Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma

AbstractPancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65–97%) and specificity (86%, 95% CI: 79–91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.

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ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer

Science Advances ◽

10.1126/sciadv.aax2770 ◽

2019 ◽

Vol 5 (9) ◽

pp. eaax2770 ◽

Cited By ~ 7

Author(s):

Praneeth R. Kuninty ◽

Ruchi Bansal ◽

Susanna W. L. De Geus ◽

Deby F. Mardhian ◽

Jonas Schnittert ◽

...

Keyword(s):

Therapeutic Potential ◽

Tumor Stroma ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Tumor Penetration ◽

Desmoplastic Stroma ◽

Integrin Α5

Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.

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Pancreatic Ductal Adenocarcinoma: Preclinical in vitro and ex vivo Models

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.741162 ◽

2021 ◽

Vol 9 ◽

Author(s):

Beate Gündel ◽

Xinyuan Liu ◽

Matthias Löhr ◽

Rainer Heuchel

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ex Vivo ◽

Treatment Options ◽

3D Cell Culture ◽

Therapy Resistance ◽

Ductal Adenocarcinoma ◽

The Past ◽

Slow Progress

Pancreatic ductal adenocarcinoma (PDAC) is one of the most overlooked cancers despite its dismal median survival time of 6 months. The biggest challenges in improving patient survival are late diagnosis due to lack of diagnostic markers, and limited treatment options due to almost complete therapy resistance. The past decades of research identified the dense stroma and the complex interplay/crosstalk between the cancer- and the different stromal cells as the main culprits for the slow progress in improving patient outcome. For better ex vivo simulation of this complex tumor microenvironment the models used in PDAC research likewise need to become more diverse. Depending on the focus of the investigation, several in vitro and in vivo models for PDAC have been established in the past years. Particularly, 3D cell culture such as spheroids and organoids have become more frequently used. This review aims to examine current PDAC in vitro models, their inherent limitations, and their successful implementations in research.

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The Role of Circular RNAs in Pancreatic Ductal Adenocarcinoma and Biliary-Tract Cancers

Cancers ◽

10.3390/cancers12113250 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3250

Author(s):

Christopher Limb ◽

Daniel S. K. Liu ◽

Morten T. Veno ◽

Eleanor Rees ◽

Jonathan Krell ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Biliary Tract ◽

Ex Vivo ◽

Expression Profiles ◽

Ductal Adenocarcinoma ◽

Circular Rnas ◽

Specific Expression ◽

Biliary Tract Cancers ◽

Cerna Network

Pancreatic Ductal Adenocarcinoma (PDAC) and biliary-tract cancers (BTC) often present at a late stage, and consequently patients have poor survival-outcomes. Circular RNAs (circRNAs) are non-coding RNA molecules whose role in tumourigenesis has recently been realised. They are stable, conserved and abundant, with tissue-specific expression profiles. Therefore, significant interest has arisen in their use as potential biomarkers for PDAC and BTC. High-throughput methods and more advanced bioinformatic techniques have enabled better profiling and progressed our understanding of how circRNAs may function in the competing endogenous RNA (ceRNA) network to influence the transcriptome in these cancers. Therefore, the aim of this systematic review was to describe the roles of circRNAs in PDAC and BTC, their potential as biomarkers, and their function in the wider ceRNA network in regulating microRNAs and the transcriptome. Medline, Embase, Scopus and PubMed were systematically reviewed to identify all the studies addressing circRNAs in PDAC and BTC. A total of 32 articles were included: 22 considering PDAC, 7 for Cholangiocarcinoma (CCA) and 3 for Gallbladder Cancer (GBC). There were no studies investigating Ampullary Cancer. Dysregulated circRNA expression was associated with features of malignancy in vitro, in vivo, and ex vivo. Overall, there have been very few PDAC and BTC tissues profiled for circRNA signatures. Therefore, whilst the current studies have demonstrated some of their functions in these cancers, further work is required to elucidate their potential role as cancer biomarkers in tissue, biofluids and biopsies.

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KRASG12D and TP53R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus Scrofa Pigs

10.1101/358416 ◽

2018 ◽

Author(s):

Daniel R. Principe ◽

Nana Haahr Overgaard ◽

Alex J. Park ◽

Andrew M. Diaz ◽

Carolina Torres ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Sus Scrofa ◽

Cancer Biology ◽

Ductal Adenocarcinoma ◽

Large Animal Model ◽

Large Animal ◽

Desmoplastic Stroma ◽

Immunocompromised Mice

AbstractAlthough survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRASG12D-TP53R167H cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreaticduct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight into new avenues of translational research not before possible in rodents.

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Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours

Gut ◽

10.1136/gutjnl-2021-325180 ◽

2021 ◽

pp. gutjnl-2021-325180

Author(s):

Hsi-Chien Huang ◽

Yun-Chieh Sung ◽

Chung-Pin Li ◽

Dehui Wan ◽

Po-Han Chao ◽

...

Keyword(s):

Nitric Oxide ◽

Phage Display ◽

Tumour Microenvironment ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Tumour Stroma ◽

Desmoplastic Stroma ◽

Trail Resistance

ObjectiveStromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC.DesignNitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro–in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo.ResultsThe delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy.ConclusionThe co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.

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In vitro, in vivo and ex vivo demonstration of the antitumoral role of hypocretin-1/orexin-A and almorexant in pancreatic ductal adenocarcinoma

Oncotarget ◽

10.18632/oncotarget.24084 ◽

2018 ◽

Vol 9 (6) ◽

pp. 6952-6967 ◽

Cited By ~ 4

Author(s):

Stéphanie Dayot ◽

Daniela Speisky ◽

Anne Couvelard ◽

Pierre Bourgoin ◽

Valérie Gratio ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ex Vivo ◽

Ductal Adenocarcinoma ◽

Orexin A ◽

Hypocretin 1

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Abstract B57: Effects of MEK inhibition alone or in combination with PI3K-mTOR pathway inhibitors in pancreatic ductal adenocarcinoma in vitro and on an innovative ex vivo fresh tumor tissue culture model

10.1158/1538-7445.panca16-b57 ◽

2016 ◽

Author(s):

Cindy Neuzillet ◽

Annemilaï Tijeras-Raballand ◽

Anguraj Sadanandam ◽

Pierre Bourgoin ◽

Philippe Bourget ◽

...

Keyword(s):

Tissue Culture ◽

Pancreatic Ductal Adenocarcinoma ◽

Tumor Tissue ◽

Ex Vivo ◽

Mtor Pathway ◽

Ductal Adenocarcinoma ◽

Mek Inhibition ◽

Culture Model ◽

Tissue Culture Model

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Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer

Nature Communications ◽

10.1038/s41467-020-18636-w ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Hemant M. Kocher ◽

Bristi Basu ◽

Fieke E. M. Froeling ◽

Debashis Sarker ◽

Sarah Slater ◽

...

Keyword(s):

Clinical Trial ◽

Retinoic Acid ◽

Controlled Trial ◽

Locally Advanced ◽

Maximum Tolerated Dose ◽

Assessment Method ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1–15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6–15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.

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The role of S100A9 in the interaction between pancreatic ductal adenocarcinoma cells and stromal cells

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-03026-y ◽

2021 ◽

Author(s):

Pin-Jui Kung ◽

Ting-Yu Lai ◽

Jerry Cao ◽

Li-Chung Hsu ◽

Tsai-Chen Chiang ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Survival Data ◽

Metastatic Potential ◽

Gene Expression Omnibus ◽

High Expression ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Cancer Tissue ◽

Pancreatic Cancer Cells

Abstract Background A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. Methods We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found candidate genes that were differentially expressed in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas. Results We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. Conclusions PSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.

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