scholarly journals Matrix-regulated integrin αvβ5 maintains α5β1-dependent desmoplastic traits prognostic of neoplastic recurrence

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Janusz Franco-Barraza ◽  
Ralph Francescone ◽  
Tiffany Luong ◽  
Neelima Shah ◽  
Raj Madhani ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Plasma Membrane ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Outcomes ◽  
Human Fibroblasts ◽  
3D Culture ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
New Algorithms ◽  
Batch Analysis

Desmoplasia, a fibrotic mass including cancer-associated fibroblasts (CAFs) and self-sustaining extracellular matrix (D-ECM), is a puzzling feature of pancreatic ductal adenocarcinoma (PDACs). Conflicting studies have identified tumor-restricting and tumor-promoting roles of PDAC-associated desmoplasia, suggesting that individual CAF/D-ECM protein constituents have distinguishable tumorigenic and tumor-repressive functions. Using 3D culture of normal pancreatic versus PDAC-associated human fibroblasts, we identified a CAF/D-ECM phenotype that correlates with improved patient outcomes, and that includes CAFs enriched in plasma membrane-localized, active α5β1-integrin. Mechanistically, we established that TGFβ is required for D-ECM production but dispensable for D-ECM-induced naïve fibroblast-to-CAF activation, which depends on αvβ5-integrin redistribution of pFAK-independent active α5β1-integrin to assorted endosomes. Importantly, the development of a simultaneous multi-channel immunofluorescence approach and new algorithms for computational batch-analysis and their application to a human PDAC panel, indicated that stromal localization and levels of active SMAD2/3 and α5β1-integrin distinguish patient-protective from patient-detrimental desmoplasia and foretell tumor recurrences, suggesting a useful new prognostic tool.

scholarly journals Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 799 ◽  
Author(s):  
Cédric Leroux ◽  
Georgia Konstantinidou
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Outcomes ◽  
Targeted Therapies ◽  
Median Overall Survival ◽  
Advanced Disease ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Personalized Oncology

Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes.

scholarly journals Syndecans and Pancreatic Ductal Adenocarcinoma

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 349
Author(s):  
Nausika Betriu ◽  
Juan Bertran-Mas ◽  
Anna Andreeva ◽  
Carlos E. Semino
Keyword(s):  
Extracellular Matrix ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Physiological Processes ◽  
Extracellular Matrix Components ◽  
Detection And Diagnosis ◽  
And Migration ◽  
Early Detection And Diagnosis

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.

scholarly journals CXCR2 signaling promotes secretory cancer‐associated fibroblasts in pancreatic ductal adenocarcinoma

2020 ◽  
Vol 34 (7) ◽  
pp. 9405-9418 ◽  
Author(s):  
Mohammad Awaji ◽  
Sugandha Saxena ◽  
Lingyun Wu ◽  
Dipakkumar R. Prajapati ◽  
Abhilasha Purohit ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts

Glycolytic regulation of the plasma membrane Ca2+ atpase in pancreatic ductal adenocarcinoma

Pancreatology ◽  
2013 ◽  
Vol 13 (2) ◽  
pp. e36
Author(s):  
A. James ◽  
A. Chan ◽  
O. Erice ◽  
A. Siriwardena ◽  
J. Bruce
Keyword(s):  
Plasma Membrane ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma

scholarly journals Cancer-associated fibroblasts promote M2 polarization of macrophages in pancreatic ductal adenocarcinoma

2017 ◽  
Vol 6 (2) ◽  
pp. 463-470 ◽  
Author(s):  
Aibin Zhang ◽  
Yigang Qian ◽  
Zhou Ye ◽  
Haiyong Chen ◽  
Haiyang Xie ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
M2 Polarization

scholarly journals Erlotinib Promotes Ligand-Induced EGFR Degradation in 3D but Not 2D Cultures of Pancreatic Ductal Adenocarcinoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4504
Author(s):  
Nausika Betriu ◽  
Anna Andreeva ◽  
Carlos E. Semino
Keyword(s):  
Tyrosine Kinase ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Kinase Inhibitor ◽  
3D Culture ◽  
Ductal Adenocarcinoma ◽  
Normal Fibroblast ◽  
Tyrosine Kinase Receptor ◽  
3D Cultures ◽  
Adenocarcinoma Cells ◽  
3D Microenvironment

The epithelial growth factor receptor (EGFR) is a tyrosine kinase receptor that participates in many biological processes such as cell proliferation. In addition, EGFR is overexpressed in many epithelial cancers and therefore is a target for cancer therapy. Moreover, EGFR responds to lots of stimuli by internalizing into endosomes from where it can be recycled to the membrane or further sorted into lysosomes where it undergoes degradation. Two-dimensional cell cultures have been classically used to study EGFR trafficking mechanisms in cancer cells. However, it has been widely demonstrated that in 2D cultures cells are exposed to a non-physiological environment as compared to 3D cultures that provide the normal cellular conformation, matrix dimensionality and stiffness, as well as molecular gradients. Therefore, the microenvironment of solid tumors is better recreated in 3D culture models, and this is why they are becoming a more physiological alternative to study cancer physiology. Here, we develop a new model of EGFR internalization and degradation upon erlotinib treatment in pancreatic ductal adenocarcinoma (PDAC) cells cultured in a 3D self-assembling peptide scaffold. In this work, we show that treatment with the tyrosine kinase inhibitor erlotinib promotes EGFR degradation in 3D cultures of PDAC cell lines but not in 2D cultures. We also show that this receptor degradation does not occur in normal fibroblast cells, regardless of culture dimensionality. In conclusion, we demonstrate not only that erlotinib has a distinct effect on tumor and normal cells but also that pancreatic ductal adenocarcinoma cells respond differently to drug treatment when cultured in a 3D microenvironment. This study highlights the importance of culture systems that can more accurately mimic the in vivo tumor physiology.

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