scholarly journals Synergistic Analysis of Circulating Tumor Cells Reveals Prognostic Signatures in Pilot Study of Treatment-Naïve Metastatic Pancreatic Cancer Patients

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 146
Author(s):  
Sarah Owen ◽  
Emily Prantzalos ◽  
Valerie Gunchick ◽  
Vaibhav Sahai ◽  
Sunitha Nagrath
Keyword(s):  
Pilot Study ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Expression Patterns ◽  
Survival Rates ◽  
Resistance Mechanisms ◽  
Mapk Signaling ◽  
Ductal Adenocarcinoma ◽  
Treatment Regimens ◽  
Treatment Naïve

Pancreatic ductal adenocarcinoma is typically diagnosed at late stages and has one of the lowest five-year survival rates of all malignancies. In this pilot study, we identify signatures related to survival and treatment response found in circulating tumor cells (CTCs). Patients with poor survival had increased mutant KRAS expression and deregulation of connected pathways such as PI3K-AKT and MAPK signaling. Further, in a subset of these patients, expression patterns of gemcitabine resistance mechanisms were observed, even prior to initiating treatment. This work highlights the need for identifying patients with these resistance profiles and designing treatment regimens to circumvent these mechanisms.

scholarly journals Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer

2021 ◽  
Author(s):  
Daniel Cui Zhou ◽  
Reyka G. Jayasinghe ◽  
John M. Herndon ◽  
Erik Storrs ◽  
Chia-Kuei Mo ◽  
...  
Keyword(s):  
Single Cell ◽  
Tumor Cells ◽  
Drug Targets ◽  
Treatment Options ◽  
Receptor Expression ◽  
Ductal Adenocarcinoma ◽  
List Type ◽  
Treatment Regimens ◽  
Coordinated Expression ◽  
Treatment Naïve

SUMMARYPancreatic Ductal Adenocarcinoma (PDAC) is a lethal disease with limited treatment options and poor survival. We studied 73 samples from 21 patients (7 treatment-naïve and 14 treated with neoadjuvant regimens), analyzing distinct spatial units and performing bulk proteogenomics, single cell sequencing, and cellular imaging. Spatial drivers, including mutant KRAS, SMAD4, and GNAQ, were associated with differential phosphosignaling and metabolic responses compared to wild type. Single cell subtyping discovered 12 of 21 tumors with mixed basal and classical features. Trefoil factor family members were upregulated in classical populations, while the basal populations showed enhanced expression of mesenchymal genes, including VIM and IGTB1. Acinar-ductal metaplasia (ADM) populations, present in 95% of patients, with 46% reduction of driver mutation fractions compared to tumor populations, exhibited suppressive and oncogenic features linked to morphologic states. We identified coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin receptor expression in tumor cells. Higher expression of angiogenic and stress response genes in dendritic cells compared to tumor cells suggests they have a pro-tumorigenic role in remodeling the microenvironment. Treated samples contain a three-fold enrichment of inflammatory CAFs when compared to untreated samples, while other CAF subtypes remain similar. A subset of tumor and/or ADM-specific biomarkers showed differential expression between treatment groups, and several known drug targets displayed potential cross-cell type reactivities. This resolution that spatially defined single cell omics provides reveals the diversity of tumor and microenvironment populations in PDAC. Such understanding may lead to more optimal treatment regimens for patients with this devastating disease.HIGHLIGHTSAcinar-ductal metaplasia (ADM) cells represent a genetic and morphologic transition state between acinar and tumor cells.Inflammatory cancer associated fibroblasts (iCAFs) are a major component of the PDAC TME and are significantly higher in treated samplesReceptor-ligand analysis reveals tumor cell-TME interactions through NECTIN4-TIGITTumor and ADM cell proteogenomics differ between treated and untreated samples, with unique and shared potential drug targets

scholarly journals High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1656 ◽  
Author(s):  
Etienne Buscail ◽  
Catherine Alix-Panabières ◽  
Pascaline Quincy ◽  
Thomas Cauvin ◽  
Alexandre Chauvet ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Liquid Biopsy ◽  
Neoadjuvant Treatment ◽  
Digital Pcr ◽  
Portal Blood ◽  
Ductal Adenocarcinoma ◽  
Clinical Value ◽  
Liquid Biopsies

Purpose: Expediting the diagnosis of pancreatic ductal adenocarcinoma (PDAC) would benefit care management, especially for the start of treatments requiring histological evidence. This study evaluated the combined diagnostic performance of circulating biomarkers obtained by peripheral and portal blood liquid biopsy in patients with resectable PDAC. Experimental design: Liquid biopsies were performed in a prospective translational clinical trial (PANC-CTC #NCT03032913) including 22 patients with resectable PDAC and 28 noncancer controls from February to November 2017. Circulating tumor cells (CTCs) were detected using the CellSearch® method or after RosetteSep® enrichment combined with CRISPR/Cas9-improved KRAS mutant alleles quantification by droplet digital PCR. CD63 bead-coupled Glypican-1 (GPC1)-positive exosomes were quantified by flow cytometry. Results: Liquid biopsies were positive in 7/22 (32%), 13/22 (59%), and 14/22 (64%) patients with CellSearch® or RosetteSep®-based CTC detection or GPC1-positive exosomes, respectively, in peripheral and/or portal blood. Liquid biopsy performance was improved in portal blood only with CellSearch®, reaching 45% of PDAC identification (5/11) versus 10% (2/22) in peripheral blood. Importantly, combining CTC and GPC1-positive-exosome detection displayed 100% of sensitivity and 80% of specificity, with a negative predictive value of 100%. High levels of GPC1+-exosomes and/or CTC presence were significantly correlated with progression-free survival and with overall survival when CTC clusters were found. Conclusion: This study is the first to evaluate combined CTC and exosome detection to diagnose resectable pancreatic cancers. Liquid biopsy combining several biomarkers could provide a rapid, reliable, noninvasive decision-making tool in early, potentially curable pancreatic cancer. Moreover, the prognostic value could select patients eligible for neoadjuvant treatment before surgery. This exploratory study deserves further validation.

scholarly journals Investigation of Circulating Tumor Cells From Cancer Patients Undergoing Radiation Therapy: A Pilot Study

2015 ◽  
Vol 93 (3) ◽  
pp. S105-S106
Author(s):  
M.J. Eblan ◽  
J.H. Myung ◽  
J.M. Caster ◽  
S.M. Miller ◽  
K. Wang ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Pilot Study ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Circulating Tumor Cells

scholarly journals Enhancing the Screening Efficiency of Breast Cancer by Combining Conventional Medical Imaging Examinations With Circulating Tumor Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Yang Gao ◽  
Wan-Hung Fan ◽  
Chaohui Duan ◽  
Wenhe Zhao ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Clinicopathological Characteristics ◽  
Screening Tools ◽  
Breast Diseases ◽  
Receiver Operating Characteristic Curves ◽  
Treatment Naïve ◽  
Screening Efficiency ◽  
Healthy Females

PurposeUltrasound (US) and mammogram (MMG) are the two most common breast cancer (BC) screening tools. This study aimed to assess how the combination of circulating tumor cells (CTC) with US and MMG would improve the diagnostic performance.MethodsCTC detection and imaging examinations, US and MMG, were performed in 238 treatment-naive BC patients, 217 patients with benign breast diseases (BBD), and 20 healthy females. Correlations of CTC, US and MMG with patients’ clinicopathological characteristics were evaluated. Diagnostic performances of CTC, US and MMG were estimated by the receiver operating characteristic curves.ResultsCTC, US and MMG could all distinguish BC patients from the control (p < 0.0001). Area under curve (AUC) of CTC, US and MMG are 0.855, 0.861 and 0.759, respectively. While US has the highest sensitivity of 0.79, CTC and MMG have the same specificity of 0.92. Notably, CTC has the highest accuracy of 0.83. Combination with CTC increases the AUC of US and MMG to 0.922 and 0.899, respectively. Combining MMG with CTC or US increases the sensitivity of MMG to 0.87, however “CTC + MMG” has a higher specificity of 0.85. “CTC + US” performs the best in BC diagnosis, followed by “CTC + MMG” and then “US + MMG”.ConclusionCTC can be used as a diagnostic aid for BC screening. Combination with CTC increases the diagnostic potency of conventional BC screening imaging examinations, US and MMG, in BC diagnosis, especially for MMG.

scholarly journals A model for the detection of pancreatic ductal adenocarcinoma circulating tumor cells

2018 ◽  
Vol 5 (3) ◽  
pp. 97 ◽  
Author(s):  
Matthew S. Alexander ◽  
Brianne R. O'Leary ◽  
Devon Moose ◽  
Juan Du ◽  
Michael D. Henry ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Ductal Adenocarcinoma

scholarly journals Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1659 ◽  
Author(s):  
Verena Martini ◽  
Sylvia Timme-Bronsert ◽  
Stefan Fichtner-Feigl ◽  
Jens Hoeppner ◽  
Birte Kulemann
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Prognostic Markers ◽  
Cancer Prognosis ◽  
Detection Methods ◽  
Ductal Adenocarcinoma ◽  
Detection Tool ◽  
The Usa ◽  
New Biomarkers

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.

Abstract 1383: Isolating circulating tumor cells from a large screening blood volume: A pilot study using diagnostic leukapheresis

2019 ◽  
Author(s):  
Liang Dong ◽  
Zhongyuan Zhang ◽  
Changxue Lu ◽  
Diane Reyes ◽  
Amber de Groot ◽  
...  
Keyword(s):  
Pilot Study ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Blood Volume

Optimized preclinical models for human pancreatic adenocarcinoma therapy research

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15019-15019
Author(s):  
N. Carbó ◽  
S. Pérez-Torras ◽  
A. Vidal-Pla ◽  
R. Miquel ◽  
V. Almendro ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Pancreatic Adenocarcinoma ◽  
Expression Patterns ◽  
Resistance Mechanisms ◽  
Tissue Array ◽  
Ductal Adenocarcinoma ◽  
Preclinical Models ◽  
Biological Behaviour ◽  
Primary Tumors ◽  
Effective Development

15019 Background: Efforts to find new therapies for human pancreatic ductal adenocarcinoma (PDAC) have not resulted in clear improvements on patient survival. Better knowledge of resistance mechanisms and redefiniton of molecular targets is essential to design more efficient therapies. The multifactorial origin of PDAC points to combined strategies as the therapy of choice, though the effective development of such strategies is hampered by the lack of optimal preclinical models. We have generated and validated optimized human PDAC models by direct implantation of fresh tumoral tissue into the pancreas of athymic mice. Methods: Thirteen pancreatic adenocarcinoma specimens from PDAC patients were obtained by surgical resection. From each specimen, several 10 mg-fragments were used to generate the corresponding intrapancreatic xenografted tumours. Eleven human PDAC orthotopic models have been successfully generated and perpetuated by succesive passages (up to 4). Histological and molecular analyses of both primary and xenografted tumors have been performed by tissue- array, western-blot and DNA sequentiation. Results: Initial engraftment rate ranged from 20 to 100% (mean 59%) and it improved with succesive passages (mean 76% at second and 90% at third generation). Ki67 expression and degree of differentiation in primary tumors correlated with xenograft growth kinetics. Furthermore, their spontaneous metastatic behaviour fairly reproduced the original patient dissemination patterns. Xenografted tumors kept the original architecture and expression patterns of common PDAC markers. Efficacy of several agents was tested on different xenografted tumors, validating this model and underlining its utility to define future therapeutic strategies for drug development and clinical trials. Conclusions: The orthotopic models described here are, probably, the closest resemblance to a patient clinical setting since they preserve human pancreatic structures, genotypic features and biological behaviour. From their use, biological relevant data could be drawn for future clinical trials and for testing new agents and new drug combinations since they represent, very likely, the most reliable animal models at present. No significant financial relationships to disclose.

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