Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

Abstract

S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11‐RAGE‐TPL2‐COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

The Calcium Binding Protein S100A11 and Its Roles in Diseases

“…They therefore suggested that S100A11 be considered as an oncogenic factor (Sobolewski et al, 2020). In these cases, the upregulation of S100A11 significantly promotes the proliferation, migration, and tissue invasion of tumor cells by activating different signal pathways (Meng et al, 2019;Mitsui et al, 2019). A S100A11/ANXA2 complex has also been shown to be able to reseal the plasma membrane if it has become damaged due to the stress of metastatic tissue invasion (Jaiswal et al, 2014;Sobolewski et al, 2020).…”

S100A11 Promotes Glioma Cell Proliferation and Predicts Grade-Correlated Unfavorable Prognosis

“…Several studies have confirmed that S100A11 was upregulated in cancers, such as pancreatic cancer, intrahepatic cholangiocarcinoma and ovarian cancer, involving in the progression of these cancers. 22 - 24 However, individual study suggested the downregulated expression of S100A11 in bladder cancer predicted the worse prognosis, indicating that S100A11 could perform both tumor suppression and promotion effects to influence the proliferation of cancer cells. 7 Whereas, the expression status and the potential role of S100A11 in different grades of glioma have not been fully elucidated.…”

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

“…Moreover, the TPL2-ERK1/2 signaling pathway can induce metastasis by activating the transcription factor ETS translocation variant 4 (ETV4) that induces the expression of matrix metalloproteinase-25 (MMP25) 64 . MMP25 is a membrane-anchored matrix metalloproteinase that plays a vital role in the onset of tumor dissemination and the induction of the COX2/PGE2 signaling pathway 64 , 65 . Clinical samples from cancer patients further confirm the connection between TPL2 and metastasis.…”

“…The tumor microenvironment in mature tumors is characterized by a heterogeneous group of activated fibroblasts known as cancer-associated fibroblasts (CAFs) that interact with cancer cells and other stromal cells to propagate tumor growth and disease progression 44 , 87 . The TPL2 activity is implicated in CAFs activation, where it sustains the pro-inflammatory transcriptional signature that contributes to tumor progression and metastasis 25 , 65 . Despite its essential role in the production of inflammatory factors, TPL2 loss in CAFs was reported to promote NF-κB activation, inflammation and tumorigenesis 88 .…”