Tumor Cells In Pancreatic Cancer Research Articles

Feasibility study utilizing a combinatorial functional precision medicine platform, Optim.AI, to help guide treatment for pancreatic cancer.

e13614 Background: Functional screening methods are increasingly applied to guide patient treatment and could be beneficial in indications with poor survival and response rates, such as pancreatic cancer. However, challenges faced when implementing ex vivo testing include complexities in obtaining sufficient tumor cells for different cancer types and maximizing the number of treatments tested with limited sample material. The latter is especially significant in informing clinical decision making as combination therapies are common with cancer, exponentially increasing the number of regimens to select from. To address this hurdle, we developed Optim.AI, a combinatorial functional precision medicine platform, which utilizes efficiently designed experiments and small data AI to expand to over 530,000 phenotypic response data points and predictively rank all actionable treatments within a 12-drug panel. In this feasibility study, we explored the application of Optim.AI on patient-derived tumor cells in pancreatic cancer. Methods: We established a procedure to run Optim.AI with isolated tumor cells from pancreatic cancer patients. After dissociation, these cells were then incubated to allow for 3D organoid formation within the following week. Upon organoid formation, the cells were treated with an FDA-approved panel of chemotherapy and targeted drugs. Cell viability was quantified post-drug treatment for analysis with Optim.AI software to rank all possible single to 4-drug combinatorial therapies for report generation. Results: The viability of the cells post-processing was high (mean = 97.4% live cells), passing the quality check of having at least 60% live cells before proceeding with Optim.AI testing. The success rate of organoid formation was 100% within 1 week of sample processing. The turnaround time from the receipt of samples to dissemination of the reports to clinicians was approximately a week (mean = 7.67 days). Z’ factor, a measurement of statistical effect size for high throughput screening, was demonstrated to be more than 0.5 for the reports generated, indicative of very good assays. The top ranked drug combinations were sensitive, with their normalized cell viability reported to be under 0.2, while the prior line of treatment was shown to be resistant, 100% concordant with previously observed clinical outcomes. Notably, Gemcitabine with either a HDAC or PI3K inhibitor was ranked high amongst the reports generated. Conclusions: Optim.AI had a high success rate in generating reports within a very short timeframe for pancreatic cancer. Comparing the top ranked therapies against the prior lines of treatment allows the clinicians to better evaluate the alternative treatments. Based on this initial feasibility study, Optim.AI could potentially be viable in guiding clinicians in managing treatment options for pancreatic cancer patients.

Abstract 1588: Identification of new signaling pathways between fibroblasts & tumor cells in pancreatic cancer

Abstract We explore the unstudied role of nanoparticles (NPs), recently discovered secreted non-vesicular nanoparticles, in signaling between pre-cancer associated fibroblasts (preCAF), CAFs, and tumor cells. We generated two novel primary lines preCAF PFUM1 from a patient with high-grade intraductal papillary mucinous neoplasms and CAF FUM2 from a patient with pancreatic ductal adenocarcinoma, all tests performed between passages 2 and 3, fibroblast purity validated by RT-PCR and ACTA2 immunofluorescence. Small extracellular vesicles (sEVs), exomeres, and supermeres (the two main forms of NPs) were isolated by the ultracentrifugation method from PF-UM1 and F-UM2 with n=2-3 experiments. To validate the isolation, we used nanoparticle tracking, electron, and fluid-phase atomic force microscopy. Proteins were quantified by BCA assay. Liquid chromatography-mass spectrometry characterized the cargo from each fraction. Human cancer lines MIAPACA2 and SU8686 were treated with 10 μg of each fraction and cell proliferation was tested by phase-contrast images (Cytation 5), analyzed by Ilastik-based 1.4.0 machine-learning. We performed fluorescent Ki-67 and vimentin staining and quantified in QuPath 0.4.3. Non-parametric statistics were performed in Prism GraphPad. NPs constitute the major fraction of small particles released by fibroblasts, containing 80.5% (PFUM1) and 77.5% (FUM2) of the protein load by quantification. Mass spectrometry reveals enrichment of growth factors, epithelial-to-mesenchymal (EMT) transition, and metabolism-associated proteins in the NPs compared to sEVs. At 72 hours, cell proliferation for Su8686 reveals a proliferative effect for all fractions from both PFUM1 and FUM2 (19-63% increase compared to controls, p=0.049 to <0.0001). For MIAPACA2, only supermeres from PFUM1 and FUM2 consistently increased proliferation (9.5-35% increase, p=0.0051 to <0.0001). Ki-67 expression in MIAPACA2, increased by 9.6-23.0% following treatment by NPs (all p<0.0001) and by 2.9-9.2% with sEVs (p=0.011 to <0.0001). EMT was estimated by vimentin in MIAPACA2, as all preCAF fractions from PFUM1 reduced vimentin expression (p<0.001), while CAF FUM2 NPs increased vimentin expression (p<0.0001) while sEVs had no effect (p=0.075). In conclusion, the majority of pancreatic tumor-associated fibroblast small secretome is composed of NPs, exhibiting significant functional pro-tumoral effects. Citation Format: Ayman Al Shoukari, Maelle Batardiere, Nooshin Movahed, Camille beaussier, Jumanah Baig, Melissa gonzalez, Patricia Moraille, Eric Bonneil, Louise Rousseau, Simon turcotte, Kathleen Delgiorno, Marcus Tan, Anna Means, Elham Dianati Ajibisheh, Quoc-huy Trinh. Identification of new signaling pathways between fibroblasts & tumor cells in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1588.

Circulating tumor cells in pancreatic cancer: more than liquid biopsy.

Circulating tumor cells (CTCs) are tumor cells that slough off the primary lesions and extravasate into the bloodstream. By forming CTC clusters and interacting with other circulating cells (platelets, NK cells, macrophage, etc.), CTCs are able to survive in the circulatory system of tumor patients and colonize to metastatic organs. In recent years, the potential of CTCs in diagnosis, prognostic assessment, and individualized therapy of various types of tumors has been gradually explored, while advances in biotechnology have made it possible to extract CTCs from patient blood samples. These biological features of CTCs provide us with new insights into cancer vulnerabilities. With the advent of new immunotherapies and personalized medicines, disrupting the heterotypical interaction between CTCs and circulatory cells as well as direct CTCs targeting hold great promise. Pancreatic cancer (PC) is one of the most malignant cancers, in part because of early metastasis, difficult diagnosis, and limited treatment options. Although there is significant potential for CTCs as a biomarker to impact PC from diagnosis to therapy, there still remain a number of challenges to the routine implementation of CTCs in the clinical management of PC. In this review, we summed up the progress made in understanding biological characteristics and exceptional technological advances of CTCs and provided insight into exploiting these developments to design future clinical tools for improving the diagnosis and treatment of PC.

Clinical Utility of Portal Venous Circulating Tumor Cells in Pancreatic Cancer

Clinical Utility of Portal Venous Circulating Tumor Cells in Pancreatic Cancer

Clinical implications and perspectives of portal venous circulating tumor cells in pancreatic cancer

Despite recent improvements in the diagnosis and treatment of pancreatic cancer (PC), clinical outcomes remain dismal. Moreover, there are no effective prognostic or predictive biomarkers or options beyond carbohydrate antigen 19-9 for personalized and precise treatment. Circulating tumor cells (CTCs), as a member of the liquid biopsy family, could be a promising biomarker; however, the rarity of CTCs in peripheral venous blood limits their clinical use. Because the first venous drainage of PC is portal circulation, the portal vein can be a more suitable location for the detection of CTCs. Endoscopic ultrasound-guided portal venous sampling of CTCs is both feasible and safe. Several studies have suggested that the detection rate and number of CTCs may be higher in the portal blood than in the peripheral blood. CTC counts in the portal blood are highly associated with hepatic metastasis, recurrence after surgery, and survival. The phenotypic and genotypic properties measured in the captured portal CTCs can help us to understand tumor heterogeneity and predict the prognosis of PC. Small sample sizes and heterogeneous CTC detection methods limit the studies to date. Therefore, a large number of prospective studies are needed to corroborate portal CTCs as a valid biomarker in PC.

Abstract 5581: Single-cell genomic analysis of patient-derived circulating tumor cells in pancreatic cancer

Abstract Metastatic pancreatic cancer suffers from an extremely low five-year survival rate of only 3%. While patients with localized disease show marginally better survival rates, 52% of pancreatic cancers are not diagnosed until metastases have already developed. There is therefore a critically unmet need in the early diagnoses of pancreatic cancer patients. Liquid biopsies have emerged as a promising tool for cancer diagnosis through the analysis of various blood-based biomarkers. Among these, circulating tumor cells (CTCs) stand out as a promising target of interest. Over the past decade, CTCs have been identified as a precursor to metastasis. CTCs have also been shown to harbor mutations matching those of the primary tumor, making them a potential surrogate for biopsied tissue. However, CTCs are an extremely heterogenous population of cells, making bulk analysis challenging. In this study, we demonstrate a workflow for the isolation and genomic characterization of single CTCs from pancreatic cancer patients. CTCs are first enriched using a size-based microfluidic system, the Labyrinth, developed in the Nagrath lab. Single CTCs are subsequently isolated using the DEPArray Nxt system, followed by whole genome amplification (WGA) and low-pass sequencing. The pipeline was optimized using three commercially available pancreatic cancer cells lines (Panc-1, Capan-2, and BxPC-3) and two pancreatic cancer CTC cell lines previously developed in-house (CTC-CL-1 and CTC-CL-2). Finally, the workflow was validated using a blood sample from a stage IV pancreatic ductal adenocarcinoma patient. Following WGA, the average nucleic material concentration of the cell lines was 26.24 ± 16.28 ng/μL and 14.43 ng/μL for cells isolated from the patient sample. The average fragment size was 746 ± 232.79 bp for cell line cells and 507 bp for patient sample cells. This was within the expected range of 100-2000 bp. Both CTC cell lines show gains on parts of chromosome 8q (Myc), 10q (FGFR2) and 17q. Myc is a known oncogene and FGFR2 has been associated with cell growth, migration, and invasion. There are also noticeable differences between the two CTC-CL-1 cells, with one cell showing a 3p12.3-3p26.3 gain (CTNNB1), and the other showing a loss of 6q12-6q15 and gain of 6q16.1-6q27 (Myb, ESR1). A patient sample CTC and patient-matched WBC were isolated and sequenced. The CTC has a noticeable gain of chromosome 1q and loss of chromosome 5q. A gain in chromosome 1q has been seen previously in pancreatic cancer and chromosome 5q is the location of multiple oncogenes including APC, CSF1R and FGFR4. The loss of APC is known to affect Wnt/β-catenin signaling, causing an increase in CD34 expression which is linked to increase in cell invasion and migration. These results demonstrate an efficient workflow for the single cell genomic analysis of pancreatic CTCs. Further studies can be conducted to characterize the heterogenous landscape of CTCs in pancreatic cancer. Citation Format: Harrison Ball, Brittany Rupp, Sarah Owen, Kaylee Smith, Valerie Gunchick, Evan T. Keller, Vaibhav Sahai, Sunitha Nagrath. Single-cell genomic analysis of patient-derived circulating tumor cells in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5581.

Single cell RNA-seq reveals the CCL5/SDC1 receptor-ligand interaction between T cells and tumor cells in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the complex tumor microenvironment (TME), consisting of an abundance of stromal cells. Among them, tumor infiltrating T cells play a pivotal role in tumor progress. To identify the full spectrum and developmental trajectory of T cells and their crosstalk with tumor cells in PDAC, we conducted scRNA-seq analysis based on multiple datasets from our institution and open databases. We delineated the cellular landscape and transcriptional dynamics of T cells in PDAC. Through the inferCNV analysis and known tumor markers, the malignant ductal cells were identified. The inter-patients heterogeneity of tumor cells was also identified. After integrating T cells and malignant ductal cells, we found the CCL5-SDC1/4 receptor-ligand interactions between them. Furthermore, we demonstrated that CCL5 promoted tumor cells migration via interacting with SDC1 in vitro. Our findings pave the way for characterizing the heterogeneity and development trajectory of T cells, and cell-to-cell communications in TME of PDAC, which might provide a new target for immunotherapy.

Integrated Workflow for the Label-Free Isolation and Genomic Analysis of Single Circulating Tumor Cells in Pancreatic Cancer.

As pancreatic cancer is the third deadliest cancer in the U.S., the ability to study genetic alterations is necessary to provide further insight into potentially targetable regions for cancer treatment. Circulating tumor cells (CTCs) represent an especially aggressive subset of cancer cells, capable of causing metastasis and progressing the disease. Here, we present the Labyrinth–DEPArray pipeline for the isolation and analysis of single CTCs. Established cell lines, patient-derived CTC cell lines and freshly isolated CTCs were recovered and sequenced to reveal single-cell copy number variations (CNVs). The resulting CNV profiles of established cell lines showed concordance with previously reported data and highlight several gains and losses of cancer-related genes such as FGFR3 and GNAS. The novel sequencing of patient-derived CTC cell lines showed gains in chromosome 8q, 10q and 17q across both CTC cell lines. The pipeline was used to process and isolate single cells from a metastatic pancreatic cancer patient revealing a gain of chromosome 1q and a loss of chromosome 5q. Overall, the Labyrinth-DEPArray pipeline offers a validated workflow combining the benefits of antigen-free CTC isolation with single cell genomic analysis.

Isolation and culture of circulating pancreatic cancer tumor cells using a microfilter.

e16230 Background: The presence and number of circulating tumor cells (CTCs) are reportedly associated with prognosis but the rarity of CTCs in peripheral circulation limits the ability of conventional technologies to provide fully accurate analyses. The purpose of this study was thus to establish a novel approach to capture and culture the CTCs using a microfilter device. Methods: This was a prospective study in preoperative patients with pancreatic cancer at the University of Tsukuba Hospital after approved by the Institutional Review Board. Five ml of whole blood was collected from each patient into an EDTA-treated collection tube before pumping through an 8μm pore microfilter. Cells isolated on the filter were stained with PE-conjugated anti-EpCAM, FITC-conjugated anti-CD45 and Hoechst 33342. The filter was then transferred to a 35mm dish and cultured with 20%FBS-IMDM-F12 medium containing 2%Matrigel- EGF-FGF-B27 for 4-6 weeks. Cells were visualized with an automatic fluorescence microscope. A CTC was defined as an intact round oval cell with a visible nucleus, positive staining for EpCAM and negative staining for CD45. Results: A total of 9 patients [male/female; 4/5, median age;71 (39-78), Stage 0/IA/IIA/IIB; 1/3/3/2, preoperative chemotherapy/chemoradiation; 1/2] were enrolled. CTCs were captured in 8 out of 9 cases and cultured CTCs were kept viable for 4-6 weeks in 6 out of 9 cases. CTCs formed colonies by 4-6 weeks of culture, colonies were expanding and blood cells disappeared. No cultured CTCs were observed in the two cases who received preoperative chemotherapy. Conclusions: We successfully developed a novel culture method of patient CTC using a microfilter device. Our system supports the possibility of accurate detection and proliferation of CTCs on microfilters. Cultured CTCs could be used for patient-specific drug susceptibility testing and mutational profiles for future cancer patients.

Abstract PO-065: SIWA318H, an advanced glycation end product (AGE) targeting antibody, is efficacious in a humanized mouse xenograft model for pancreatic cancer

Abstract SIWA318H is a novel monoclonal antibody that selectively targets a biomarker (an advanced glycation end product) found on the surface of cells exhibiting a combination of: (a) an abnormally high level of aerobic glycolysis, a process known to be associated with initiation and progression of cancer as well as metastasis; and (b) oxidative stress. Cells with this biomarker are often dysfunctional and associated with aging, cancer, and infectious diseases. In this study, we evaluated the antitumor activity of SIWA318H in a humanized xenograft model for pancreatic cancer. SIWA318H was found to react to pancreatic cancer cells (PSN1) and cancer associated fibroblasts (CAF08) using immunofluorescent staining. SIWA318H also showed strong reactivity with tumor xenografts derived from patients with pancreatic cancer as demonstrated by immunohistochemistry. Humanized CD34+ NSG mice were injected subcutaneously with PSN1 pancreatic cancer tumor cells. Ten days later, mice were randomized and enrolled in one of the following groups (n=16/group): 1) IgG1 isotype control (20mg/kg, BIWx1 followed by 10 mg/kg, BIWx2); 2) high dose SIWA318H (20mg/kg, BIWx1 followed by 10 mg/kg, BIWx2); and 3) low dose SIWA318H (10 mg/kg, BIWx1 followed by 5mg/kg, BIWx2). Tumors in mice treated with SIWA318H grew significantly slower than those in mice treated with isotype control antibody (p<0.001). After 3 weeks of treatment with the high dose or the low dose of SIWA318H, the tumor growth was suppressed by 68.8% and 61.5%, respectively, when compared to the isotype antibody control (ANOVA p<0.002). Moreover, a significant increase in complete remission (CR) rate was observed in mice receiving high (60%, p<0.05) or low dose (77.8%, p<0.02) of SIWA318H treatment compared with the control mice (6.7%). No significant antibody treatment related weight loss in mice was observed. These results provide compelling evidence that SIWA318H is a promising novel therapeutic for pancreatic cancer. Additional studies to better understand the mechanism of action of this novel immunotherapy agent are underway. Citation Format: Ashley Jensen, Gabriela R. Rossi, Ruben Muñoz, Kimberly Brothers, Lewis Gruber, Misty Gruber, Haiyong Han. SIWA318H, an advanced glycation end product (AGE) targeting antibody, is efficacious in a humanized mouse xenograft model for pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-065.

A transcriptional signature detects homologous recombination deficiency in pancreatic cancer at the individual level

Pancreatic cancer (PC) with homologous recombination deficiency (HRD) has been reported to benefit from poly ADP-ribose polymerase (PARP) inhibitors. However, accurate identification of HRD status for PC patients from the transcriptional level is still a great challenge. Here, based on a relative expression ordering (REO)-based algorithm, we developed an HRD signature including 24 gene pairs (24-GPS) using PC transcriptional profiles from The Cancer Genome Atlas (TCGA). HRD samples classified by 24-GPS showed worse overall survival (p = 4.4E-3 for TCGA; p = 1.2E-3 for International Cancer Genome Consortium-Australia cohort; p = 6.4E-2 for GSE17891; p = 7.5E-2 for GSE57495) and higher HRD scores than non-HRD samples (p = 1.4E-4). HRD samples showed highly unstable genomic characteristics and also displayed HRD-related alterations at the epigenomic and proteomic levels. Moreover, HRD cell lines identified by 24-GPS tended to be sensitive to PARP inhibitors (p = 6.6E-2 for olaparib; p = 2.6E-3 for niraparib). Compared with the non-HRD group, the HRD group presented lower immune scores and CD4/CD8 T cell infiltration proportion. Interestingly, PC tumor cells with co-inhibition of PARP-related genes and ATR showed reduced survival ability. In conclusion, 24-GPS can robustly identify PC patients with HRD status at the individualized level.

Notch signaling inhibitor and anti-PD-L1 antibody combination therapies decelerate tumor progression in pancreatic cancer

Abstract Objective: Pancreatic cancer (PC) is a highly lethal malignancy with an immunosuppressive environment. Yet, current immune checkpoint inhibitor monotherapies have shown limited efficacy in PC, prompting the need for combination therapies. Herein, we hypothesized that combinations of Notch signaling inhibitor and anti-ligand programmed death-ligand 1 (PD-L1) antibody immunotherapy would show synergistic efficacy. Methods: The baseline expression of PD-L1 and HES1 was measured in PC cell lines, single-cell RNA-seq data of PC (GSA: CRA001160), and cBioPortal databases. In an in vitro study, MIA PaCa2 and SW1990 were used to explore the mechanism between Notch signaling and PD-L1. To study the effects in vivo, a subcutaneous tumor model was established using Pan02 cells treated with either anti-PD-L1 monoclonal antibody and/or Notch inhibitor DAPT. The study performed involving human samples was approved by the Ethics Committee of Peking Union Medical College Hospital (approval No. S-K460, approval date: April 23, 2018). Animal studies were approved by the Animal Research Ethics Committee of Peking Union Medical College Hospital (approval No. XHDW-2019-049, approval date: November 28, 2019). Results: The Notch signaling inhibitor upregulated PD-L1 expression in PC tumor cells both in vitro and in vivo. Notch effector HES1 knockdown produced PD-L1 upregulation in both MIA PaCa2 and SW1990 cells. Combined DAPT and anti-PD-L1 antibody treatment of Pan02 subcutaneous tumor model resulted in significantly reduced tumor weights compared to that with monotherapy, as well as significantly reduced Ki67 than that in the monotherapy group and control group. Flow cytometry analysis revealed significantly increased CD8+ T cell infiltration in tumors of the combination group compared with those of the monotherapy group. Conclusion: Notch signaling blockade might enhance the antitumor effect of anti-PD-L1 therapy in PC.

PTPRO is a therapeutic target and correlated with immune infiltrates in pancreatic cancer.

As a member of protein tyrosine phosphatases (PTPs), the protein tyrosine phosphatase receptor type O (PTPRO) has attracted increasing attention for its important roles in cell signaling. Currently, the roles of PTPRO in human cancers remain elusive. Herein, we performed bioinformatic analyses and revealed the potential oncogenic role of PTPRO in specific cancer types. Further in vitro experiments indicated that inhibition of PTPRO suppresses the proliferative abilities of tumor cells in pancreatic cancer, blood cancer, and breast cancer. Moreover, small molecular PTPRO inhibitor could induce cell apoptosis and affect the cell cycle in pancreatic cancer. In addition, PTPRO expression promoted the infiltration of CD8+ T, macrophages, dendritic cells, and neutrophils, in pancreatic cancers. Our findings suggested PTPRO may serve as a potential drug target for pancreatic cancer.

Circulating tumour cells in pancreatic cancer: A systematic review and meta-analysis of clinicopathological implications

BackgroundThe detection and quantification of circulating tumour cells (CTCs) in pancreatic cancer (PC) has the potential to provide prognostic information. The aim of this review was to provide an overview of the literature surrounding CTCs in PC. MethodsA systematic literature review on CTCs in PC between 2005–2020 was performed. Data based on peripheral vein samples were used to determine the positivity rate of CTCs, their prognostic significance and their relative numbers compared to portal vein (PV) samples. ResultsThe overall CTC detection rate in forty-four articles was 65% (95%CI: 55–75%). Detection rate for CellSearch was 26% (95%CI: 14–38%), which was lower than for both filtration and microfluidic techniques. In nine studies with >50 patients, overall survival was worse with CTC positivity (HR 1.82; 95%CI: 1.61–2.05). Five of seven studies which described PV CTC collection provided patient-level data. PV CTC yield was 7.7-fold (95%CI 1.35–43.9) that of peripheral blood. ConclusionsCTCs were detected in the peripheral circulation of most patients with PC and may be related to prognosis and disease stage. PV blood contains more CTCs than peripheral blood sampling. This review points to the maturation of techniques of CTC enrichment, and its evidence base for eventual clinical deployment.

Characterization of Stem-like Circulating Tumor Cells in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most frequent cause of death from cancer. Circulating tumor cells (CTCs) with stem-like characteristics lead to distant metastases and thus contribute to the dismal prognosis of PDAC. Our purpose is to investigate the role of stemness in CTCs derived from a genetically engineered mouse model of PDAC and to further explore the potential molecular mechanisms. The publically available RNA sequencing dataset GSE51372 was analyzed, and CTCs with (CTC-S) or without (CTC-N) stem-like features were discriminated based on a principal component analysis (PCA). Differentially expressed genes, weighted gene co-expression network analysis (WGCNA), and further functional enrichment analyses were performed. The prognostic role of the candidate gene (CTNNB1) was assessed in a clinical PDAC patient cohort. Overexpression of the pluripotency marker Klf4 (Krüppel-like factor 4) in CTC-S cells positively correlates with Ctnnb1 (β-Catenin) expression, and their interaction presumably happens via protein–protein binding in the nucleus. As a result, the adherens junction pathway is significantly enriched in CTC-S. Furthermore, the overexpression of Ctnnb1 is a negative prognostic factor for progression-free survival (PFS) and relapse-free survival (RFS) in human PDAC cohort. Overexpression of Ctnnb1 may thus promote the metastatic capabilities of CTCs with stem-like properties via adherens junctions in murine PDAC.

Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives.

Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and Europe; early symptoms and screenings are lacking, and it is usually diagnosed late with a poor prognosis. Circulating tumor cells (CTCs) have been promising new biomarkers in solid tumors. In the last twenty years (1999–2019), 140 articles have contained the key words “Circulating tumor cells, pancreatic cancer, prognosis and diagnosis.” Articles were evaluated for the use of CTCs as prognostic markers and their correlation to survival in pancreatic ductal adenocarcinoma (PDAC). In the final selected 17 articles, the CTC detection rate varied greatly between different enrichment methodologies and ranged from 11% to 92%; the majority of studies used the antigen-dependent CellSearch© system for CTC detection. Fifteen of the reviewed studies showed a correlation between CTC presence and a worse overall survival. The heterogeneity of CTC-detection methods and the lack of uniform results hinder a comparison of the evaluated studies. However, CTCs can be detected in pancreatic cancer and harbor a hope to serve as an early detection tool. Larger studies are needed to corroborate CTCs as valid biomarkers in pancreatic cancer.

The importance of circulating and disseminated tumor cells in pancreatic cancer

Pancreatic cancer is a lethal disease in a large part due to the systemic nature at the time of diagnosis. In those patients who undergo a potentially curative resection of pancreatic cancer, the overwhelming majority will have systemic relapse. Circulating tumor cells are an important mediator of the development of metastases. Circulating tumor cells have been identified in patients with clinically localized resectable pancreatic cancer and exist as several phenotypes. Mesenchymal and stem cell–like phenotypes of circulating tumor cells predict early recurrence and worse survival. This review focuses on the current understanding of circulating tumor cells in pancreatic cancer and how this information can be used in developing more effective therapy in the future.

The Importance of Circulating and Disseminated Tumor Cells in Pancreatic Cancer

Pancreatic Cancer is a lethal disease in a large part due to the systemic nature at the time of diagnosis. In those patients who undergo a potentially curative resection of pancreatic cancer the overwhelming majority will have systemic relapse. Circulating tumor cells (CTC) are an important mediator of the development of metastases. CTC have been identified in patients with clinically localized resectable pancreatic cancer and exist as several phenotypes. Mesenchymal and stem cell-like phenotypes of CTC predict early recurrence and worse survival. This review focuses on the current understanding of CTCs in pancreatic cancer and how this information can be used in developing more effective therapy in the future.

Circulating tumor cells in pancreatic cancer: a review

Abstract Pancreatic cancer remains one of the deadliest types of cancer with little or no recent evidence of significant improvement in survival. This is, in large part, due to the current unavailability of effective screening or even early detection methods. Circulating tumor cells (CTCs), particularly with the rapidly improving methods for isolation, enrichment, and characterization methods, have emerged as the next best hope to overcome these challenges. This paper reviews the current state-of-the-art of CTC technologies with particular focus on the various isolation and enrichment methods based on liquid biopsy, the current limitations of these technologies and, consequently, the areas of further research and improvements in CTC methods that are needed to translate it to the clinical setting of routine diagnosis, treatment, and management of pancreatic cancer.

Capture and biological release of circulating tumor cells in pancreatic cancer based on peptide-functionalized silicon nanowire substrate.

BackgroundEfficient and precise circulating tumor cells’ (CTCs) capture and release with minimal effect on cell viability for CTCs’ analysis are general requirements of CTCs’ detection device in clinical application. However, these two essential factors are difficult to be achieved simultaneously.MethodsIn order to reach the aforementioned goal, we integrated multiple strategies and technologies of staggered herringbone structure, nanowires’ substrate, peptides, enzymatic release, specific cell staining, and gene sequencing into microfluidic device and the sandwich structure peptide-silicon nanowires’ substrate was termed as Pe-SiNWS.ResultsThe Pe-SiNWS demonstrated excellent capture efficiency (95.6%) and high release efficiency (92.6%). The good purity (28.5%) and cell viability (93.5%) of CTCs could be obtained through specific capture and biological release by using Pe-SiNWS. The good purity of CTCs facilitated precise and quick biological analysis, and five types of KRAS mutation were detected in 16 pancreatic cancer patients but not in healthy donors.ConclusionThe results proved that the effective capture, minor damage release, and precise analysis of CTCs could be realized simultaneously by our novel strategy. The successful clinical application indicated that our work was anticipated to open up new opportunities for the design of CTC microfluidic device.