Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 8%, and is predicted to become the second leading cause of cancer-related death by 2030. Alongside late detection, which impacts upon surgical treatment, PDAC tumours are challenging to treat due to their desmoplastic stroma and hypovascular nature, which limits the effectiveness of chemotherapy and radiotherapy. Pancreatic stellate cells (PSCs), which form a key part of this stroma, become activated in response to tumour development, entering into cross-talk with cancer cells to induce tumour cell proliferation and invasion, leading to metastatic spread. We and others have shown that Fibroblast Growth Factor Receptor (FGFR) signalling can play a critical role in the interactions between PDAC cells and the tumour microenvironment, but it is clear that the FGFR signalling pathway is not acting in isolation. Here we describe our current understanding of the mechanisms by which FGFR signalling contributes to PDAC progression, focusing on its interaction with other pathways in signalling networks and discussing the therapeutic approaches that are being developed to try and improve prognosis for this terrible disease.

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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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Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem

Nature Communications ◽

10.1038/s41467-018-05906-x ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 77

Author(s):

Xuexiang Han ◽

Yiye Li ◽

Ying Xu ◽

Xiao Zhao ◽

Yinlong Zhang ◽

...

Keyword(s):

Drug Delivery ◽

Stromal Cells ◽

Stellate Cells ◽

Tumour Microenvironment ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Combination Strategy ◽

Therapeutic Modalities ◽

Wide Range ◽

Desmoplastic Stroma

AbstractPancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.

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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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CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target

Cancers ◽

10.3390/cancers14010086 ◽

2021 ◽

Vol 14 (1) ◽

pp. 86

Author(s):

Shivani Malik ◽

Jill M. Westcott ◽

Rolf A. Brekken ◽

Francis J. Burrows

Keyword(s):

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Therapeutic Drug ◽

Cancer Associated Fibroblasts ◽

Term Survival ◽

Farnesyl Transferase ◽

Chemokine Cxcl12 ◽

Tumor Environment ◽

Desmoplastic Stroma ◽

Activated Fibroblasts

Pancreatic ductal adenocarcinoma (PDAC) is a disease with limited therapeutic options and dismal long-term survival. The unique tumor environment of PDAC, consisting of desmoplastic stroma, immune suppressive cells, and activated fibroblasts, contributes to its resistance to therapy. Activated fibroblasts (cancer-associated fibroblasts and pancreatic stellate cells) secrete chemokines and growth factors that support PDAC growth, spread, chemoresistance, and immune evasion. In this review, we focus on one such chemokine, CXCL12, secreted by the cancer-associated fibroblasts and discuss its contribution to several of the classical hallmarks of PDAC and other tumors. We review the various therapeutic approaches in development to target CXCL12 signaling in PDAC. Finally, we propose an unconventional use of tipifarnib, a farnesyl transferase inhibitor, to inhibit CXCL12 production in PDAC.

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Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

Journal of Experimental Medicine ◽

10.1084/jem.20162024 ◽

2017 ◽

Vol 214 (3) ◽

pp. 579-596 ◽

Cited By ~ 471

Author(s):

Daniel Öhlund ◽

Abram Handly-Santana ◽

Giulia Biffi ◽

Ela Elyada ◽

Ana S. Almeida ◽

...

Keyword(s):

Direct Evidence ◽

Smooth Muscle Actin ◽

Tumor Biology ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Neoplastic Cells ◽

Disease Etiology ◽

Elevated Expression ◽

Therapeutic Development ◽

Desmoplastic Stroma

Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.

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Does the Microenvironment Hold the Hidden Key for Functional Precision Medicine in Pancreatic Cancer?

Cancers ◽

10.3390/cancers13102427 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2427

Author(s):

John Kokkinos ◽

Anya Jensen ◽

George Sharbeen ◽

Joshua A. McCarroll ◽

David Goldstein ◽

...

Keyword(s):

Precision Medicine ◽

Ex Vivo ◽

Performance Status ◽

Treatment Options ◽

Critical Role ◽

Tumour Microenvironment ◽

Tumour Cells ◽

Ductal Adenocarcinoma ◽

Preclinical Models ◽

Culture Models

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and no significant improvement in patient survival has been seen in the past three decades. Treatment options are limited and selection of chemotherapy in the clinic is usually based on the performance status of a patient rather than the biology of their disease. In recent years, research has attempted to unlock a personalised treatment strategy by identifying actionable molecular targets in tumour cells or using preclinical models to predict the effectiveness of chemotherapy. However, these approaches rely on the biology of PDAC tumour cells only and ignore the importance of the microenvironment and fibrotic stroma. In this review, we highlight the importance of the microenvironment in driving the chemoresistant nature of PDAC and the need for preclinical models to mimic the complex multi-cellular microenvironment of PDAC in the precision medicine pipeline. We discuss the potential for ex vivo whole-tissue culture models to inform precision medicine and their role in developing novel therapeutic strategies that hit both tumour and stromal compartments in PDAC. Thus, we highlight the critical role of the tumour microenvironment that needs to be addressed before a precision medicine program for PDAC can be implemented.

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Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma

Cancers ◽

10.3390/cancers13163969 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3969

Author(s):

Juliana B. Candido ◽

Oscar Maiques ◽

Melanie Boxberg ◽

Verena Kast ◽

Eleonora Peerani ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Standard Of Care ◽

Tumour Microenvironment ◽

Ductal Adenocarcinoma ◽

Therapeutic Approaches ◽

Novel Treatments ◽

Pancreatic Cancer Cells ◽

Invasive Tumour ◽

Mrna And Protein Expression

As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.

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

npj Precision Oncology ◽

10.1038/s41698-021-00192-1 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Michelle R. Goulart ◽

Jennifer Watt ◽

Imran Siddiqui ◽

Rita T. Lawlor ◽

Ahmet Imrali ◽

...

Keyword(s):

Clinical Trial ◽

Pancreatic Ductal Adenocarcinoma ◽

Ex Vivo ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Diagnostic Biomarkers ◽

All Trans Retinoic Acid ◽

Desmoplastic Stroma ◽

Predictive Role

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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Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches

Cancers ◽

10.3390/cancers13236135 ◽

2021 ◽

Vol 13 (23) ◽

pp. 6135

Author(s):

Tiago M. A. Carvalho ◽

Daria Di Molfetta ◽

Maria Raffaella Greco ◽

Tomas Koltai ◽

Khalid O. Alfarouk ◽

...

Keyword(s):

Gene Mutations ◽

Response To Therapy ◽

Ductal Adenocarcinoma ◽

Therapeutic Approaches ◽

Stromal Compartment ◽

Multiple Gene ◽

New Concepts ◽

Acidic Extracellular Ph ◽

Desmoplastic Stroma

Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.

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Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

10.21203/rs.3.rs-22558/v2 ◽

2020 ◽

Author(s):

Shatovisha Dey ◽

Sheng Liu ◽

Tricia D Factora ◽

Solaema Taleb ◽

Primavera Riverahernandez ◽

...

Keyword(s):

Differentially Expressed Genes ◽

Stellate Cell ◽

Critical Role ◽

Differentially Expressed ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Pancreatic Stellate Cell ◽

Western Blots ◽

Incidence And Mortality

Abstract BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. MethodsIn this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing hPSC cells and controls. Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top candidate miR-29a targets in hPSC cells transfected with miR-29a mimic or scramble control. ResultsRNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. ConclusionsTogether, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-tumor cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies.

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