EAES/SAGES evidence-based recommendations and expert consensus on optimization of perioperative care in older adults.

BACKGROUND: As the population ages, more older adults are presenting for surgery. Age-related declines in physiological reserve and functional capacity can result in frailty and poor outcomes after surgery. Hence, optimizing perioperative care in older patients is imperative. Enhanced Recovery After Surgery (ERAS) pathways and Minimally Invasive Surgery (MIS) may influence surgical outcomes, but current use and impact on older adults patients is unknown. The aim of this study was to provide evidence-based recommendations on perioperative care of older adults undergoing major abdominal surgery. METHODS: Expert consensus determined working definitions for key terms and metrics related to perioperative care. A systematic literature review and meta-analysis was performed using the PubMed, Embase, Cochrane Library, and Clinicaltrials.gov databases for 24 pre-defined key questions in the topic areas of prehabilitation, MIS, and ERAS in major abdominal surgery (colorectal, upper gastrointestinal (UGI), Hernia, and hepatopancreatic biliary (HPB)) to generate evidence-based recommendations following the GRADE methodology. RESULT: Older adults were defined as 65 years and older. Over 20,000 articles were initially retrieved from search parameters. Evidence synthesis was performed across the three topic areas from 172 studies, with meta-analyses conducted for MIS and ERAS topics. The use of MIS and ERAS was recommended for older adult patients particularly when undergoing colorectal surgery. Expert opinion recommended prehabilitation, cessation of smoking and alcohol, and correction of anemia in all colorectal, UGI, Hernia, and HPB procedures in older adults. All recommendations were conditional, with low to very low certainty of evidence, with the exception of ERAS program in colorectal surgery. CONCLUSIONS: MIS and ERAS are recommended in older adults undergoing major abdominal surgery, with evidence supporting use in colorectal surgery. Though expert opinion supported prehabilitation, there is insufficient evidence supporting use. This work has identified evidence gaps for further studies to optimize older adults undergoing major abdominal surgery.

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

Global review of COVID-19 mitigation strategies and their impact on cancer service disruptions.

During the COVID-19 pandemic, countries adopted mitigation strategies to reduce disruptions to cancer services. We reviewed their implementation across health system functions and their impact on cancer diagnosis and care during the pandemic. A systematic search was performed using terms related to cancer and COVID-19. Included studies reported on individuals with cancer or cancer care services, focusing on strategies/programs aimed to reduce delays and disruptions. Extracted data were grouped into four functions (governance, financing, service delivery, and resource generation) and sub-functions of the health system performance assessment framework. We included 30 studies from 16 countries involving 192,233 patients with cancer. Multiple mitigation approaches were implemented, predominantly affecting sub-functions of service delivery to control COVID-19 infection via the suspension of non-urgent cancer care, modified treatment guidelines, and increased telemedicine use in routine cancer care delivery. Resource generation was mainly ensured through adequate workforce supply. However, less emphasis on monitoring or assessing the effectiveness and financing of these strategies was observed. Seventeen studies suggested improved service uptake after mitigation implementation, yet the resulting impact on cancer diagnosis and care has not been established. This review emphasizes the importance of developing effective mitigation strategies across all health system (sub)functions to minimize cancer care service disruptions during crises. Deficiencies were observed in health service delivery (to ensure equity), governance (to monitor and evaluate the implementation of mitigation strategies), and financing. In the wake of future emergencies, implementation research studies that include pre-prepared protocols will be essential to assess mitigation impact across cancer care services.

The Safety and Efficacy of Concurrent Laparoscopic Cholecystectomy during Minimally Invasive Roux-en-Y Gastric Bypass: A Systematic Review.

We conducted a systematic review to examine perioperative outcomes for adults undergoing minimally invasive Roux-en-Y gastric bypass (RYGB) with and without concurrent cholecystectomy (CCE). We reviewed the literature using OVID MEDLINE(R), Embase, Cochrane CENTRAL, Web of Science, and medRxiv and identified studies published between 1946 and May 2023. We identified a total of 2402 studies with 11 included in the final analysis (combined 149,356 patients). Studies suggested increased operative time associated with RYGB-CCE, with mixed results regarding length of stay and rates of bile duct injury. Presently available data is not robust enough to conclude whether minimally invasive RYGB with CCE harms or benefits patients compared to RYGB alone.

SAGES guideline for the diagnosis and treatment of appendicitis.

BACKGROUND: Appendicitis is an extremely common disease with a variety of medical and surgical treatment approaches. A multidisciplinary expert panel was convened to develop evidence-based recommendations to support clinicians and patients in decisions regarding the diagnosis and treatment of appendicitis. METHODS: A systematic review was conducted from 2010 to 2022 to answer 8 key questions relating to the diagnosis of appendicitis, operative or nonoperative management, and specific technical and post-operative issues for appendectomy. The results of this systematic review were then presented to a panel of adult and pediatric surgeons. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. RESULTS: Conditional recommendations were made in favor of uncomplicated and complicated appendicitis being managed operatively, either delayed (>12h) or immediate operation (<12h), either suction and lavage or suction alone, no routine drain placement, treatment with short-term antibiotics postoperatively for complicated appendicitis, and complicated appendicitis previously treated nonoperatively undergoing interval appendectomy. A conditional recommendation signals that the benefits of adhering to a recommendation probably outweigh the harms although it does also indicate uncertainty. CONCLUSIONS: These recommendations should provide guidance with regard to current controversies in appendicitis. The panel also highlighted future research opportunities where the evidence base can be strengthened.

ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.

MIF/NR3C2 Axis Regulates Glucose Metabolism Reprogramming in Pancreatic Cancer through MAPK-ERK and AP-1 Pathways.

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth and progression in PDAC. MIF positively correlates with the HK1 (hexokinase 1), HK2 (hexokinase 2), and LDHA (lactate dehydrogenase) expression and increased pyruvate and lactate production in PDAC patients. Additionally, MIF augments glucose uptake and lactate efflux by upregulating HK1, HK2 and LDHA expression in pancreatic cancer cells in vitro and in mouse models of PDAC. Conversely, a reduction in HK1, HK2, LDHA expression is observed in tumors with high NR3C2 expression in PDAC patients. NR3C2 suppresses HK1, HK2, and LDHA expression, thereby inhibiting glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves the activation of MAPK-ERK signaling pathway, whereas NR3C2 interacts with the activator protein 1 (AP-1) to regulate glycolysis. Our findings reveal an interactive role of the MIF/NR3C2 axis in regulating glucose metabolism supporting tumor growth and progression and may be a potential target for designing novel approaches for improving disease outcome.

Management of symptomatic, asymptomatic, and recurrent hiatal hernia: a systematic review and meta-analysis.

BACKGROUND: The surgical management of hiatal hernia remains controversial. We aimed to compare outcomes of mesh versus no mesh and fundoplication versus no fundoplication in symptomatic patients; surgery versus observation in asymptomatic patients; and redo hernia repair versus conversion to Roux-en-Y reconstruction in recurrent hiatal hernia. METHODS: We searched PubMed, Embase, CINAHL, Cochrane Library and the ClinicalTrials.gov databases between 2000 and 2022 for randomized controlled trials (RCTs), observational studies, and case series (asymptomatic and recurrent hernias). Screening was performed by two trained independent reviewers. Pooled analyses were performed on comparative data. Risk of bias was assessed using the Cochrane Risk of Bias tool and Newcastle Ottawa Scale for randomized and non-randomized studies, respectively. RESULTS: We included 45 studies from 5152 retrieved records. Only six RCTs had low risk of bias. Mesh was associated with a lower recurrence risk (RR = 0.50, 95%CI 0.28, 0.88; I2 = 57%) in observational studies but not RCTs (RR = 0.98, 95%CI 0.47, 2.02; I2 = 34%), and higher total early dysphagia based on five observational studies (RR = 1.44, 95%CI 1.10, 1.89; I2 = 40%) but was not statistically significant in RCTs (RR = 3.00, 95%CI 0.64, 14.16). There was no difference in complications, reintervention, heartburn, reflux, or quality of life. There were no appropriate studies comparing surgery to observation in asymptomatic patients. Fundoplication resulted in higher early dysphagia in both observational studies and RCTs ([RR = 2.08, 95%CI 1.16, 3.76] and [RR = 20.58, 95%CI 1.34, 316.69]) but lower reflux in RCTs (RR = 0.31, 95%CI 0.17, 0.56, I2 = 0%). Conversion to Roux-en-Y was associated with a lower reintervention risk after 30 days compared to redo surgery. CONCLUSIONS: The evidence for optimal management of symptomatic and recurrent hiatal hernia remains controversial, underpinned by studies with a high risk of bias. Shared decision making between surgeon and patient is essential for optimal outcomes.

LMO3 is a suppressor of the basal-like/squamous subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism.

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.

SAGES peritoneal dialysis access guideline update 2023.

BACKGROUND: Minimally invasive surgery has been used for both de novo insertion and salvage of peritoneal dialysis (PD) catheters. Advanced laparoscopic, basic laparoscopic, open, and image-guided techniques have evolved as the most popular techniques. The aim of this guideline was to develop evidence-based guidelines that support surgeons, patients, and other physicians in decisions on minimally invasive peritoneal dialysis access and the salvage of malfunctioning catheters in both adults and children. METHODS: A guidelines committee panel of the Society of American Gastrointestinal and Endoscopic Surgeons reviewed the literature since the prior guideline was published in 2014 and developed seven key questions in adults and four in children. After a systematic review of the literature, by the panel, evidence-based recommendations were formulated using the Grading of Recommendations Assessment, Development and Evaluation approach. Recommendations for future research were also proposed. RESULTS: After systematic review, data extraction, and evidence to decision meetings, the panel agreed on twelve recommendations for the peri-operative performance of laparoscopic peritoneal dialysis access surgery and management of catheter dysfunction. CONCLUSIONS: In the adult population, conditional recommendations were made in favor of: staged hernia repair followed by PD catheter insertion over simultaneous and traditional start over urgent start of PD when medically possible. Furthermore, the panel suggested advanced laparoscopic insertion techniques rather than basic laparoscopic techniques or open insertion. Conditional recommendations were made for either advanced laparoscopic or image-guided percutaneous insertion and for either nonoperative or operative salvage. A recommendation could not be made regarding concomitant clean-contaminated surgery in adults. In the pediatric population, conditional recommendations were made for either traditional or urgent start of PD, concomitant clean or clean-contaminated surgery and PD catheter placement rather than staged, and advanced laparoscopic placement rather than basic or open insertion.

SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) exhibits distinct molecular subtypes: classical/progenitor and basal-like/squamous. Our study aimed to identify genes contributing to the development of the basal-like/squamous subtype, known for its aggressiveness. Transcriptome analyses revealed consistent upregulation of SERPINB3 in basal-like/squamous PDAC, correlating with reduced patient survival. SERPINB3 transgene expression in PDAC cells enhanced in vitro invasion and promoted lung metastasis in a mouse PDAC xenograft model. Metabolome analyses unveiled a metabolic signature linked to both SERPINB3 and the basal-like/squamous subtype, characterized by heightened carnitine/acylcarnitine and amino acid metabolism, associated with poor prognosis in patients with PDAC and elevated cellular invasiveness. Further analysis uncovered that SERPINB3 inhibited the cysteine protease calpain, a key enzyme in the MYC degradation pathway, and drove basal-like/squamous subtype and associated metabolic reprogramming through MYC activation. Our findings indicate that the SERPINB3-MYC axis induces the basal-like/squamous subtype, proposing SERPINB3 as a potential diagnostic and therapeutic target for this variant.

Diagnosis and treatment of appendicitis: systematic review and meta-analysis.

BACKGROUND: The optimal diagnosis and treatment of appendicitis remains controversial. This systematic review details the evidence and current best practices for the evaluation and management of uncomplicated and complicated appendicitis in adults and children. METHODS: Eight questions regarding the diagnosis and management of appendicitis were formulated. PubMed, Embase, CINAHL, Cochrane and clinicaltrials.gov/NLM were queried for articles published from 2010 to 2022 with key words related to at least one question. Randomized and non-randomized studies were included. Two reviewers screened each publication for eligibility and then extracted data from eligible studies. Random effects meta-analyses were performed on all quantitative data. The quality of randomized and non-randomized studies was assessed using the Cochrane Risk of Bias 2.0 or Newcastle Ottawa Scale, respectively. RESULTS: 2792 studies were screened and 261 were included. Most had a high risk of bias. Computerized tomography scan yielded the highest sensitivity (> 80%) and specificity (> 93%) in the adult population, although high variability existed. In adults with uncomplicated appendicitis, non-operative management resulted in higher odds of readmission (OR 6.10) and need for operation (OR 20.09), but less time to return to work/school (SMD - 1.78). In pediatric patients with uncomplicated appendicitis, non-operative management also resulted in higher odds of need for operation (OR 38.31). In adult patients with complicated appendicitis, there were higher odds of need for operation following antibiotic treatment only (OR 29.00), while pediatric patients had higher odds of abscess formation (OR 2.23). In pediatric patients undergoing appendectomy for complicated appendicitis, higher risk of reoperation at any time point was observed in patients who had drains placed at the time of operation (RR 2.04). CONCLUSIONS: This review demonstrates the diagnosis and treatment of appendicitis remains nuanced. A personalized approach and appropriate patient selection remain key to treatment success. Further research on controversies in treatment would be useful for optimal management.

Muscarinic receptor agonist-induced ßPix binding to ß-catenin promotes colon neoplasia.

M3 muscarinic receptors (M3R) modulate ß-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, ßPix, binds to ß-catenin in colon cancer cells, augmenting ß-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M3R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of ßPix and ß-catenin in stem cells overexpressing M3R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M3R agonist-induced cytoplasmic and nuclear association of ßPix with ß-catenin. ßPix knockdown attenuated M3R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing ßPix dose-dependently augmented ß-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of ßPix. Expression levels of ß-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from ßPix-deficient conditional knockout mice. Targeting the M3R/ßPix/ß-catenin axis may have therapeutic potential.

Survival outcomes used to validate version 9 of the American Joint Committee on Cancer staging system for appendiceal cancer.

The standard for cancer staging in the United States for all cancer sites, including primary carcinomas of the appendix, is the American Joint Committee on Cancer (AJCC) staging system. AJCC staging criteria undergo periodic revisions, led by a panel of site-specific experts, to maintain contemporary staging definitions through the evaluation of new evidence. Since its last revision, the AJCC has restructured its processes to include prospectively collected data because large data sets have become increasingly robust and available over time. Thus survival analyses using AJCC eighth edition staging criteria were used to inform stage group revisions in the version 9 AJCC staging system, including appendiceal cancer. Although the current AJCC staging definitions were maintained for appendiceal cancer, incorporating survival analysis into the version 9 staging system provided unique insight into the clinical challenges in staging rare malignancies. This article highlights the critical clinical components of the now published version 9 AJCC staging system for appendix cancer, which (1) justified the separation of three different histologies (non-mucinous, mucinous, signet-ring cell) in terms of prognostic variance, (2) demonstrated the clinical implications and challenges in staging heterogeneous and rare tumors, and (3) emphasized the influence of data limitations on survival analysis for low-grade appendiceal mucinous neoplasms.

Influence of a patient navigation program on timeliness of care in patients with esophageal cancer.

BACKGROUND: Patient navigation (P.N.) is designed to eliminate barriers to care. The objective of this study was to evaluate the impact of a novel P.N. program on timeliness of care in patients with esophageal cancer. METHODS: This retrospective study compared the timeliness of care for esophageal cancer patients before (January 2014-March 2018) and after the implementation of a novel P.N. program (April 2018-March 2020), called EDAP, at a tertiary care center. The primary outcome was time from biopsy to first treatment; secondary outcomes included time from biopsy to complete staging, biopsy to complete preoperative workup, and referral to the first point of contact. The outcomes were evaluated in the entire cohort and then in a subgroup of patients undergoing curative multimodality therapy. RESULTS: There were 96 patients in the pre-EDAP group and 98 patients in the post-EDAP group. There was no significant difference between pre- and post-EDAP in the time from biopsy to first treatment and time from biopsy to staging in the overall cohort. In the subgroup of patients undergoing curative multimodality therapy, there was a significant decrease in time from biopsy to first treatment postnavigation (60-51 days, p = 0.02), in addition to a significant decrease in time from biopsy to preoperative workup and time from biopsy to staging. CONCLUSIONS: This is the first study demonstrating that a novel P.N. program for patients with esophageal cancer improved timeliness of care. The group of patients who benefited most were those undergoing curative multimodality therapy, likely given the extensive coordination of services required by this group.

Outcomes after endoscopic local excision of early-stage gastric adenocarcinoma in the United States.

BACKGROUND AND OBJECTIVES: Local excision (LE) for early-stage gastric cancer has expanded in the United States over recent years, however, national outcomes are unknown. The objective of the study was to evaluate national survival outcomes following LE for early-stage gastric cancer. METHODS: Patients with resectable gastric adenocarcinoma between 2010 and 2016 were identified from the National Cancer Database then classified by LE curability into eCuraA (high) and eCuraC (low) according to Japanese Gastric Cancer Association guidelines. Demographics, clinical/provider descriptors, and perioperative/survival outcomes were extracted. Propensity-weighted cox proportional hazards regression assessed factors associated with overall survival. RESULTS: Patients were stratified into eCuraA (N = 1167) and eCuraC (N = 13,905) subgroups. Postoperative 30-day mortality (0% vs 2.8%, p < 0.001) and readmission (2.3% vs 7.8%, p = 0.005) favored LE. Local excision was not associated with survival on propensity-weighted analyses. However, among eCuraC patients, LE was associated with higher likelihood of positive margins (27.1% vs 7.0%, p < 0.001), which was the strongest predictor of poor survival (HR 2.0, p < 0.001). CONCLUSIONS: Although early morbidity is low, oncologic outcomes following LE are compromised for eCuraC patients. These findings support careful patient selection and treatment centralization in the early adoption phase of LE for gastric cancer.

Dysregulation of HNF1B/Clusterin axis enhances disease progression in a highly aggressive subset of pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is largely refractory to available treatments. Identifying key pathways associated with disease aggressiveness and therapeutic resistance may characterize candidate targets to improve patient outcomes. We used a strategy of examining the tumors from a subset of PDAC patient cohorts with the worst survival to understand the underlying mechanisms of aggressive disease progression and to identify candidate molecular targets with potential therapeutic significance. Non-negative matrix factorization (NMF) clustering, using gene expression profile, revealed three patient subsets. A 142-gene signature specific to the subset with the worst patient survival, predicted prognosis and stratified patients with significantly different survival in the test and validation cohorts. Gene-network and pathway analysis of the 142-gene signature revealed dysregulation of Clusterin (CLU) in the most aggressive patient subset in our patient cohort. Hepatocyte nuclear factor 1 b (HNF1B) positively regulated CLU, and a lower expression of HNF1B and CLU was associated with poor patient survival. Mechanistic and functional analyses revealed that CLU inhibits proliferation, 3D spheroid growth, invasiveness and epithelial-to-mesenchymal transition (EMT) in pancreatic cancer cell lines. Mechanistically, CLU enhanced proteasomal degradation of EMT-regulator, ZEB1. In addition, orthotopic transplant of CLU-expressing pancreatic cancer cells reduced tumor growth in mice. Furthermore, CLU enhanced sensitivity of pancreatic cancer cells representing aggressive patient subset, to the chemotherapeutic drug gemcitabine. Taken together, HNF1B/CLU axis negatively regulates pancreatic cancer progression and may potentially be useful in designing novel strategies to attenuate disease progression in PDAC patients.