs was predicted by using the pRRophetic algorithm. Finally, quantitative real-time polymerase chain reaction was used to determine FAM53B mRNA expression and TIMER database was utilized to uncover its possible role in immune infiltration of PDAC.ResultsHerein, 17,932 genes in 234 samples (214 tumor and 20 normal) were extracted from three platforms. Taking advantage of WGCNA, significant module (royalblue) and 135 candidate genes were considered as M2 Macrophages-related genes. Subsequently, risk signature including 5 hub genes was developed by multiple analysis, which exhibited excellent prognostic performance. Besides, comprehensive prognostic nomogram was constructed to quantitatively estimate risk. Then, intrinsic link between risk score with tumor mutation burden (TMB) was explored. Additionally, risk score significantly correlated with diversity of tumor immune microenvironment (TIME). PDAC samples within different risk presented diverse signaling pathways activity and experienced significantly distinct sensitivity to administering chemotherapeutic or immunotherapeutic agents. Finally, the biological roles of FAM53B were revealed in PDAC.ConclusionsTaken together, comprehensive analyses of M2 Macrophages profiling will facilitate prognostic prediction, delineating complexity of TIME, and contribute insight into precision therapy for PDAC.

Dataset Information

Myeloid-derived macrophages and secreted HSP90? induce pancreatic ductal adenocarcinoma development.

Publications

Myeloid-derived macrophages and secreted HSP90α induce pancreatic ductal adenocarcinoma development.

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