Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis

• Published in: Journal of experimental & clinical cancer research Vol. 38; no. 1; p. 221
• Main Authors: Yan, Zilong, Ohuchida, Kenoki, Fei, Shuang, Zheng, Biao, Guan, Weiyu, Feng, Haimin, Kibe, Shin, Ando, Yohei, Koikawa, Kazuhiro, Abe, Toshiya, Iwamoto, Chika, Shindo, Koji, Moriyama, Taiki, Nakata, Kohei, Miyasaka, Yoshihiro, Ohtsuka, Takao, Mizumoto, Kazuhiro, Hashizume, Makoto, Nakamura, Masafumi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.05.2019; BioMed Central; BMC
• Subjects: Autophagy; Breast cancer; Cancer cells; Cancer metastasis; Cancer prevention; Cancer–stromal interaction; Cell cycle; Cell differentiation; Cell growth; Cellular senescence; Colorectal cancer; Diagnosis; ERK1/2; Fibroblasts; Growth factors; Internet; Kinases; Liver; Liver cancer; Lung cancer; Medical prognosis; Metastasis; Pancreatic cancer; Pancreatic stellate cell; Penicillin; R&D; Research & development; Risk factors; Senescence; Stem cells; Surgery; Tumors; United States > US; Japan; ERK1/2; Cancer–stromal interaction; Pancreatic cancer; Cellular senescence; Pancreatic stellate cell
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-019-1226-8

Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer-stromal interaction. Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor. Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer-stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model. These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis.