Identification and Validation of Novel Subtype-Specific Protein Biomarkers in Pancreatic Ductal Adenocarcinoma

Kuhlmann, Laura; Nadler, Wiebke; Kerner, Alexander; Hanke, Sabrina; Noll, Elisa M.; Eisen, Christian; Espinet, Elisa; Vogel, Vanessa; Trumpp, Andreas; Sprick, Martin R.; Roesli, Christoph

doi:10.1097/mpa.0000000000000743

Cited by 23 publications

(18 citation statements)

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“…As a result, the implications of tumour cellularity on transcriptomic analysis remain a priority area of research. However, several studies have demonstrated that epithelial cell lines of PDAC recapitulate published transcriptomic subtypes, including transcripts native to pancreatic exocrine and endocrine cells defining an aberrantly differentiated endocrine exocrine subtype (ADEX).…”

Section: Discussionmentioning

confidence: 99%

Defining the molecular pathology of pancreatic body and tail adenocarcinoma

Dreyer

Jamieson

Upstill-Goddard

et al. 2018

British Journal of Surgery

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BackgroundPancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large‐scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas.MethodsDetailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study.ResultsClinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole‐genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial‐to‐mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer.ConclusionPDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Defining the molecular pathology of pancreatic body and tail adenocarcinoma

Dreyer

Jamieson

Upstill-Goddard

et al. 2018

British Journal of Surgery

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“…Collisson and colleagues have classified pancreatic cancer into three molecular subtypes, that is, classical, exocrine-like and quasimesenchymal, with each subtype presenting different response rates to therapy and survival [19]. Notably, by a recent proteomics approach, galectin 4 was identified as a biomarker for the exocrine-like subtype, characterized by resistance to tyrosine kinase inhibitors and paclitaxel [20]. This information has high clinical relevance as it indicates that galectin 4 expression may be used to predict the response to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Galectin 4 is a biomarker for early recurrence and death after surgical resection for pancreatic ductal adenocarcinoma

Ansari

Zhou

et al. 2019

Scandinavian Journal of Gastroenterology

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Background: Galectins are a group of carbohydrate-binding proteins that are involved in neoplastic development and progression. In a previous mass spectrometry-based study, we identified galectin 4 as a down-regulated protein in short-term survivors of pancreatic cancer. This study was performed to validate the prognostic value of galectin 4 in a larger cohort of pancreatic cancer patients undergoing surgical resection. Methods: Galectin 4 expression was evaluated by tissue microarrays and immunohistochemistry in 140 patients with surgically resected pancreatic cancer. Kaplan-Meier and Cox proportional hazards modeling were used to explore the association between galectin 4 and survival. Results: Galectin 4 staining expression was positive in 111 cases (79.3%). The expression of galectin 4 was significantly associated with tumor size (p ¼ .008) and differentiation (p ¼ .001). Galectin 4 expression was significantly correlated with disease recurrence within 1 year of surgery (adjusted HR 0.485, p ¼ .027). There was also a significant association between galectin 4 and overall survival at 1 year (adjusted HR 0.482, p ¼ .047) and at 3 years (adjusted HR 0.550, p ¼ .025). Conclusion: Galectin 4 expression is a novel biomarker for early recurrence and mortality after surgical resection for pancreatic cancer.

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“…In primary colorectal cancers and intestinal metaplasia of the stomach, CDX2 and CDH17 expression are highly correlated in a positive way as CDX2 promotes CDH17 expression [26]. CDH17 is highly expressed in hepatocellular carcinoma [32][33][34], gastric cancer [35,36], pancreatic cancer [37,38]-and particularly in the exocrine-like subtype of pancreatic ductal adenocarcinoma [39], esophagus carcinoma, neuroendocrine tumors [40,41] and colorectal cancer [26,38,42,43]-with 96% of tumor samples showing expression of this molecule [38] ( Table 1). Different studies have described a clear association of high expression of CDH17 with either lung [42] or liver metastasis in human colon cancer [44], in which it correlates with poor prognosis [45].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

RGD cadherins and α2β1 integrin in cancer metastasis: A dangerous liaison

Casal

Bartolomé

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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We propose a new cadherin family classification comprising epithelial cadherins (cadherin 17 [CDH17], cadherin 16, VE-cadherin, cadherin 6 and cadherin 20) containing RGD motifs within their sequences. Expression of some RGD cadherins is associated with aggressive forms of cancer during the late stages of metastasis, and CDH17 and VE-cadherin have emerged as critical actors in cancer metastasis. After binding to α2β1 integrin, these cadherins promote integrin β1 activation, and thereby cell adhesion, invasion and proliferation, in liver and lung metastasis. Activation of α2β1 integrin provokes an affinity increase for type IV collagen, a major component of the basement membrane and a critical partner for cell anchoring in liver and other metastatic organs. Activation of α2β1 integrin by RGD motifs breaks an old paradigm of integrin classification and supports an important role of this integrin in cancer metastasis. Recently, synthetic peptides containing the RGD motif of CDH17 elicited highly specific and selective antibodies that block the ability of CDH17 RGD to activate α2β1 integrin. These monoclonal antibodies inhibit metastatic colonization in orthotopic mouse models of liver and lung metastasis for colorectal cancer and melanoma, respectively. Hopefully, blocking the cadherin RGD ligand capacity will give us control over the integrin activity in solid tumors metastasis, paving the way for development of new agents of cancer treatment.

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Identification and Validation of Novel Subtype-Specific Protein Biomarkers in Pancreatic Ductal Adenocarcinoma

Abstract: The study reports the identification and validation of novel PDAC biomarkers relevant for the development of patient stratification tools. In addition, cadherin-17 and galectin-4 may serve as targets for bispecific antibodies as novel therapeutics in PDAC.

Cited by 23 publications

References 50 publications

Defining the molecular pathology of pancreatic body and tail adenocarcinoma

Defining the molecular pathology of pancreatic body and tail adenocarcinoma

Galectin 4 is a biomarker for early recurrence and death after surgical resection for pancreatic ductal adenocarcinoma

RGD cadherins and α2β1 integrin in cancer metastasis: A dangerous liaison

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