The implication of long non-coding RNAs in the diagnosis, pathogenesis and drug resistance of pancreatic ductal adenocarcinoma and their possible therapeutic potential

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.

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Increased Expression of Tissue Transglutaminase in Pancreatic Ductal Adenocarcinoma and Its Implications in Drug Resistance and Metastasis

Cancer Research ◽

10.1158/0008-5472.can-06-2387 ◽

2006 ◽

Vol 66 (21) ◽

pp. 10525-10533 ◽

Cited By ~ 105

Author(s):

Amit Verma ◽

Huamin Wang ◽

Bramanandam Manavathi ◽

Jansina Y. Fok ◽

Aman P. Mann ◽

...

Keyword(s):

Drug Resistance ◽

Pancreatic Ductal Adenocarcinoma ◽

Tissue Transglutaminase ◽

Ductal Adenocarcinoma

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

International Journal of Molecular Sciences ◽

10.3390/ijms19103219 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3219 ◽

Cited By ~ 11

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.

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Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels

Bioscience Reports ◽

10.1042/bsr20200401 ◽

2020 ◽

Vol 40 (7) ◽

Cited By ~ 1

Author(s):

Jiali Du ◽

Jichun Gu ◽

Ji Li

Keyword(s):

Drug Resistance ◽

Clinical Trials ◽

Phase I ◽

Pancreatic Ductal Adenocarcinoma ◽

Solid Tumours ◽

Phase Iii ◽

Ductal Adenocarcinoma ◽

Phase Iii Trials ◽

Exploitation And Exploration ◽

Different Levels

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.

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

Tumor Biology ◽

10.1177/1010428320965279 ◽

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.

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