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Background Resistance to standard therapy is a major reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Developing novel therapy to overcome PDAC drug-resistance is urgently needed. CRABP-II was highly expressed in all PDAC but not expressed in normal pancreatic tissues and chronic pancreatitis. CRABP-II was shown to promote PDAC migration and metastasis while its potential role in promoting PDAC drug-resistance was not known. Methods A paired cohort of human primary and relapsing PDAC tissues was assessed for CRABP-II expression by immunohistochemistry. CRISPR/cas9 gene editing was used to establish CRABP-II knockout cell lines and MTT assays were performed to assess gemcitabine sensitivity in vitro. Cleaved caspase-3/PARP blots and Annexin V staining were conducted to detect cell apoptosis. Gene expression microarray, Q-PCR, western blots, Co-IP and RNA-IP were used to study the molecular function of CRABP-II. Sucrose gradient ultracentrifugation was applied to isolate lipid rafts and LC–MS-MS was used to assess cholesterol content. Both subcutaneous CDX models and orthotopic PDX models were established to examine the efficacy of SNIPER-11 and the synergistic effect between SNIPER-11 and gemcitabine in vivo. Results A higher expression of CRABP-II was found in relapsing PDAC tissue and was associated with poor prognosis. Gemcitabine-resistant cell lines exhibited increased level of CRABP-II, while CRABP-II knockout resensitized PDAC cells to gemcitabine. Mechanistically, aberrant expression of CRABP-II increased the stability of SREBP-1c mRNA through cooperation with HuR and upregulated the downstream genes of SREBP-1c to favor cholesterol uptake and accumulation in lipid rafts. Increased lipid raft cholesterol accumulation facilitated ATK survival signaling and PDAC drug resistance. The small compound SNIPER-11 treatment effectively induced CRABP-II protein degradation, induced apoptosis, and suppressed tumor growth. Combination of SNIPER-11 and gemcitabine significantly reduced the lipid raft cholesterol content in CDX/PDX and profoundly inhibited tumor progression. Conclusions These findings identified CRABP-II as a novel regulator of cholesterol metabolism and suggested that CRABP-II is a selective target for overcoming PDAC drug resistance.

IL-33 is a new member of the IL-1 cytokine family known to promote, epithelial hyperplasia, most prominently for goblet cells, within the GI and airway mucosa and has been linked to several autoimmune and inflammatory disorders, including inflammatory bowel disease (IBD). Emerging evidence suggests that IL-33 is important in the development of GI-related cancers, including gastric cancer. We characterized the features and mechanisms of chronic gastritis in SAMP1/YitFc (SAMP) mice, a spontaneous model of Crohn's Disease-like ileitis, in which gastritis develops spontaneously and IL-33 is up-regulated. Loss of parietal cells in the stomach causes the development of spasmolytic polypeptide-expressing metaplasia (SPEM) through transdifferentiation of chief cells. In the presence of inflammation, SPEM can advance into a more proliferative metaplasia with increased expression of intestine-specific transcripts. In this context, IL-33 represents an ideal candidate cytokine that may be critical in promoting the gastritis-metaplasia-carcinoma sequence due to its ability to potently stimulate epithelial proliferation and metaplasia.MethodsFour and-20-week-old SAMP and age-matched AKR/J (AKR) parental strain control were used to evaluate baseline SPEM and progression to intestinalized SPEM. For IL-33 administration experiments, 8-week-old AKR were injected i.p. (33 μg/kg, daily for 1 wk) with either murine rIL-33 or PBS (vehicle controls) and then euthanized for tissue collection.ResultsIn SAMP Alcian Blue/PAS staining showed an increased intense blue staining along the body and at the base of corpus glands, indicating the presence of acid mucins which are commonly found in gastric metaplasia and gastric adenocarcinoma. Furthermore, evaluation of full-thickness corpus tissues for expression of markers of normal gastric homeostasis, Gif, Atp4a, and Tff1, showed a striking decrease in 20-week-old SAMP versus age-matched AKR. Moreover, SPEM (He4 and Clu), as well as intestinalized SPEM (Dmbt1 and Cftr) markers were dramatically increased in 20-week-old SAMP versus age-matched AKR. After IL-33 administration to AKR mice the stomach developed thickened gastric mucosal folds, which were absent in vehicle-treated mice. Histologic evaluation of these folds revealed overall hypertrophy of the gastric mucosa, epithelial hyperplasia, as well as oxyntic and chief cell atrophy. Vehicle-treated AKR instead showed healthy stomach morphology, with normal presence and localization of parietal and chief cells. The emergence of prominent hyperplastic mucus neck cells was detected in IL-33-treated AKR and appeared deep blue upon alcian blue/PAS staining, but were absent in vehicle-treated mice. Consistent with parietal cell loss, expression of Gif and Atp4a was potently downregulated in whole corpus tissues from IL-33-treated AKR, and Tff1 showed a similar trend towards decreased expression. He4 and Clu were consistently upregulated after IL-33, however, only Cftr was considerably increased for the intestinalized SPEM markers assayed. The presence of SPEM in IL-33-treated AKR was further characterized by prominent proliferation of cells within the gastric glands, demonstrated by a greater number of BrdU+ cells present along the neck and at the base of the glands, and by increased epithelial hyperplasia.ConclusionsTaken together, our data suggest that IL-33 may play an important role in the early events leading to intestinalized gastric metaplasia by promoting epithelial proliferation in the stomach of gastritis-prone SAMP mice.

The endoplasmic reticulum unfolded protein response (UPR) is a conserved adaptive signaling in ER homeostasis and has emerged as critical in highly proliferating cells and potential treatment target for acute T-cell lymphoblastic leukemia (T-ALL). in this study, we assessed the transcriptomic and phenotypic alterations in UPR response of the bone marrow endothelial cells (ECs) in mice engrafted with T-ALL and in bone marrow specimens from patients who have T-ALL. We used PERK inhibitor and generated endothelial specific PERK knockout mice to study the impact of PERK on leukemia progression and hematopoiesis. We performed chromatin immunoprecipitation (ChIP) to study the mechanistic regulation of JAG1 by ATF4. We characterized small extracellular vesicles (SEV) from leukemia-developing mice and studied the effect of SEVs on EC function. we found that T-ALL development induced a robust activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dominant UPR in the bone marrow endothelial vascular niche. The activation of PERK-eIF2a-ATF4 axis remodels the vascular niche, upregulates angiogenic factors including VEGFα and ATF4-regulated JAG1, and suppresses the expression of SCF and CXCL12, which are important to HSC maintenance and regeneration. Further, targeting endothelial PERK significantly improved T-ALL outcome. EC-specific deletion of PERK abolished the aberrant JAG1 up-regulation, improved HSC maintenance, promoted leukemia apoptosis, and improved overall survival. Finally, we showed that small extracellular vesicles are critical mediators of endothelial PERK-eIF2a-ATF4 activation and JAG1 up-regulation in leukemia. Corroborating animal model studies, activation of PERK-ATF4-JAG1 is prominent in human T-ALL bone marrow and T-ALL xenografts. our studies thus revealed for the first time that the leukemia-initiated PERK-ATF4-JAG1 axis plays a critical role in the remodeling of the bone marrow vascular niche and that targeting vascular niche UPR is a potential therapeutic opportunity in T-ALL.