Dataset Information

Endothelial-mesenchymal transition harnesses HSP90?-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma.

ABSTRACT:

Background

Endothelial-to-mesenchymal transition (EndoMT) can provide a source of cancer-associated fibroblasts which contribute to desmoplasia of many malignancies including pancreatic ductal adenocarcinoma (PDAC). We investigated the clinical relevance of EndoMT in PDAC, and explored its underlying mechanism and therapeutic implication.

Methods

Expression levels of 29 long non-coding RNAs were analyzed from the cells undergoing EndoMT, and an EndoMT index was proposed to survey its clinical associations in the PDAC patients of The Cancer Genome Atlas database. The observed clinical correlation was further confirmed by a mouse model inoculated with EndoMT cells-involved PDAC cell grafts. In vitro co-culture with EndoMT cells or treatment with the conditioned medium were performed to explore the underlying mechanism. Because secreted HSP90? was involved, anti-HSP90? antibody was evaluated for its inhibitory efficacy against the EndoMT-involved PDAC tumor.

Results

A combination of low expressions of LOC340340, LOC101927256, and MNX1-AS1 was used as an EndoMT index. The clinical PDAC tissues with positive EndoMT index were significantly correlated with T4-staging and showed positive for M2-macrophage index. Our mouse model and in vitro cell-culture experiments revealed that HSP90? secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90? secretion to promote PDAC tumor growth. Furthermore, anti-HSP90? antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth.

Conclusions

EndoMT cells can secrete HSP90? to harness HSP90?-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90? antibody.

SUBMITTER: Fan CS

PROVIDER: S-EPMC6918594 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma.

Fan Chi-Shuan CS Chen Li-Li LL Hsu Tsu-An TA Chen Chia-Chi CC Chua Kee Voon KV Li Chung-Pin CP Huang Tze-Sing TS

Journal of hematology & oncology 20191217 1

<h4>Background</h4>Endothelial-to-mesenchymal transition (EndoMT) can provide a source of cancer-associated fibroblasts which contribute to desmoplasia of many malignancies including pancreatic ductal adenocarcinoma (PDAC). We investigated the clinical relevance of EndoMT in PDAC, and explored its underlying mechanism and therapeutic implication.<h4>Methods</h4>Expression levels of 29 long non-coding RNAs were analyzed from the cells undergoing EndoMT, and an EndoMT index was proposed to survey ...[more]

PMID: 31847880

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