Survival outcomes of adjuvant chemotherapy in patients with stage I pancreatic cancer stratified by pathologic risk.

BACKGROUND: This study aimed to evaluate the impact of adjuvant chemotherapy on survival in patients with stage I pancreatic ductal adenocarcinoma, stratified according to pathologic risk factors. METHODS: A total of 259 patients with stage I pancreatic ductal adenocarcinoma who underwent radical resection were retrospectively analyzed. The patients were categorized into groups with and without pathologic risk based on the presence of perineural and/or lymphovascular invasion. Subset Kaplan-Meier survival and multivariate analyses were performed to determine the recurrence-free survival and overall survival. RESULTS: Adjuvant chemotherapy did not significantly prolong recurrence-free survival (P = .213) but increased overall survival (P = .019) in patients with stage I pancreatic ductal adenocarcinoma. In subgroup analysis, adjuvant chemotherapy significantly improved recurrence-free survival (P = .037) and overall survival (P = .007) in patients with pathologic risk (n = 160). However, patients without pathologic risk (n = 99) showed no enhancement of recurrence-free survival (P = .870) and overall survival (P = .413) after adjuvant chemotherapy. Subset multivariate analyses indicated that adjuvant chemotherapy was an independent favorable prognostic factor in patients with pathologic risk but not in those without pathologic risk. CONCLUSION: Adjuvant chemotherapy for stage I pancreatic ductal adenocarcinoma may provide survival benefits specifically to patients with pathologic risk.

CD64+ fibroblast-targeted vilanterol and a STING agonist augment CLDN18.2 BiTEs efficacy against pancreatic cancer by reducing desmoplasia and enriching stem-like CD8+ T cells.

OBJECTIVE: The objective of this study is to improve the efficacy of CLDN18.2/CD3 bispecific T-cell engagers (BiTEs) as a promising immunotherapy against pancreatic ductal adenocarcinoma (PDAC). DESIGN: Humanised hCD34+/hCD3e+, Trp53R172HKrasG12DPdx1-Cre (KPC), pancreas-specific Cldn18.2 knockout (KO), fibroblast-specific Fcgr1 KO and patient-derived xenograft/organoid mouse models were constructed. Flow cytometry, Masson staining, Cell Titer Glo assay, virtual drug screening, molecular docking and chromatin immunoprecipitation were conducted. RESULTS: CLDN18.2 BiTEs effectively inhibited early tumour growth, but late-stage efficacy was significantly diminished. Mechanically, the Fc fragment of BiTEs interacted with CD64+ cancer-associated fibroblasts (CAFs) via activation of the SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A-α-SMA/collagen-I pathway, which enhanced desmoplasia and limited late-stage infiltration of T cells. Molecular docking analysis found that vilanterol suppressed BiTEs-induced phosphorylation of VAV2 (Y172) in CD64+ CAFs and weakened desmoplasia. Additionally, decreased cyclic guanosine-adenosine monophosphate synthase/stimulator of interferon genes (STING) activity reduced proliferation of TCF-1+PD-1+ stem-like CD8+ T cells, which limited late-stage effects of BiTEs. Finally, vilanterol and the STING agonist synergistically boosted the efficacy of BiTEs by inhibiting the activation of CD64+ CAFs and enriching proliferation of stem-like CD8+ T cells, resulting in sustained anti-tumour activity. CONCLUSION: Vilanterol plus the STING agonist sensitised PDAC to CLDN18.2 BiTEs and augmented efficacy as a potential novel strategy.

BICC1 drives pancreatic cancer stemness and chemoresistance by facilitating tryptophan metabolism.

Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD+ synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.

Targeting ESE3/EHF With Nifurtimox Inhibits CXCR2+ Neutrophil Infiltration and Overcomes Pancreatic Cancer Resistance to Chemotherapy and Immunotherapy.

BACKGROUND & AIMS: Because pancreatic cancer responds poorly to chemotherapy and immunotherapy, it is necessary to identify novel targets and compounds to overcome resistance to treatment. METHODS: This study analyzed genomic single nucleotide polymorphism sequencing, single-cell RNA sequencing, and spatial transcriptomics. Ehf-knockout mice, KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx1-Cre) mice, CD45.1+ BALB/C nude mice, and CD34+ humanized mice were also used as subjects. Multiplexed immunohistochemistry and flow cytometry were performed to investigate the proportion of tumor-infiltrated C-X-C motif chemokine receptor 2 (CXCR2)+ neutrophils. In addition, multiplexed cytokines assays and chromatin immunoprecipitation assays were used to examine the mechanism. RESULTS: The TP53 mutation-mediated loss of tumoral EHF increased the recruitment of CXCR2+ neutrophils, modulated their spatial distribution, and further induced chemo- and immunotherapy resistance in clinical cohorts and preclinical syngeneic mice models. Mechanistically, EHF deficiency induced C-X-C motif chemokine ligand 1 (CXCL1) transcription to enhance in vitro and in vivo CXCR2+ neutrophils migration. Moreover, CXCL1 or CXCR2 blockade completely abolished the effect, indicating that EHF regulated CXCR2+ neutrophils migration in a CXCL1-CXCR2-dependent manner. The depletion of CXCR2+ neutrophils also blocked the in vivo effects of EHF deficiency on chemotherapy and immunotherapy resistance. The single-cell RNA-sequencing results of PDAC treated with Nifurtimox highlighted the therapeutic significance of Nifurtimox by elevating the expression of tumoral EHF and decreasing the weightage of CXCL1-CXCR2 pathway within the microenvironment. Importantly, by simultaneously inhibiting the JAK1/STAT1 pathway, it could significantly suppress the recruitment and function of CXCR2+ neutrophils, further sensitizing PDAC to chemotherapy and immunotherapies. CONCLUSIONS: The study demonstrated the role of EHF in the recruitment of CXCR2+ neutrophils and the promising role of Nifurtimox in sensitizing pancreatic cancer to chemotherapy and immunotherapy.

Tumor-derived interleukin 35 mediates the dissemination of gemcitabine resistance in pancreatic adenocarcinoma.

Rapid development of drug resistance after chemotherapy is a major cause of treatment failure in individuals with pancreatic ductal adenocarcinoma (PDAC). In this study, we illustrate that tumor-derived interleukin 35 (IL-35) mediates the accelerated resistance of PDAC to gemcitabine (GEM). We observe that GEM resistance can spread from GEM-resistant PDAC cells to GEM-sensitive cells, and that IL-35 is responsible for the propagation of chemoresistance, which is supported by sequencing and experimental data. Additionally, we discover that GEM-resistant cells have significantly higher levels of IL-35 expression. Mechanistically, aberrantly expressed IL-35 triggers transcriptional activation of SOD2 expression via GP130-STAT1 signaling, scavenging reactive oxygen species (ROS) and leading to GEM resistance. Furthermore, GEM treatment stimulates IL-35 expression through activation of the NF-κB pathway, resulting in acquired chemoresistance. In the mouse model, a neutralizing antibody against IL-35 enhances the tumor suppressive effect of GEM. Collectively, our data suggests that IL-35 is critical in mediating GEM resistance in pancreatic cancer, and therefore could be a valuable therapeutic target in overcoming PDAC chemoresistance.

Comparison of adjuvant nab-paclitaxel plus gemcitabine, S-1 and gemcitabine chemotherapy for resectable pancreatic cancer: a real-world study.

Background: A survival benefit has been seen for both adjuvant nab-paclitaxel plus gemcitabine (AG) and S-1 chemotherapy compared to gemcitabine (GEM) for resectable pancreatic cancer in the APACT (2019) and JASPAC01 trials (2016), respectively. However, supporting evidence regarding the effectiveness of AG or S-1 compared to gemcitabine in real-world clinical practice remains lacking. Methods: Our study included all 246 pancreatic cancer patients who underwent surgical treatment and received postoperative adjuvant chemotherapy with AG, S-1, or GEM except for those meeting exclusion criteria (R2 resection, neoadjuvant therapy, or synchronous malignancy) at Tianjin Medical University Cancer Institute and Hospital from June 2015 to July 2021. The primary outcome was overall survival (OS) and recurrence-free survival (RFS). Results: In total, 246 patients were included, of whom 54(22%) received adjuvant AG, 103(41%) received adjuvant S-1, and 89(37%) received adjuvant GEM. Adjuvant S-1 was associated with a prolonged OS compared to GEM (median OS S-1 vs GEM: 27.0 vs 20.0 months; HR: 0.65, P = .016) and a significantly prolonged RFS compared to GEM (median RFS S-1 vs GEM: 20.0 vs 8.2 months; HR: 0.58, P = .002). After adjusting for known prognostic factors in multivariate Cox regression analysis, this survival benefit persists and is consistent in most subgroups in our subgroup analysis. However, no statistically significant differences in OS or RFS were seen between patients treated with AG and patients treated with GEM. Conclusions: In this retrospective real-world study, adjuvant S-1 chemotherapy was associated with improved survival compared to GEM while no differences in OS or RFS were observed for AG compared to GEM.

Nuclear GRP78 Promotes Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma.

PURPOSE: Stromal fibrosis limits nutritional supply and disarrays metabolism in pancreatic cancer (PDA, pancreatic ductal adenocarcinoma). Understanding of the molecular basis underlying metabolic cues would improve PDA management. The current study determined the interaction between glucose-regulated proteins 78 (GRP78) and hypoxia-inducible factor 1α (HIF-1α) and its mechanistic roles underlying PDA response to oxygen and glucose restrains. EXPERIMENTAL DESIGN: Gene expression and its association with clinicopathologic characteristics of patients with PDA and mouse models were analyzed using IHC. Protein expression and their regulation were measured by Western blot and immunoprecipitation analyses. Protein interactions were determined using gain- and loss-of-function assays and molecular methods, including chromatin immunoprecipitation, co-immunoprecipitation, and dual luciferase reporter. RESULTS: There was concomitant overexpression of both GRP78 and HIF-1α in human and mouse PDA tissues and cells. Glucose deprivation increased the expression of GRP78 and HIF-1α, particularly colocalization in nucleus. Induction of HIF-1α expression by glucose deprivation in PDA cells depended on the expression of and its own interaction with GRP78. Mechanistically, increased expression of both HIF-1α and LDHA under glucose deprivation was caused by the direct binding of GRP78 and HIF-1α protein complexes to the promoters of HIF-1α and LDHA genes and transactivation of their transcriptional activity. CONCLUSIONS: Protein complex of GRP78 and HIF-1α directly binds to HIF-1α own promoter and LDHA promoter, enhances the transcription of both HIF-1α and LDHA, whereas glucose deprivation increases GRP78 expression and further enhances HIF-1α and LDHA transcription. Therefore, crosstalk and integration of hypoxia- and hypoglycemia-responsive signaling critically impact PDA metabolic reprogramming and therapeutic resistance.

Biological risk based on preoperative serum CA19-9 and histological grade predicts prognosis and improves accuracy of classification in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Carbohydrate antigen (CA) 19-9 and histological grade can serve as indicators of the biological characteristics of pancreatic ductal adenocarcinoma (PDAC). AIMS: The aim of this study was to investigate the combined impact of preoperative CA19-9 levels and histological grade on prognosis and classification accuracy in PDAC patients. METHODS AND RESULTS: A retrospective cohort study was conducted on 612 patients with PDAC who underwent curative pancreatectomy, and a biological risk model based on preoperative CA19-9 levels and histology grade was established. The prognostic importance of the biological risk model was evaluated, and its validity was confirmed through a validation cohort of 218 patients. The survival of patients with PDAC was independently associated with preoperative CA19-9 levels and histology grade, indicating a biological risk. This biological risk was incorporated into the eighth edition of the TNM staging system, leading to the development of a modified TNM (mTNM) staging system. Receiver operating characteristic (ROC) curves demonstrated that the mTNM staging system had a significantly larger area under the curve (AUC) than the TNM staging system. The discriminatory capacity of the mTNM staging system was further validated in an independent cohort. CONCLUSION: Biological risk based on preoperative CA19-9 and histological grade could predict the survival of patients with PDAC. The incorporation of biological risk into the TNM staging system has the potential to enhance the accuracy of patient classification in PDAC, predicting patient survival and enabling the development of individualized treatment plans.

BICC1 drives pancreatic cancer progression by inducing VEGF-independent angiogenesis.

VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner. Mechanistically, as an RNA binding protein, BICC1 bounds to the 3'UTR of Lipocalin-2 (LCN2) mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells. When its level is elevated, LCN2 binds to its receptor 24p3R, which directly phosphorylates JAK2 and activates JAK2/STAT3 signal, leading to increased production of an angiogenic factor CXCL1. Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice, and increased the tumor suppressive effect of gemcitabine. In conclusion, BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer, leading to resistance to VEGF inhibitors. BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.

Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%. Of PDAC patients, 15%-20% are eligible for radical surgery. Gemcitabine is an important chemotherapeutic agent for patients with PDAC; however, the efficacy of gemcitabine is limited due to resistance. Therefore, reducing gemcitabine resistance is essential for improving survival of patients with PDAC. Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC. METHODS: We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment. Then, co-IP, ChIP, ChIP-seq, transcriptome sequencing, and qPCR were used to determine the specific mechanism by which phospholipase D1 (PLD1) confers resistance to gemcitabine. RESULTS: PLD1 combines with nucleophosmin 1 (NPM1) and triggers NPM1 nuclear translocation, where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor (IL7R) expression. Upon interleukin 7 (IL-7) binding, IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein, BCL-2, and induce gemcitabine resistance. The PLD1 inhibitor, Vu0155069, targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells. CONCLUSIONS: PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1, further promoting the downstream JAK1/STAT5/Bcl-2 pathway. Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.

Survival outcomes of neoadjuvant therapy followed by radical resection versus upfront surgery for stage I-III pancreatic ductal adenocarcinoma: a retrospective cohort study.

BACKGROUND: Neoadjuvant therapy remains controversial in treating resectable pancreatic ductal adenocarcinoma (PDAC) patients. This study aims to assess the impact of neoadjuvant therapy on survival in patients with PDAC according to their clinical stage. METHODS: Patients with resected clinical Stage I-III PDAC from 2010 to 2019 were identified in the surveillance, epidemiology, and end results database. A propensity score matching method was utilized within each stage to reduce potential selection bias between patients who underwent neoadjuvant chemotherapy followed by surgery and patients who underwent upfront surgery. An overall survival (OS) analysis was performed using the Kaplan-Meier method and a multivariate Cox proportional hazards model. RESULTS: A total of 13 674 patients were included in the study. The majority of the patients ( N =10 715, 78.4%) underwent upfront surgery. Patients receiving neoadjuvant therapy followed by surgery had significantly longer OS than those with upfront surgery. Subgroup analysis revealed that the neoadjuvant chemoradiotherapy group's OS is comparable to neoadjuvant chemotherapy. In clinical Stage IA PDAC, there was no difference in survival between the neoadjuvant treatment and upfront surgery groups before or after matching. In stage IB-III patients, neoadjuvant therapy followed by surgery improved OS before and after matching compared to upfront surgery. The results revealed the same OS benefits using the multivariate Cox proportional hazards model. CONCLUSION: Neoadjuvant therapy followed by surgery could improve OS over upfront surgery in Stage IB-III PDAC but did not provide a significant survival advantage in Stage IA PDAC.

Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis.

BACKGROUND: Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. METHODS: We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. RESULTS: High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy. CONCLUSIONS: Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

Retraction notice to "HIF-1α mediates tumor-nerve interactions through the up-regulation of GM-CSF in pancreatic ductal adenocarcinoma" [Cancer Lett. 453 (2019) 10-20].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief and Authors. Following concerns raised in the public domain, the authors contacted the journal to request the retraction of the article. Sections of panels from various figures appear similar to each other, particularly panels from Figs. 3G, 5B and 3G and 5F, 3F, S4D, S5D, S5C and S10C, as well as S10E.

Long-term exposure to genistein inhibits the proliferation of gallbladder cancer by downregulating the MCM complex.

Soy isoflavones are natural tyrosine kinase inhibitors closely associated with decreased morbidity and mortality of various tumors. The activation of tyrosine kinases such as ERBB2 is the mechanism by which cholecystitis transforms into gallbladder cancer (GBC), therefore, it is important to investigate the relationship between long-term exposure to soy isoflavones and the occurrence and progression of GBC. This case-control study (n = 85 pairs) found that the high level of plasma soy isoflavone-genistein (GEN) was associated with a lower risk of gallbladder cancer (≥326.00 ng/mL compared to ≤19.30 ng/mL, crude odds ratio 0.15, 95% CI 0.04-0.59; P for trend = 0.016), and that the level of GEN exposure negatively correlated with Ki67 expression in GBC tissue (n = 85). Consistent with these results, the proliferation of GBC cells was inhibited in the long-term exposure models of GEN in vitro and in vivo. The long-term exposure to GEN reduced the tyrosine kinase activity of ERBB2 and impaired the function of the PTK6-AKT-GSK3ß axis, leading to downregulation of the MCM complex in GBC cells. In summary, long-term exposure to GEN associated with soy products intake might play a certain role in preventing GBC and even inhibiting the proliferation of GBC cells.

Preoperative ultrasound combined with routine blood tests in predicting the malignant risk of pancreatic cystic neoplasms.

OBJECTIVE: Accurate preoperative identification of benign or malignant pancreatic cystic neoplasms (PCN) may help clinicians make better intervention choices and will be essential for individualized treatment. METHODS: Preoperative ultrasound and laboratory examination findings, and demographic characteristics were collected from patients. Multiple logistic regression was used to identify independent risk factors associated with malignant PCN, which were then included in the nomogram and validated with an external cohort. The Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI) were calculated to evaluate the improvement in the predictive power of the new model with respect to that of a combined imaging and tumor marker prediction model. RESULTS: Malignant PCN were found in 83 (40.7%) and 33 (38.7%) of the model and validation cohorts, respectively. Multivariate analysis identified age, tumor location, imaging of tumor boundary, blood type, mean hemoglobin concentration, neutrophil-to-lymphocyte ratio, carbohydrate antigen 19-9, and carcinoembryonic antigen as independent risk factors for malignant PCN. The calibration curve indicated that the predictions based on the nomogram were in excellent agreement with the actual observations. A nomogram score cutoff of 192.5 classified patients as having low vs. high risk of malignant PCN. The model achieved good C-statistics of 0.929 (95% CI 0.890-0.968, P < 0.05) and 0.951 (95% CI 0.903-0.998, P < 0.05) in predicting malignancy in the development and validation cohorts, respectively. NRI = 0.268; IDI = 0.271 (P < 0.001 for improvement). The DCA curve indicated that our model yielded greater clinical benefits than the comparator model. CONCLUSIONS: The nomogram showed excellent performance in predicting malignant PCN and may help surgeons select patients for detailed examination and surgery. The nomogram is freely available at https://wangjunjinnomogram.shinyapps.io/DynNomapp/.

ESE3-positive PSCs drive pancreatic cancer fibrosis, chemoresistance and poor prognosis via tumour-stromal IL-1ß/NF-κB/ESE3 signalling axis.

BACKGROUND: Desmoplastic stroma, a feature of pancreatic ductal adenocarcinoma (PDAC), contains abundant activated pancreatic stellate cells (PSCs). How PSCs promote PDAC progression remains incompletely understood. METHODS: Effect of epithelium-specific E-twenty six factor 3 (ESE3)-positive PSCs on PDAC fibrosis and chemoresistance was examined by western blot, RT-PCR, immunofluorescence, flow cytometry assay, chromatin immunoprecipitation, luciferase assay, immunohistochemistry and subcutaneous pancreatic cancer mouse model. RESULTS: ESE3 expression increased in PSCs in PDAC tissues compared with those in normal PSCs. Clinical data showed that ESE3 upregulation in PSCs was positively correlated with tumour size, pTNM stage, CA19-9, carcinoembryonic antigen and serum CA242 level. ESE3 overexpression in PSCs was an independent negative prognostic factor for disease-free survival and overall survival amongst patients with PDAC. Mechanistically, the conditional medium from the loss and gain of ESE3-expressing PSCs influenced PDAC chemoresistance and tumour growth. ESE3 directly induced the transcription of α-SMA, collagen-I and IL-1ß by binding to ESE3-binding sites on their promoters to activate PSCs. IL-1ß upregulated ESE3 in PSCs through NF-κB activation, and ESE3 was required for PSC activation by tumour cell-derived IL-1ß. CONCLUSION: Inhibiting the IL-1ß/ESE3 (PSCs)/IL-1ß-positive feedback loop is a promising therapeutic strategy to reduce tumour fibrosis and increase chemotherapeutic efficacy in PDAC.

Genome-wide CRISPR screen identifies MTA3 as an inducer of gemcitabine resistance in pancreatic ductal adenocarcinoma.

Gemcitabine (GEM) resistance is one of the major causes of treatment failure in pancreatic ductal adenocarcinoma (PDAC) in clinic. Here, through CRISPR/Cas9 activation library screen, we found that MTA3 mediates the GEM resistance of PDAC and thus might be a potential therapeutic target for combination chemotherapy. The CRISPR library screening showed that MTA3 is the most enriched gene in the surviving GEM-treated cells, and bioinformatic and histology analysis implied its high correlation with GEM resistance. MTA3 promoted GEM resistance of PDAC cells in in vitro and in vivo experiments. Mechanistically, as a component of the Mi-2/nucleosome remodeling and deacetylase transcriptional repression complex, MTA3 transcriptionally represses CRIP2, a transcriptional repressor of NF-κB/p65, activating NF-κB signaling and consequently leading to GEM resistance. Furthermore, the treatment of GEM increases MTA3 expression in PDAC cells via activating STAT3 signaling, thereby inducing the acquired chemoresistance of PDAC to GEM. In patients derived xenografts (PDX) mouse model, Colchicine suppresses the expression of MTA3 and increases the sensitivity of tumor cells to GEM. Based on these findings, MTA3 plays a key role in GEM resistance in pancreatic cancer and is a promising therapeutic target for reversing GEM chemotherapy resistance.

An Integrative Pan-Cancer Analysis Revealing MLN4924 (Pevonedistat) as a Potential Therapeutic Agent Targeting Skp2 in YAP-Driven Cancers.

Background: YAP, coded by YAP1 gene, is critical in the Hippo pathway. It has been reported to be involved in the tumorigenesis and progression of several cancers. However, its roles on tumor cell proliferation in diverse cancers remain to be elucidated. And there is currently no clinically feasible drug that can directly target YAP in cancers. This research aimed to explore the regulatory mechanism of YAP in promoting tumor proliferation of multiple cancers, in order to find new strategies for inhibiting the overgrowth of YAP-driven cancers. Methods: We investigated the expression pattern of YAP1 in pan-cancer across numerous databases and our cohorts. First, univariate Cox regression analysis and survival analysis were used to evaluate the effect of YAP1 on the prognosis of cancer patients. Second, TIMER was used to explore the relationship between YAP1 expression and tumor cell proliferation. Third, functional and pathway enrichment was performed to search for targets of YAP involved in cell cycle in cancers. At last, GDSC and CCLE datasets were used to assess the correlation between SKP2 expression and MLN4924 IC50 values. Results: Differential expression analysis of multiple databases and qPCR validation showed that YAP1 was generally overexpressed in pan-cancers. Survival analysis revealed that YAP1 over-expression was significantly related to poor prognosis of patients with PAAD. The expression level of YAP1 was positively correlated with the proliferation in varieties of tumors. Further, SKP2 was confirmed as a target of YAP in promoting tumor cell proliferation. In addition, SKP2 expression was negatively correlated with MLN4924 IC50 values in almost all cancer types. Conclusion: YAP1 is frequently overexpressed in human cancers. YAP promoted tumor cell proliferation by up-regulating SKP2 expression in multiple cancers. The comprehensive pan-cancer analysis suggested that inhibition of Skp2 with MLN4924 might be an effective therapeutic strategy for attenuating tumor cell proliferation in YAP-driven cancers.

Perioperative Serum Scoring Systems Predict Early Recurrence and Poor Prognosis of Resectable Pancreatic Cancer.

Objective: Some patients with pancreatic ductal adenocarcinoma (PDAC) are prone to rapid recurrence or metastasis after radical resection. However, evaluation methods for effectively identifying these patients are lacking. In this study, we established perioperative serum scoring systems to screen patients with early recurrence and poor prognosis. Methods: We systematically analysed 44 perioperative serum parameters, including systemic inflammatory parameters, coagulation system parameters, tumor markers, and 18 clinicopathological characteristics of 218 patients with radical resection in our centre. Univariate Cox regression and LASSO regression models were used to screen variables. Kaplan-Meier survival analysis was used to compare relapse-free survival and overall survival. Multivariate Cox regression was used to evaluate the independent risk variables. AUC and C-index were used to reveal the effectiveness of the models. In addition, the effectiveness was also verified in an independent cohort of 109 patients. Results: Preoperative systemic immune coagulation cascade (SICC) (including increased neutrophil to lymphocyte ratio, decreased lymphocyte to monocyte ratio, increased platelet and fibrinogen) and increased postoperative tumor markers (TMs) (CA199, CEA and CA242) were independent risk factors for early recurrence of resectable pancreatic cancer. On this basis, we established the preoperative SICC score and postoperative TMs score models. The patients with higher preoperative SICC or postoperative TMs score were more likely to have early relapse and worse prognosis. The nomogram based on preoperative SICC, postoperative TMs, CACI, smoking index, vascular cancer embolus and adjuvant chemotherapy can effectively evaluate the recurrence rate (AUC1 year: 0.763, AUC2 year: 0.679, AUC3 year: 0.657) and overall survival rate (AUC1 year: 0.770, AUC3 year: 0.804, AUC5 year: 0.763). Conclusion: Preoperative SICC and postoperative TMs can help identify resectable PDAC patients with early recurrence and poor prognosis.