Proteomic profiling of small extracellular vesicles derived from mouse pancreatic cancer and stellate cells: Role in pancreatic cancer.

Small extracellular vesicles (sEVs) are cell-derived vesicles evolving as important elements involved in all stages of cancers. sEVs bear unique protein signatures that may serve as biomarkers. Pancreatic cancer (PC) records a very poor survival rate owing to its late diagnosis and several cancer cell-derived proteins have been reported as candidate biomarkers. However, given the pivotal role played by stellate cells (PSCs, which produce the collagenous stroma in PC), it is essential to also assess PSC-sEV cargo in biomarker discovery. Thus, this study aimed to isolate and characterise sEVs from mouse PC cells and PSCs cultured alone or as co-cultures and performed proteomic profiling and pathway analysis. Proteomics confirmed the enrichment of specific markers in the sEVs compared to their cells of origin as well as the proteins that are known to express in each of the culture types. Most importantly, for the first time it was revealed that PSC-sEVs are enriched in proteins (including G6PI, PGAM1, ENO1, ENO3, and LDHA) that mediate pathways related to development of diabetes, such as glucose metabolism and gluconeogenesis revealing a potential role of PSCs in pancreatic cancer-related diabetes (PCRD). PCRD is now considered a harbinger of PC and further research will enable to identify the role of these components in PCRD and may develop as novel candidate biomarkers of PC.

Role of Pancreatic Tumour-Derived Exosomes and Their Cargo in Pancreatic Cancer-Related Diabetes.

One of the most common and deadly types of pancreatic cancer (PC) is pancreatic ductal adenocarcinoma (PDAC), with most patients succumbing to the disease within one year of diagnosis. Current detection strategies do not address asymptomatic PC; therefore, patients are diagnosed at an advanced stage when curative treatment is often no longer possible. In order to detect PC in asymptomatic patients earlier, the risk factors that could serve as reliable markers need to be examined. Diabetic mellitus (DM) is a significant risk factor for this malignancy and can be both a cause and consequence of PC. Typically, DM caused by PC is known as new-onset, pancreatogenic, pancreoprivic, or pancreatic cancer-related diabetes (PCRD). Although PCRD is quite distinct from type 2 DM (T2DM), there are currently no biomarkers that differentiate PCRD from T2DM. To identify such biomarkers, a better understanding of the mechanisms mediating PCRD is essential. To this end, there has been a growing research interest in recent years to elucidate the role of tumour-derived exosomes and their cargo in the pathogenesis of PCRD. Exosomes derived from tumours can be recognized for their specificity because they reflect the characteristics of their parent cells and are important in intercellular communication. Their cargo consists of proteins, lipids, and nucleic acids, which can be transferred to and alter the behaviour of recipient cells. This review provides a concise overview of current knowledge regarding tumour-derived exosomes and their cargo in PCRD and discusses the potential areas worthy of further study.

Emerging role of pancreatic stellate cell-derived extracellular vesicles in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that is characterised by a prominent collagenous stromal reaction/desmoplasia surrounding tumour cells. Pancreatic stellate cells (PSCs) are responsible for the production of this stroma and have been shown to facilitate PDAC progression. Recently, extracellular vesicles (EVs), in particular, small extracellular vesicles (exosomes) have been a topic of interest in the field of cancer research for their emerging roles in cancer progression and diagnosis. EVs act as a form of intercellular communication by carrying their molecular cargo from one cell to another, regulating functions of the recipient cells. Although the knowledge of the bi-directional interactions between the PSCs and cancer cells that promote disease progression has advanced significantly over the past decade, studies on PSC-derived EVs in PDAC are currently rather limited. This review provides an overview of PDAC, pancreatic stellate cells and their interactions with cancer cells, as well as the currently known role of extracellular vesicles derived from PSCs in PDAC progression.

Small extracellular vesicles (exosomes) and their cargo in pancreatic cancer: Key roles in the hallmarks of cancer.

Pancreatic cancer (PC) is a devastating disease, offering poor mortality rates for patients. The current challenge being faced is the inability to diagnose patients in a timely manner, where potentially curative resection provides the best chance of survival. Recently, small/nanosized extracellular vesicles (sEVs), including exosomes, have gained significant preclinical and clinical attention due to their emerging roles in cancer progression and diagnosis. Extracellular vesicles (EVs) possess endogenous properties that offer stability and facilitate crossing of biological barriers for delivery of molecular cargo to cells, acting as a form of intercellular communication to regulate function and phenotype of recipient cells. This review provides an overview of the role of EVs, their subtypes and their oncogenic cargo (as characterised by targeted studies as well as agnostic '-omics' analyses) in the pathobiology of pancreatic cancer. The discussion covers the progress of 'omics technology' that has enabled elucidation of the molecular mechanisms that mediate the role of EVs and their cargo in pancreatic cancer progression.

Targeting Wnt/tenascin C-mediated cross talk between pancreatic cancer cells and stellate cells via activation of the metastasis suppressor NDRG1.

A major barrier to successful pancreatic cancer (PC) treatment is the surrounding stroma, which secretes growth factors/cytokines that promote PC progression. Wnt and tenascin C (TnC) are key ligands secreted by stromal pancreatic stellate cells (PSCs) that then act on PC cells in a paracrine manner to activate the oncogenic ß-catenin and YAP/TAZ signaling pathways. Therefore, therapies targeting oncogenic Wnt/TnC cross talk between PC cells and PSCs constitute a promising new therapeutic approach for PC treatment. The metastasis suppressor N-myc downstream-regulated gene-1 (NDRG1) inhibits tumor progression and metastasis in numerous cancers, including PC. We demonstrate herein that targeting NDRG1 using the clinically trialed anticancer agent di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibited Wnt/TnC-mediated interactions between PC cells and the surrounding PSCs. Mechanistically, NDRG1 and DpC markedly inhibit secretion of Wnt3a and TnC by PSCs, while also attenuating Wnt/ß-catenin and YAP/TAZ activation and downstream signaling in PC cells. This antioncogenic activity was mediated by direct inhibition of ß-catenin and YAP/TAZ nuclear localization and by increasing the Wnt inhibitor, DKK1. Expression of NDRG1 also inhibited transforming growth factor (TGF)-ß secretion by PC cells, a key mechanism by which PC cells activate PSCs. Using an in vivo orthotopic PC mouse model, we show DpC downregulated ß-catenin, TnC, and YAP/TAZ, while potently increasing NDRG1 expression in PC tumors. We conclude that NDRG1 and DpC inhibit Wnt/TnC-mediated interactions between PC cells and PSCs. These results further illuminate the antioncogenic mechanism of NDRG1 and the potential of targeting this metastasis suppressor to overcome the oncogenic effects of the PC-PSC interaction.

Role of Pancreatic Stellate Cell-Derived Exosomes in Pancreatic Cancer-Related Diabetes: A Novel Hypothesis.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating condition characterised by vague symptomatology and delayed diagnosis. About 30% of PDAC patients report a history of new onset diabetes, usually diagnosed within 3 years prior to the diagnosis of cancer. Thus, new onset diabetes, which is also known as pancreatic cancer-related diabetes (PCRD), could be a harbinger of PDAC. Diabetes is driven by progressive ß cell loss/dysfunction and insulin resistance, two key features that are also found in PCRD. Experimental studies suggest that PDAC cell-derived exosomes carry factors that are detrimental to ß cell function and insulin sensitivity. However, the role of stromal cells, particularly pancreatic stellate cells (PSCs), in the pathogenesis of PCRD is not known. PSCs are present around the earliest neoplastic lesions and around islets. Given that PSCs interact closely with cancer cells to drive cancer progression, it is possible that exosomal cargo from both cancer cells and PSCs plays a role in modulating ß cell function and peripheral insulin resistance. Identification of such mediators may help elucidate the mechanisms of PCRD and aid early detection of PDAC. This paper discusses the concept of a novel role of PSCs in the pathogenesis of PCRD.

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition.

Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. SIGNIFICANCE: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.

Breaking the cycle: Targeting of NDRG1 to inhibit bi-directional oncogenic cross-talk between pancreatic cancer and stroma.

Pancreatic cancer (PaCa) is characterized by dense stroma that hinders treatment efficacy, with pancreatic stellate cells (PSCs) being a major contributor to this stromal barrier and PaCa progression. Activated PSCs release hepatocyte growth factor (HGF) and insulin-like growth factor (IGF-1) that induce PaCa proliferation, metastasis and resistance to chemotherapy. We demonstrate for the first time that the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), is a potent inhibitor of the PaCa-PSC cross-talk, leading to inhibition of HGF and IGF-1 signaling. NDRG1 also potently reduced the key driver of PaCa metastasis, namely GLI1, leading to reduced PSC-mediated cell migration. The novel clinically trialed anticancer agent, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which upregulates NDRG1, potently de-sensitized PaCa cells to ligands secreted by activated PSCs. DpC and NDRG1 also inhibited the PaCa-mediated activation of PSCs via inhibition of sonic hedgehog (SHH) signaling. In vivo, DpC markedly reduced PaCa tumor growth and metastasis more avidly than the standard chemotherapy for this disease, gemcitabine. Uniquely, DpC was selectively cytotoxic against PaCa cells, while "re-programming" PSCs to an inactive state, decreasing collagen deposition and desmoplasia. Thus, targeting NDRG1 can effectively break the oncogenic cycle of PaCa-PSC bi-directional cross-talk to overcome PaCa desmoplasia and improve therapeutic outcomes.

Circulating tumour cells in pancreatic cancer: A systematic review and meta-analysis of clinicopathological implications.

BACKGROUND: The detection and quantification of circulating tumour cells (CTCs) in pancreatic cancer (PC) has the potential to provide prognostic information. The aim of this review was to provide an overview of the literature surrounding CTCs in PC. METHODS: A systematic literature review on CTCs in PC between 2005-2020 was performed. Data based on peripheral vein samples were used to determine the positivity rate of CTCs, their prognostic significance and their relative numbers compared to portal vein (PV) samples. RESULTS: The overall CTC detection rate in forty-four articles was 65% (95%CI: 55-75%). Detection rate for CellSearch was 26% (95%CI: 14-38%), which was lower than for both filtration and microfluidic techniques. In nine studies with >50 patients, overall survival was worse with CTC positivity (HR 1.82; 95%CI: 1.61-2.05). Five of seven studies which described PV CTC collection provided patient-level data. PV CTC yield was 7.7-fold (95%CI 1.35-43.9) that of peripheral blood. CONCLUSIONS: CTCs were detected in the peripheral circulation of most patients with PC and may be related to prognosis and disease stage. PV blood contains more CTCs than peripheral blood sampling. This review points to the maturation of techniques of CTC enrichment, and its evidence base for eventual clinical deployment.

Targeting HGF/c-MET Axis in Pancreatic Cancer.

Pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC/PC)) has been an aggressive disease that is associated with early metastases. It is characterized by dense and collagenous desmoplasia/stroma, predominantly produced by pancreatic stellate cells (PSCs). PSCs interact with cancer cells as well as other stromal cells, facilitating disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells and endothelial cells. The current review discusses the role of the MET/HGF axis in tumour progression and dissemination of pancreatic cancer. Therapeutic approaches that were developed targeting either the ligand (HGF) or the receptor (c-MET) have not been shown to translate well into clinical settings. We discuss a two-pronged approach of targeting both the components of this pathway to interrupt the stromal-tumour interactions, which may represent a potential therapeutic strategy to improve outcomes in PC.

An Orthotopic Resectional Mouse Model of Pancreatic Cancer.

There is a lack of satisfactory animal models to study adjuvant and/or neoadjuvant therapy in patients being considered for surgery of pancreatic cancer (PC). To address this deficiency, we describe a mouse model involving orthotopic implantation of PC followed by distal pancreatectomy and splenectomy. The model has been demonstrated to be safe and suitably flexible for the study of various therapeutic approaches in adjuvant and neo adjuvant settings. In this model, a pancreatic tumor is first generated by implanting a mixture of human pancreatic cancer cells (luciferase-tagged AsPC-1) and human cancer associated pancreatic stellate cells into the distal pancreas of Balb/c athymic nude mice. After three weeks, the cancer is resected by re-laparotomy, distal pancreatectomy and splenectomy. In this model, bioluminescence imaging can be used to follow the progress of cancer development and effects of resection/treatments. Following resection, adjuvant therapy can be given. Alternatively, neoadjuvant treatment can be given prior to resection. Representative data from 45 mice are presented. All mice underwent successful distal pancreatectomy/splenectomy with no issues of hemostasis. A macroscopic proximal pancreatic margin greater than 5 mm was achieved in 43 (96%) mice. The technical success rate of pancreatic resection was 100%, with 0% early mortality and morbidity. None of the animals died during the week after resection. In summary, we describe a robust and reproducible technique for a surgical resection model of pancreatic cancer in mice which mimics the clinical scenario. The model may be useful for the testing of both adjuvant and neoadjuvant treatments.

Targeting the HGF/c-MET pathway in advanced pancreatic cancer: a key element of treatment that limits primary tumour growth and eliminates metastasis.

BACKGROUND: Stromal-tumour interactions facilitate pancreatic cancer (PC) progression. The hepatocyte growth factor (HGF)/c-MET pathway is upregulated in PC and mediates the interaction between cancer cells and stromal pancreatic stellate cells (PSCs). This study assessed the effect of HGF/c-MET inhibition plus gemcitabine (G) on the progression of advanced PC. METHODS: Orthotopic PC was produced by implantation of luciferase-tagged human cancer cells + human PSCs into mouse pancreas. Tumours were allowed to develop without treatment for 4 weeks. Mice were then treated for 6 weeks with one of the following: IgG, G, HGF inhibitor (Hi), c-MET inhibitor (Ci), Hi + Ci, Hi + G, Ci + G, or Hi + Ci + G. RESULTS: Bioluminescence imaging showed similar tumour sizes in all mice at the initiation of treatments. Triple therapy (Hi + Ci + G): (1) completely eliminated metastasis; (2) significantly reduced tumour size as assessed by bioluminescence and at necropsy; (3) significantly reduced proliferating cancer cell density and stem cell marker DCLK1 expression in tumours. In vitro 3D culture studies supported our in vivo findings. CONCLUSION: Even at an advanced disease stage, a two-pronged approach, targeting (a) HGF/c-MET with relevant inhibitors and (b) cancer cells with chemotherapy, completely eliminated metastasis and significantly decreased tumour growth, suggesting that this is a promising treatment approach for PC.

Pancreatic stellate cells: Aiding and abetting pancreatic cancer progression.

Tumour-stromal interactions have now been acknowledged to play a major role in pancreatic cancer (PC) progression. The abundant collagenous stroma is produced by a specific cell type in the pancreas-the pancreatic stellate cell (PSC). Pancreatic stellate cells (PSCs) are a unique resident cell type of pancreas and with a critical role in both healthy and diseased pancreas. Accumulating evidence indicates that PSCs interact closely with cancer cells as well as with other cell types of the stroma such as immune cells, endothelial cells and neuronal cells, to set up a growth permissive microenvironment for pancreatic tumours, which facilitates local tumour growth as well as distant metastasis. Consequently, recent work in the field has focused on the development of novel therapeutic approaches targeting the stroma to inhibit PC progression. Such a multi-pronged approach targeting both tumour and stromal elements of PC has been successfully applied in pre-clinical settings. The challenge now is to translate the pre-clinical findings into the clinical setting to achieve better outcomes for pancreatic cancer patients.

Targeting the HGF/c-MET pathway: stromal remodelling in pancreatic cancer.

Stromal-tumor interactions in pancreatic cancer (PC) impact on treatment outcomes. Pancreatic stellate cells (PSCs) produce the collagenous stroma of PC and interact with cancer cells to facilitate disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells. We studied the effects on PC progression of inhibiting the HGF/c-MET pathway in the presence and absence of a representative chemotherapeutic agent, gemcitabine. Using an orthotopic model of PC we have shown that "triple therapy" (inhibition of both HGF and c-MET combined with gemcitabine) resulted in the greatest reduction in tumor volume compared to each of the treatments alone or in dual combinations. Importantly, metastasis was virtually eliminated in mice receiving triple therapy. Our in vivo findings were supported by in vitro studies showing that the increase in cancer cell proliferation and migration in response to PSC secretions was significantly inhibited by the triple regimen. Our studies suggest that a combined approach, that targets tumor cells by chemotherapy while inhibiting specific pathways that mediate stromal-tumor interactions, may represent a novel therapeutic strategy to improve outcomes in PC.

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells.

BACKGROUND & AIMS: Smoking, an independent risk factor for pancreatitis, accelerates the development of alcoholic pancreatitis. Alcohol feeding of mice induces up-regulation of spliced X-box binding protein 1 (XBP1s), which regulates the endoplasmic reticulum (ER) unfolded protein response and promotes cell survival upon ER stress. We examined whether smoking affects the adaptive mechanisms induced by alcohol and accelerates disorders of the ER in pancreatic acinar cells. METHODS: We studied the combined effects of ethanol (EtOH) and cigarette smoke extract (CSE) on ER stress and cell death responses in mouse and human primary acini and the acinar cell line AR42J. Cells were incubated with EtOH (50 mmol/L), CSE (20-40 µg/mL), or both (CSE+EtOH), and analyzed by immunoblotting, quantitative reverse-transcription polymerase chain reaction, and cell death assays. Some cells were incubated with MKC-3946, an inhibitor of endoplasmic reticulum to nucleus signaling 1 (ERN1, also called IRE1) that blocks XBP1s formation. Male Sprague-Dawley rats were fed isocaloric amounts of an EtOH-containing (Lieber-DeCarli) or control diet for 11 weeks and exposed to cigarette smoke or room air in an exposure chamber for 2 hours each day. During the last 3 weeks, a subset of rats received intravenous injections of lipopolysaccharide (LPS, 3 mg/kg per week) to induce pancreatitis or saline (control). Pancreatic tissues were collected and analyzed by histology and immunostaining techniques. RESULTS: In AR42J and primary acini, CSE+EtOH induced cell death (necrosis and apoptosis), but neither agent alone had this effect. Cell death was associated with a significant decrease in expression of XBP1s. CSE+EtOH, but neither agent alone, slightly decreased adenosine triphosphate levels in AR42J cells, but induced oxidative stress and sustained activation (phosphorylation) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK) and increased protein levels of DNA damage inducible transcript 3 (DDIT3, also called CHOP). CHOP regulates transcription to promote apoptosis. Incubation of AR42J or primary mouse or human acinar cells with MKC-3946 reduced expression of XBP1s, increased levels of CHOP, and induced cell death. In rats fed an EtOH diet, exposure to cigarette smoke increased ER stress in acinar cells and sensitized the pancreas to LPS-induced pathology. CONCLUSIONS: Cigarette smoke promotes cell death and features of pancreatitis in EtOH-sensitized acinar cells by suppressing the adaptive unfolded protein response signaling pathway. It also activates ER stress pathways that promote acinar cell death.

Pancreatic stellate cells: what's new?

PURPOSE OF REVIEW: Pancreatic stellate cells (PSCs) play an integral role in the pathogenesis of pancreatitis and pancreatic cancer. With the developing knowledge of this important cell type, we are at the cusp of developing effective therapies for the above diseases based upon targeting the PSC and modulating its function. RECENT FINDINGS: The major themes of the recent PSC literature include: PSC interactions with the extracellular matrix and other stromal components; intracellular calcium physiology as drivers of mechanical interactions and necrosis; the relationship between proinflammatory, protumoural, angiogenic, and metabolic pathways in pancreatic necrosis, fibrosis, and carcinogenesis; and targeting of the stroma for antitumoural and antifibrotic effects. SUMMARY: Traditionally, there have been few treatment options for pancreatitis and pancreatic cancer. The elucidation of the wide-ranging functions of PSCs provide an opportunity for treatments based on stromal reprogramming.

Circulating pancreatic stellate (stromal) cells in pancreatic cancer-a fertile area for novel research.

Pancreatic stellate cells (PSCs) are known to play an important role in facilitating pancreatic cancer progression-both in terms of local tumour growth as well as the establishment of metastases. We have previously demonstrated that PSCs from the primary cancer seed to distant metastatic sites. We therefore hypothesise that PSCs circulate along with pancreatic cancer cells (circulating tumour cells-CTCs) to help create a growth permissive microenvironment at distant metastatic sites. This review aims to explore the concept of circulating PSCs in pancreatic cancer and suggests future directions for research in this area.

Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer.

BACKGROUND: Pancreatic stellate cells (PSCs, which produce the stroma of pancreatic cancer (PC)) interact with cancer cells to facilitate PC growth. A candidate growth factor pathway that may mediate this interaction is the HGF-c-MET pathway. METHODS: Effects of HGF inhibition (using a neutralising antibody AMG102) alone or in combination with gemcitabine were assessed (i) in vivo using an orthotopic model of PC, and (ii) in vitro using cultured PC cells (AsPC-1) and human PSCs. RESULTS: We have shown that human PSCs (hPSCs) secrete HGF but do not express the receptor c-MET, which is present predominantly on cancer cells. HGF inhibition was as effective as standard chemotherapy in inhibiting local tumour growth but was significantly more effective than gemcitabine in reducing tumour angiogenesis and metastasis. HGF inhibition has resulted in reduced metastasis; however, interestingly this antimetastatic effect was lost when combined with gemcitabine. This suggests that gemcitabine treatment selects out a subpopulation of cancer cells with increased epithelial-mesenchymal transition (EMT) and stem-cell characteristics, as supported by our findings of increased expression of EMT and stem-cell markers in tumour sections from our animal model. In vitro studies showed that hPSC secretions induced proliferation and migration, but inhibited apoptosis, of cancer cells. These effects were countered by pretreatment of hPSC secretions with a HGF-neutralising antibody but not by gemcitabine, indicating a key role for HGF in PSC-PC interactions. CONCLUSIONS: Our studies suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC that will require careful modelling for optimal integration with existing treatment modalities.