Cancer-associated fibroblasts (CAFs), which are an important component of the tumor microenvironment, have been identified in the blood circulation of patients with cancer metastasis, and metastatic cancer cells can recruit circulating CAFs. However, primary carcinoma sites usually regulate the behavior of metastatic cancer cells through exosomes. Here, we hypothesized that cancer-derived exosomes could enhance CAF recruitment. Exosomes secreted by pancreatic cancer cells (PANC-1 and MIA PaCa-2) were isolated and characterized. The ability of pancreatic cancer to recruit pancreatic stellate cells (PSCs) was assessed with Transwell assays in vitro and bioluminescent imaging in a mouse model in vivo , and the underlying molecular mechanism was also investigated. The results showed that pancreatic cancer cell-derived exosomes (Exo-Pan and Exo-Mia) promoted the pancreatic cancer recruitment of PSCs. This effect was mediated partially by the transfer of the exosomal protein Lin28B to the recipient cells to activate the Lin28B/let-7/HMGA2/PDGFB signaling pathway. These results suggested that exosomes derived from local cancer could promote the formation of distant metastases through transferring the exosomal protein Lin28B to the metastatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and its dismal prognosis indicates the urgent need to elucidate the potential oncogenic mechanisms. SIRT7 is a classic NAD+-dependent deacetylase that stabilizes the transformed state of cancer cells. However, its functional roles in PDAC are still unclear. Here, we found that SIRT7 expression is upregulated and predicts poor prognosis in PDAC. Then we screened the new interacting proteins of SIRT7 by mass spectrometry and the results showed that SIRT7 can interact with O-GlcNAc transferase (OGT). O-GlcNAcylation stabilizes the SIRT7 protein by inhibiting its interaction with REGγ to prevent degradation, and hyper-O-GlcNAcylation in pancreatic cancer cells leads to hypoacetylation of H3K18 via SIRT7, which promotes transcriptional repression of several tumour suppressor genes. In addition, SIRT7 O-GlcNAcylation at the serine 136 residue (S136) is required to maintain its protein stability and deacetylation ability. In vivo and in vitro experiments showed that blocking SIRT7 O-GlcNAcylation at S136 attenuates tumour progression. Collectively, we demonstrate that O-GlcNAcylation is an important post-translational modification of SIRT7 in pancreatic cancer cells, and elucidating this mechanism of SIRT7 is expected to pave the way for the development of novel therapeutic methods in the future.

Background Pancreatic cancer is a highly malignant tumor of the digestive system. Early pancreatic cancer is often difficult to diagnosis due to its atypical clinical symptoms. Patients with pancreatic cancer have a very poor prognosis because they have lost the opportunity for radical surgical tumor resection and they are less sensitive to the clinically used radiotherapy and chemotherapy. Methods In this study, a peptide targeting pancreatic cancer cells was screened by phage display technology, and its targeting property was evaluated in vitro using PANC1 cells by fluorescence imaging and flow cytometry. Furthermore, the targeting peptide was conjugated to the pro-apoptotic KLAKLAKKLAKLAK (KLA), the fusion peptide and its targeting ability that allowing KLA to specifically enter pancreatic tumor cells in vitro and in vivo was confirmed by fluorescence imaging and in vivo imaging system (IVIS). Its mechanism was determined using flow cytometry, mitochondrial membrane potential evaluation and Western blot. The inhibitory effect on pancreatic tumor growth and toxic effects were evaluated by animal experiment. Results Due to the internalization facilitated by the targeting mechanism of the targeting peptide, KLA specifically entered pancreatic cancer cells, destroyed mitochondria and induced apoptosis. The fusion peptide and its targeting ability that allowing KLA to specifically enter pancreatic tumor cells and exert a significant inhibitory effect on pancreatic tumor growth with reduced toxic effects. Conclusion This approach possesses potential advantages in the clinical diagnosis and treatment of pancreatic cancer.

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