Cathepsin D expression in pancreatic ductal adenocarcinoma (PDAC) cells increases proliferation and reduces survival of pancreatic cancer patients

290 Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3+ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

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MYC controls metastatic heterogeneity in pancreatic cancer

10.1101/2021.01.30.428641 ◽

2021 ◽

Author(s):

Ravikanth Maddipati ◽

Robert J. Norgard ◽

Timour Baslan ◽

Komal S. Rathi ◽

Amy Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Patients ◽

Ductal Adenocarcinoma ◽

Tumor Type ◽

Metastatic Progression ◽

Primary Tumors ◽

Functional Differences ◽

Metastatic Burden

AbstractThe degree of metastatic disease varies widely amongst cancer patients and impacts clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multi-fluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC) – a tumor type where most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor associated macrophages (TAMs), leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC.

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Identification of Novel Molecular Therapeutic Targets and Their Potential Prognostic Biomarkers Among Kinesin Superfamily of Proteins in Pancreatic Ductal Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.708900 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yang Yang ◽

Lanyang Gao ◽

Ning-Na Weng ◽

Jun-Jun Li ◽

Jin Lu Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Outcome ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Patients ◽

Gene Set Enrichment Analysis ◽

Prognostic Biomarkers ◽

Ductal Adenocarcinoma ◽

Aberrant Expression ◽

Pancreatic Cell ◽

Kinesin Superfamily

BackgroundKinesin superfamily of proteins (KIFs) has been broadly reported to play an indispensable role in the biological process. Recently, emerging evidence reveals its oncogenic role in various cancers. However, the prognostic, oncological, and immunological values of KIFs have not been comprehensively explored in pancreatic ductal adenocarcinoma (PDAC) patients. We aimed to illustrate the relationship between KIFs and pancreatic ductal adenocarcinoma by using bioinformatical analysis.MethodsWe use GEPIA, Oncomine datasets, cBioPortal, LOGpc, TIMER, and STRING bioinformatics tools and web servers to investigate the aberrant expression, prognostic values, and oncogenic role of KIFs. The two-gene prognostic model and the correlation between KIFs and KRAS and TP53 mutation were performed using an R-based computational framework.ResultsOur results demonstrated that KIFC1/2C/4A/11/14/15/18A/18B/20B/23 (we name it prognosis-related KIFs) were upregulated and associated with unfavorable clinical outcome in pancreatic cancer patients. KIF21B overexpression is associated with better clinical outcome. The KIFC1/2C/4A/11/14/15/18A/18B/20B/23 profiles were significantly increased compared to grade 1 and grade 2/3. Besides, KIFC1/2C/4A/11/14/15/18A/18B/20B/23 was significantly associated with the mutation status of KRAS and TP53.Notably, most prognosis-related KIFs have strong correlations with tumor growth and myeloid-derived suppressor cells infiltration (MDSCs). A prognostic signature based on KIF20B and KIF21B showed a reliable predictive performance. Receiver operating characteristic (ROC) curve was employed to assess the predictive power of two-gene signature. Consequently, the gene set enrichment analysis (GSEA) showed that KIF20B and KIF21B’s overexpression was associated with the immunological and oncogenic pathway activation in pancreatic cancer. Finally, real-time quantitative PCR (RT-qPCR) was utilized to investigate the expression pattern of KIF20B and KIF21B in pancreatic cancer cell lines and normal pancreatic cell.ConclusionsKnowledge of the expression level of the KIFs may provide novel therapeutic molecular targets and potential prognostic biomarkers to pancreatic cancer patients.

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Pancreatic Cancer Intrinsic PI3Kα Activity accelerates Metastasis and rewires Macrophage Component

10.1101/2020.09.23.307884 ◽

2020 ◽

Author(s):

B. Thibault ◽

F. Ramos Delgado ◽

E. Pons-Tostivint ◽

N. Therville ◽

C. Cintas ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Patients ◽

Metastatic Disease ◽

Tumour Cell ◽

Primary Tumour ◽

Pi3k Pathway ◽

Ductal Adenocarcinoma ◽

Preclinical Models ◽

Micrometastatic Disease

AbstractPancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micrometastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas.We researched a gene signature that could discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events.Amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature predict PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by inhibiting tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the lipid second messenger PIP3 produced, with selective reduction of C36:2 PI-3,4,5-P3. PI3Kα inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue.Tumour-cell intrinsic PI3Kα therefore promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution.The paper explainedPROBLEM Pancreatic cancer is one of the most lethal solid cancers characterised by rapid progression after primary tumour detection by imaging. Key signalling events that specifically drives this rapid evolution into macro-metastatic disease are so far poorly understood.RESULT With two unbiased approaches to patient data analysis, higher PI3K pathway and more specifically higher PI3Kα activation signature can now be identified in the most aggressive pancreatic cancer primary tumours, that lead to earlier patient death. Our in vitro data showed that PI3Kα is a major positive regulator of tumour cell escape from the primary tumour: tumour-intrinsic PI3Kα activity enables actin cytoskeleton remodelling to escape the pancreatic tumour. We chose to use two preclinical models of pancreatic cancer to validate that PI3Kα is a target for delaying evolution of PDAC. The first one mimicked pancreatic patient micrometastatic disease that is undetected by echography and consisted in treating mice presenting echography detected primary tumours combined with increased circulating DNA as a blood biomarker of the most aggressive tumours. The second model consisted in studying the tumour cell implantation and their early proliferation in metastatic organ after injection in blood. We treated both preclinical models with a clinically relevant PI3K α-selective inhibitor (BYL-719/Alpelisib), that is currently being tested in pancreatic cancer patients (without any patient selection). We found that PI3Kα activity drives evolution of micrometastatic disease towards macro-metastatic stage in both models: inhibition of PI3Kα delayed primary tumour and micro-metastasis evolution. Finally, PI3Kα activity increases protumoural characteristics in peritumoural immune cells via tumour cell-intrinsic cytokine production that could facilitate metastatic evolution.IMPACT Circulating tumour DNA represents a strong independent biomarker linked to relapse and poor survival in solid cancer patients. A clinical study in resected PDAC patients with micrometastatic disease characterised by high circulating tumoural DNA levels is needed to assess if PI3Kα-selective inhibitors significantly delay metastatic progression and death.Graphical AbstractPancreatic ductal adenocarcinoma requires tumour-intrinsic PI3Kα activity to accelerate inflammatory metastatic disease.Biorender illustration.

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Increased Cathepsin D expression has a negative prognostic effect on survival in gemcitabine treated patients with pancreatic ductal adenocarcinoma

Zeitschrift für Gastroenterologie ◽

10.1055/s-0038-1668984 ◽

2018 ◽

Vol 56 (08) ◽

pp. e324-e325

Author(s):

UM Mahajan ◽

E Goni ◽

E Langhoff ◽

S Kruger ◽

S Ormanns ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cathepsin D ◽

Ductal Adenocarcinoma ◽

Prognostic Effect

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A Proteomic Study on the Personalized Protein Corona of Liposomes. Relevance for Early Diagnosis of Pancreatic DUCTAL Adenocarcinoma and Biomarker Detection

Journal of Nanotheranostics ◽

10.3390/jnt2020006 ◽

2021 ◽

Vol 2 (2) ◽

pp. 82-93

Author(s):

Luca Digiacomo ◽

Francesca Giulimondi ◽

Daniela Pozzi ◽

Alessandro Coppola ◽

Vincenzo La Vaccara ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Protein Corona ◽

Detection Sensitivity ◽

Ductal Adenocarcinoma ◽

Protein Biomarkers ◽

Ca 19.9 ◽

Proteomic Study

Due to late diagnosis, high incidence of metastasis, and poor survival rate, pancreatic cancer is one of the most leading cause of cancer-related death. Although manifold recent efforts have been done to achieve an early diagnosis of pancreatic cancer, CA-19.9 is currently the unique biomarker that is adopted for the detection, despite its limits in terms of sensitivity and specificity. To identify potential protein biomarkers for pancreatic ductal adenocarcinoma (PDAC), we used three model liposomes as nanoplatforms that accumulate proteins from human plasma and studied the composition of this biomolecular layer, which is known as protein corona. Indeed, plasma proteins adsorb on nanoparticle surface according to their abundance and affinity to the employed nanomaterial, thus even small differences between healthy and PDAC protein expression levels can be, in principle, detected. By mass spectrometry experiments, we quantified such differences and identified possible biomarkers for PDAC. Some of them are already known to exhibit different expressions in PDAC proteomes, whereas the role of other relevant proteins is still not clear. Therefore, we predict that the employment of nanomaterials and their protein corona may represent a useful tool to amplify the detection sensitivity of cancer biomarkers, which may be used for the early diagnosis of PDAC, with clinical implication for the subsequent therapy in the context of personalized medicine.

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Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00138.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. G524-G536 ◽

Cited By ~ 12

Author(s):

Sandrina Maertin ◽

Jason M. Elperin ◽

Ethan Lotshaw ◽

Matthias Sendler ◽

Steven D. Speakman ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Oxidative Phosphorylation ◽

Pancreatic Ductal Adenocarcinoma ◽

Environmental Stresses ◽

Ductal Adenocarcinoma ◽

Cell Adaptation ◽

Autophagy Inhibition ◽

Dependent Mechanism

Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC. NEW & NOTEWORTHY Cancer cells in the highly desmoplastic pancreatic ductal adenocarcinoma confront nutrient [i.e., amino acids (AA)] deprivation and hypoxia, but how pancreatic cancer (PaCa) cells adapt to these conditions is poorly understood. This study provides evidence that the maintenance of mitochondrial function, in particular, oxidative phosphorylation (OXPHOS), is a key mechanism that supports PaCa cell growth, both in normal conditions and under the environmental stresses. OXPHOS in PaCa cells critically depends on autophagy and AA supply. Furthermore, the oncogenic activation mutation in GTPase Kras upregulates OXPHOS through an autophagy-dependent mechanism.

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