PO-302 Deconvolution of the tumour microenvironment of primary human pancreatic ductal adenocarcinoma and normal pancreas reveals specific deregulated signalling nodes

AbstractPancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide due to delayed diagnosis and limited treatments. More than 90% of all pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). Extensive communication between tumour cells and other cell types in the tumour microenvironment have been identified which regulate cancer hallmarks during pancreatic tumorigenesis via secretory factors and extracellular vesicles (EVs). The EV-capsuled factors not only facilitate tumour growth locally, but also enter circulation and reach distant organs to construct a pre-metastatic niche. In this review, we delineate the key factors in pancreatic ductal adenocarcinoma derived EVs that mediate different tumour processes. Also, we highlight the factors that are related to the crosstalk with cancer stem cells/cancer-initiating cells (CSC/CIC), the subpopulation of cancer cells that can efficiently metastasize and resist currently used chemotherapies. Lastly, we discuss the potential of EV-capsuled factors in early diagnosis and antitumour therapeutic strategies.

Download Full-text

Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma

Oncology Reports ◽

10.3892/or.2011.1461 ◽

2011 ◽

Cited By ~ 1

Author(s):

Graziella Bellone

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Comparative Evaluation ◽

Ductal Adenocarcinoma ◽

Stem Cell Markers ◽

Normal Pancreas ◽

Cell Markers ◽

Cancer Stem Cell Markers

Download Full-text

Transcriptomic and Immunohistochemical Profiling of SLC6A14 in Pancreatic Ductal Adenocarcinoma

BioMed Research International ◽

10.1155/2015/593572 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Alan R. Penheiter ◽

Sibel Erdogan ◽

Stephen J. Murphy ◽

Steven N. Hart ◽

Joema Felipe Lima ◽

...

Keyword(s):

Computed Tomography ◽

Pancreatic Ductal Adenocarcinoma ◽

Functional Imaging ◽

Basic Amino Acid ◽

Tissue Microarrays ◽

Ductal Adenocarcinoma ◽

Transcriptional Level ◽

Normal Pancreas ◽

Anatomical Imaging

We used a target-centric strategy to identify transporter proteins upregulated in pancreatic ductal adenocarcinoma (PDAC) as potential targets for a functional imaging probe to complement existing anatomical imaging approaches. We performed transcriptomic profiling (microarray and RNASeq) on histologically confirmed primary PDAC tumors and normal pancreas tissue from 33 patients, including five patients whose tumors were not visible on computed tomography. Target expression was confirmed with immunohistochemistry on tissue microarrays from 94 PDAC patients. The best imaging target identified was SLC6A14 (a neutral and basic amino acid transporter). SLC6A14 was overexpressed at the transcriptional level in all patients and expressed at the protein level in 95% of PDAC tumors. Very little is known about the role of SLC6A14 in PDAC and our results demonstrate that this target merits further investigation as a candidate transporter for functional imaging of PDAC.

Download Full-text

Immune responses in pancreatic cancer may be restricted by prevalence of activated regulatory T-cells, dysfunctional and senescent T-cells

10.1101/2020.06.20.163071 ◽

2020 ◽

Author(s):

Shivan Sivakumar ◽

Enas Abu-Shah ◽

David J Ahern ◽

Edward H Arbe-Barnes ◽

Nagina Mangal ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

T Cell ◽

Single Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Regulatory T Cell ◽

Rational Design ◽

Tumour Microenvironment ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma

AbstractObjectivePancreatic cancer has the worst prognosis of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify better therapeutic strategies.DesignIn this study, a multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight human pancreatic cancer patients. Single-cell RNA sequencing dataset analysis was performed on a cohort of 24 patients. Multiplex immunohistochemistry imaging and spatial analysis were performed to map immune infiltration into the tumour microenvironment.ResultsRegulatory T-cell populations demonstrated highly immunosuppressive states with high TIGIT, ICOS and CD39 expression. CD8+ T-cells were found to be either in senescence or an exhausted state. The exhausted CD8 T-cells had low PD-1 expression but high TIGIT and CD39 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset from 24 patients.ConclusionsThese data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.Statement of SignificanceThis study elucidates the T-cell phenotypes in pancreatic ductal adenocarcinoma (PDAC). T-cells potentiate immune-suppression through an activated regulatory T-cell population expressing high TIGIT, ICOS and CD39. CD8+ T-cells were primarily senescent or TIGIT+ exhausted, but with minimal PD-1 expression. These findings propose new immunotherapy targets for PDAC.

Download Full-text

Sonic Hedgehog Ligand: A Role in Formation of a Mesenchymal Niche in Human Pancreatic Ductal Adenocarcinoma

Cells ◽

10.3390/cells8050424 ◽

2019 ◽

Vol 8 (5) ◽

pp. 424 ◽

Cited By ~ 6

Author(s):

Francesca Saini ◽

Richard H. Argent ◽

Anna M. Grabowska

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Sonic Hedgehog ◽

Stromal Cells ◽

Mesenchymal Cell ◽

Tumour Microenvironment ◽

Mixed Population ◽

Ductal Adenocarcinoma ◽

Mesenchymal Phenotype ◽

Poorly Differentiated

Pancreatic ductal adenocarcinoma (PDAC) is characterised by desmoplasia, thought to support progression and chemotherapeutic resistance. The Hedgehog pathway is known to play an important role in this cancer. While the upregulation of Sonic hedgehog (Shh) in the epithelium of PDAC is known, we investigated its expression in the tumour microenvironment in order to find new targets for new chemotherapeutical approaches. Immunohistochemistry was used for the investigation of Shh and Vimentin in primary human pancreatic tissues. Gene (qRT-PCR) and protein (immunofluorescence) expression of Shh, αSMA (a marker of the mesenchymal phenotype) and periostin (a marker of mesenchymal cells within a mixed population) were investigated in in vitro cell models. Shh expression was significantly upregulated in the stromal and epithelial compartments of poorly-differentiated PDAC samples, with a strong correlation with the amount of stroma present. Characterisation of stromal cells showed that there was expression of Shh ligand in a mixed population comprising αSMA+ myofibroblasts and αSMA− mesenchymal stem cells. Moreover, we demonstrated the interaction between these cell lines by showing a higher rate of mesenchymal cell proliferation and the upregulation of periostin. Therefore, targeting stromal Shh could affect the equilibrium of the tumour microenvironment and its contribution to tumour growth.

Download Full-text

Comparison of tumour and serum specific microRNA changes dissecting their role in pancreatic ductal adenocarcinoma: a meta-analysis

BMC Cancer ◽

10.1186/s12885-019-6380-z ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Bishnupriya Chhatriya ◽

Moumita Mukherjee ◽

Sukanta Ray ◽

Piyali Sarkar ◽

Shatakshee Chatterjee ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Target Genes ◽

Meta Analysis ◽

Mirna Expression Profile ◽

Tumour Tissue ◽

Ductal Adenocarcinoma ◽

Disease Development ◽

Normal Pancreas ◽

Circulating Mirnas ◽

Pancreatic Tumour

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive cancers lacking efficient early detection biomarkers. Circulating miRNAs are now being considered to have potency to be used as diagnostic and prognostic biomarkers in different diseases as well as cancers. In case of cancer, a fraction of the circulating miRNAs is actually derived from the tumour tissue. This fraction would function as stable biomarker for the disease and also would contribute to the understanding of the disease development. There are not many studies exploring this aspect in pancreatic cancer and even there is not much overlap of results between existing studies. Methods In order to address that gap, we performed a miRNA microarray analysis to identify differentially expressed circulating miRNAs between PDAC patients and normal healthy individuals and also found two more similar datasets to perform a meta-analysis using a total of 182 PDAC patients and 170 normal, identifying a set of miRNAs significantly altered in patient serum. Next, we found five datasets studying miRNA expression profile in tumour tissues of PDAC patients as compared to normal pancreas and performed a second meta-analysis using data from a total of 183 pancreatic tumour and 47 normal pancreas to detect significantly deregulated miRNAs in pancreatic carcinoma. Comparison of these two lists and subsequent search for their target genes which were also deregulated in PDAC in inverse direction to miRNAs was done followed by investigation of their role in disease development. Results We identified 21 miRNAs altered in both pancreatic tumour tissue and serum. While deciphering the functions of their target genes, we characterized key miR-Gene interactions perturbing the biological pathways. We identified important cancer related pathways, pancreas specific pathways, AGE-RAGE signaling, prolactin signaling and insulin resistance signaling pathways among the most affected ones. We also reported the possible involvement of crucial transcription factors in the process. Conclusions Our study identified a unique meta-signature of 21 miRNAs capable of explaining pancreatic carcinogenesis and possibly holding the potential to act as biomarker for the disease detection which could be explored further.

Download Full-text