Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic cancer, exhibiting conspicuous desmoplasia and deadly prognosis [
1]. The desmoplastic stroma of PDAC is composed of large amounts of extracellular matrix as well as great numbers of α-smooth muscle actin (α-SMA)-expressing myofibroblastic cells. Such myofibroblastic cells, also called activated fibroblasts or cancer-associated fibroblasts (CAFs), contribute to tumor growth, immunosuppression, and malignant progression [
2‐
5]. They constitute the majority of tumor stromal cells and can be derived from diverse resources such as tissue-resident fibroblasts, stellate cells, mesenchymal stem/progenitor cells, and infiltrating fibrocytes [
6]. Additionally, 30~40% of CAFs can arise from the endothelial-to-mesenchymal transition (EndoMT) of endothelial cells [
7], exhibiting a remarkable cancer-associated cell plasticity. EndoMT is first observed with heart development [
8‐
10], and is also involved in transforming growth factor (TGF)-β-associated fibrotic diseases [
11]. Despite the fact that EndoMT can be detected in cancers and is thought as a source of CAFs, the knowledge about the relevance of EndoMT to other clinical characteristics and the underlying mechanism(s) is still lacking. In our previous study, EndoMT cells (exhibiting α-SMA
+ and CD31
+) were detected nearby osteopontin (OPN)-expressing macrophages in colorectal cancer (CRC) tissue specimens [
12]. OPN induced the EndoMT of endothelial cells, and the resultant EndoMT cells exhibited a potent tumor-promoting effect by secreting HSP90α to foster the stemness of CRC cells [
12]. HSP90α is a well-known cellular chaperone aiding the folding, maturation, and trafficking of many client proteins including cancer-related Bcr-Abl, ErbB2/Neu, Akt, HIF-1α, mutated p53, and Raf-1 [
13]. It can also be expressed and secreted from the keratinocytes and fibroblasts in wounded tissues, as well as from cancer cells [
14‐
16]. Clinically, elevation of serum/plasma HSP90α levels has been detected from several malignancies including CRC and PDAC [
15‐
18]. Elevated levels of such extracellular HSP90α (eHSP90α) can also be detected from pancreatitis patients and PDAC-developing transgenic mice driven by mutant K-Ras [
18]. eHSP90α could be produced from myeloid-derived macrophages and the stimulated pancreatic ductal epithelial cells to promote the macrophage-associated PDAC development [
18]. Macrophages are one of the most abundant myeloid-derived cells infiltrating the tumor microenvironment. Earlier studies have demonstrated that inflammatory macrophages have tumoricidal activity, but macrophages polarize to M2-type and exhibit distinct tumor-promoting activities after interacting with tumor cells and other components within the tumor microenvironment [
19,
20]. Higher level of M2-macrophages has been clinically correlated with PDAC malignancy [
18,
21], while a significant correlation between the levels of M2-macrophage and CAF was also revealed in CRC tissues [
22]. However, the relations among EndoMT, M2-macrophages, eHSP90α level, and PDAC malignancy remain poorly disclosed.
To investigate EndoMT-associated PDAC microenvironment and clinical significance, we first identified an expression profile of 3 long non-coding RNAs (lncRNAs) as EndoMT index to characterize the clinical PDAC specimens in TCGA dataset. The PDAC tissues with positive EndoMT index were significantly correlated with T4-staging and showed positive for M2-macrophage index. Furthermore, our mouse model and in vitro co-culture experiments revealed that HSP90α secreted by EndoMT cells was able to induce macrophage M2-polarization and more HSP90α secretion to promote PDAC tumor growth. Anti-HSP90α antibody exhibited a potent therapeutic efficacy against the EndoMT-promoted and M2-macrophage-involved PDAC tumor.