scholarly journals Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. I. Alexander ◽  
D. B. Vendramini-Costa ◽  
R. Francescone ◽  
T. Luong ◽  
J. Franco-Barraza ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Ductal Adenocarcinoma ◽  
Transforming Growth Factor Beta1 ◽  
Cancer Associated Fibroblast ◽  
Specific Tumor ◽  
Immunosuppressive Microenvironment ◽  
Anti Tumor Activity ◽  
Immunosuppressive Cytokines

AbstractPancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

scholarly journals The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma

2018 ◽  
Vol 19 (10) ◽  
pp. 3219 ◽  
Author(s):  
Balbina García-Reyes ◽  
Anna-Laura Kretz ◽  
Jan-Philipp Ruff ◽  
Silvia von Karstedt ◽  
Andreas Hillenbrand ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Transcriptional Elongation ◽  
Cyclin Dependent Kinases ◽  
Dismal Prognosis ◽  
The Family ◽  
Cycle Regulation

The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.

scholarly journals The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma

2022 ◽  
Vol 9 ◽  
Author(s):  
Xuefei Liu ◽  
Ziwei Luo ◽  
Xuechen Ren ◽  
Zhihang Chen ◽  
Xiaoqiong Bao ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Malignant Cells ◽  
Sequencing Data ◽  
Immunosuppressive Microenvironment

Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies.Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups.Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy.Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.

scholarly journals Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 766 ◽  
Author(s):  
Yao-Yu Hsieh ◽  
Tsang-Pai Liu ◽  
Chia-Jung Chou ◽  
Hsin-Yi Chen ◽  
Kuen-Haur Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Gene Deletion ◽  
Transforming Growth Factor ◽  
Ductal Adenocarcinoma ◽  
Gene Copy ◽  
Chemotherapy Response ◽  
Specific Cell ◽  
Smad4 Gene ◽  
Therapeutic Benefits

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFβ) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment.

scholarly journals Carbohydrate 3′-sialyllactose as a novel target for theranostics in pancreatic ductal adenocarcinoma

Tumor Biology ◽  
2020 ◽  
Vol 42 (10) ◽  
pp. 101042832096527
Author(s):  
Kiyoshi Higashi ◽  
Keiko Maeda ◽  
Kaori Miyata ◽  
Saori Yoshimura ◽  
Keita Yamada ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Ductal Adenocarcinoma ◽  
Significant Activity ◽  
Gastric Cancer Cells ◽  
Complement Dependent Cytotoxicity ◽  
Elevated Expression ◽  
Novel Target

We previously demonstrated that the carbohydrate 3′-sialyllactose is overexpressed in cancer stem-like cells such as metastatic pancreatic and poorly differentiated gastric cancer cells, and undifferentiated human embryonic stem cells. In this study, we investigated the possibility of 3′-sialyllactose as a target for theranostics in cancers using a recombinant mouse monoclonal antibody r3B1E2 that binds to 3′-sialyllactose. Immunohistochemistry analysis confirmed an elevated expression of 3′-sialyllactose in tumors of pancreas, stomach, and testis, while no expression of 3′-sialyllactose was observed in corresponding normal controls. In addition, a stage-independent expression of 3′-sialyllactose was observed, especially in pancreatic ductal adenocarcinoma (PDAC). The level of serum 3′-sialyllactose in PDAC subjects was significantly higher than that in healthy controls, providing excellent AUC of 0.88. We next explored the therapeutic potential of r3B1E2 for PDAC in vitro. Treatment of r3B1E2 with 3′-sialyllactose-bearing human PDAC cells exhibited a complement-dependent cytotoxicity, whereas no significant activity of r3B1E2 against 3′-sialyllactose-negative cells was observed. Collectively, these findings raise the possibility of 3′-sialyllactose as a novel target for theranostics in PDAC.

scholarly journals Anti-tumor activity of antibody drug conjugate targeting aspartate-β-hydroxylase in pancreatic ductal adenocarcinoma

2019 ◽  
Vol 449 ◽  
pp. 87-98 ◽  
Author(s):  
Katsuya Nagaoka ◽  
Xuewei Bai ◽  
Kosuke Ogawa ◽  
Xiaoqun Dong ◽  
Songhua Zhang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Anti Tumor Activity ◽  
Antibody Drug

scholarly journals Pancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy

2019 ◽  
Author(s):  
Zhikai Wang ◽  
Ran Yan ◽  
Jiayun Li ◽  
Ya Gao ◽  
Philip Moresco ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Transglutaminase 2 ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblast ◽  
Pancreatic Cancer Cells ◽  
Keratin 19

AbstractHow pancreatic ductal adenocarcinoma (PDA) cells stimulate CXCR4 to exclude T cells and resist T cell checkpoint inhibitors is not known. Here, we find that CXCL12, the ligand for CXCR4 that is produced by the cancer-associated fibroblast, “coats” human PDA and colorectal cancer cells as covalent heterodimers with keratin 19 (KRT19). Modeling the formation of the heterodimer with three proteins shows that KRT19 binds CXCL12 and transglutaminase-2 (TGM2), and that TGM2 converts the reversible KRT19-CXCL12 complex into a covalent heterodimer. We validate this model by showing that cancer cells in mouse PDA tumors must express KRT19 and TGM2 to become coated with CXCL12, exclude T cells, and resist immunotherapy with anti-PD-1 antibody. Thus, PDA cells have a cell-autonomous means by which they capture CXCL12 to mediate immune suppression, which is potentially amenable to therapy.One Sentence SummaryCancer cells in pancreatic ductal adenocarcinoma use transglutaminase-2 to assemble a coating comprised of covalent CXCL12-keratin 19 heterodimers that excludes T cells and mediates resistance to inhibition of the PD-1 T cell checkpoint.

scholarly journals Microfluidic Platforms for High-Throughput Pancreatic Ductal Adenocarcinoma Organoid Culture and Drug Screening

2021 ◽  
Vol 9 ◽  
Author(s):  
Marlene Geyer ◽  
Karla Queiroz
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
High Throughput ◽  
Ductal Adenocarcinoma ◽  
Surgical Removal ◽  
Cancer Type ◽  
Tumor Type ◽  
Hypoxic Conditions ◽  
Physicochemical Features ◽  
Immunosuppressive Microenvironment

Pancreatic Ductal Adenocarcinoma (PDAC), the most common pancreatic cancer type, is believed to become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. It is often detected at a late stage due to lacking symptoms, and therefore surgical removal of the tumor is the only treatment option for patients. Only 20% of the tumors are resectable, mainly due to early metastasis. Therefore, for 80% of cases chemotherapeutic treatment is the leading therapy for patients. PDAC is characterized by high-density stroma which induces hypoxic conditions and high interstitial pressure. These factors impact carcinogenesis and progression of PDAC and support the formation of an immunosuppressive microenvironment that renders this tumor type refractory to immunotherapies. Most in vitro PDAC models have limited translational relevance, as these fail to recapitulate relevant aspects of PDAC complexity. Altogether, there is an urgent need for novel and innovative PDAC modeling platforms. Here, we discuss the relevance of microfluidic and organoid technologies as platforms for modeling bio- and physicochemical features of PDAC and as translational models that enable high-throughput phenotypic drug screenings, while also allowing for the development of novel personalized models used to identify treatment responsive patient subsets.

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