The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy

Reader, Claire S.; Vallath, Sabari; Steele, Colin W.; Haider, Syed; Brentnall, Adam R.; Desai, Ami; Moore, Kate M.; Jamieson, Nigel B.; Chang, David K.; Bailey, Peter J.; Scarpa, Aldo; Lawlor, Rita T.; Chelala, Claude; Keyse, Stephen M.; Biankin, Andrew V.; Morton, Jennifer P.; Evans, T.R.J.; Barry, Simon T.; Sansom, Owen J.; Kocher, Hemant M.; Marshall, John F.

doi:10.1002/path.5320

Cited by 73 publications

(74 citation statements)

References 30 publications

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“…Notably, violin plots of gene expression by pathological stages based on the TCGA PAAD data showed that twenty-one of the identified prognostic genes (ITGB6, LAMC2, KRT7, SERPINB5, IGF2BP3, IL1RN, MPZL2, SFTA2, MET, LAMA3, ARNTL2, SLC2A1, LAMB3, COL17A1, EPSTI1, IL1RAP, AK4, ANXA2, S100A16, KRT19, and GPRC5A) also significantly correlated with pathological stages of the disease, indicating that these genes may play crucial roles in the tumorigenesis of PDAC. As expected, some of these identified genes have been reported to be associated with poor overall survival of patients with pancreatic cancer ( Cheng et al, 2019 ; Hu et al, 2019 ; Jahny et al, 2017 ; Pei, Yin & Liu, 2018 ; Reader et al, 2019 ; Schaeffer et al, 2010 ; Takahashi et al, 2019 ; Wu et al, 2019 ; Yao et al, 2016 ; Zhang et al, 2019 ). However, the functional and clinicopathological significance of IL1RN, MPZL2, SFTA2, EPSTI1, IL1RAP, AK4 and S100A16 in PDAC have not been reported.…”

Section: Discussionsupporting

confidence: 73%

Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

Atay

2020

PeerJ

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A comprehensive meta-analysis of publicly available gene expression microarray data obtained from human-derived pancreatic ductal adenocarcinoma (PDAC) tissues and their histologically matched adjacent tissue samples was performed to provide diagnostic and prognostic biomarkers, and molecular targets for PDAC. An integrative meta-analysis of four submissions (GSE62452, GSE15471, GSE62165, and GSE56560) containing 105 eligible tumor-adjacent tissue pairs revealed 344 differentially over-expressed and 168 repressed genes in PDAC compared to the adjacent-to-tumor samples. The validation analysis using TCGA combined GTEx data confirmed 98.24% of the identified up-regulated and 73.88% of the down-regulated protein-coding genes in PDAC. Pathway enrichment analysis showed that “ECM-receptor interaction”, “PI3K-Akt signaling pathway”, and “focal adhesion” are the most enriched KEGG pathways in PDAC. Protein-protein interaction analysis identified FN1, TIMP1, and MSLN as the most highly ranked hub genes among the DEGs. Transcription factor enrichment analysis revealed that TCF7, CTNNB1, SMAD3, and JUN are significantly activated in PDAC, while SMAD7 is inhibited. The prognostic significance of the identified and validated differentially expressed genes in PDAC was evaluated via survival analysis of TCGA Pan-Cancer pancreatic ductal adenocarcinoma data. The identified candidate prognostic biomarkers were then validated in four external validation datasets (GSE21501, GSE50827, GSE57495, and GSE71729) to further improve reliability. A total of 28 up-regulated genes were found to be significantly correlated with worse overall survival in patients with PDAC. Twenty-one of the identified prognostic genes (ITGB6, LAMC2, KRT7, SERPINB5, IGF2BP3, IL1RN, MPZL2, SFTA2, MET, LAMA3, ARNTL2, SLC2A1, LAMB3, COL17A1, EPSTI1, IL1RAP, AK4, ANXA2, S100A16, KRT19, and GPRC5A) were also found to be significantly correlated with the pathological stages of the disease. The results of this study provided promising prognostic biomarkers that have the potential to differentiate PDAC from both healthy and adjacent-to-tumor pancreatic tissues. Several novel dysregulated genes merit further study as potentially promising candidates for the development of more effective treatment strategies for PDAC.

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Section: Discussionsupporting

confidence: 73%

Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

Atay

2020

PeerJ

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“…Peptide sequences from other viruses had also been shown to target an Ad-based therapy towards cancer cells. Insertion of a 20-aa peptide, NAVPNLRGDLQVLAQKART, native to foot and mouth disease virus (FMDV) was identified as a binding peptide sequence to αvβ6 integrin [ 145 ], an integrin that is reported to be upregulated in certain epithelial cancers, including breast, ovarian, pancreatic and colorectal [ 146 , 147 , 148 ]. Figure 6 illustrates the Ad5 fibre knob protein engineered to present the A20 peptide within the HI loop in complex with αvβ6 integrin.…”

Section: Retargeting Strategiesmentioning

confidence: 99%

Hitting the Target but Missing the Point: Recent Progress towards Adenovirus-Based Precision Virotherapies

Cunliffe

Bates

Parker

2020

Cancers

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More people are surviving longer with cancer. Whilst this can be partially attributed to advances in early detection of cancers, there is little doubt that the improvement in survival statistics is also due to the expansion in the spectrum of treatments available for efficacious treatment. Transformative amongst those are immunotherapies, which have proven effective agents for treating immunogenic forms of cancer, although immunologically “cold” tumour types remain refractive. Oncolytic viruses, such as those based on adenovirus, have great potential as anti-cancer agents and have seen a resurgence of interest in recent years. Amongst their many advantages is their ability to induce immunogenic cell death (ICD) of infected tumour cells, thus providing the alluring potential to synergise with immunotherapies by turning immunologically “cold” tumours “hot”. Additionally, enhanced immune mediated cell killing can be promoted through the local overexpression of immunological transgenes, encoded from within the engineered viral genome. To achieve this full potential requires the development of refined, tumour selective “precision virotherapies” that are extensively engineered to prevent off-target up take via native routes of infection and targeted to infect and replicate uniquely within malignantly transformed cells. Here, we review the latest advances towards this holy grail within the adenoviral field.

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“…However, after three days co-culture, only SB321542 was effective, indicating that whilst initial CAF activation was αvβ6-dependent, once activated, alternative TGFβ activating pathways maintain the phenotype [53,136]. Treatment of αvβ6-expressing transgenic pancreatic ductal adenocarcinoma (PDAC) with 264RAD plus gemcitabine significantly increased overall survival compared with gemcitabine alone and was associated with reductions in both pSmad3 and nuclear Smad4 levels, as well as reductions in αSMA-positive fibroblasts and blood vessel density, both targets of TGFβ signalling [137].…”

Section: Tgfβ In Cancermentioning

confidence: 99%

Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment

Brown

Marshall

2019

Cancers

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TGFβ (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGFβ acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream signalling within the TGFβ pathway, and in established tumours, TGFβ then acts as a tumour promotor through multiple mechanisms including inducing epithelial-to-mesenchymal transition (EMT), promoting formation of cancer-associated fibroblasts (CAFs) and increasing angiogenesis. TGFβ is secrereted as a large latent complex and is embedded in the extracellular matrix or held on the surface of cells and must be activated before mediating its multiple functions. Thus, whilst TGFβ is abundant in the tumour microenvironment (TME), its functionality is regulated by local activation. The αv-integrins are major activators of latent-TGFβ. The potential benefits of manipulating the immune TME have been highlighted by the clinical success of immune-checkpoint inhibitors in a number of solid tumour types. TGFβ is a potent suppressor of T-cell-mediated immune surveillance and a key cause of resistance to checkpoint inhibitors. Therefore, as certain integrins locally activate TGFβ, they are likely to have a role in the immunosuppressive TME, although this remains to be confirmed. In this review, we discussed the role of TGFβ in cancer, the role of integrins in activating TGFβ in the TME, and the potential benefits of targeting integrins to augment immunotherapies.

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The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy

Cited by 73 publications

References 30 publications

Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

Hitting the Target but Missing the Point: Recent Progress towards Adenovirus-Based Precision Virotherapies

Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment

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