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Proteome landscapes of pancreatic cancer human-in-mouse patient-derived xenograft (PDX) models.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of relatively few tumor cells surrounded a heterocellular non-cancerous cell population embedded in extracellular matrix, collectively named stroma. Despite the recognition that the stroma is an important contributor to the typically poor outcome of PDAC, its analysis has been hampered by the analysis of bulk tissue. Here we present a landscape of human epithelial PDAC cells of primary tumors (n=6) and metastases (n=4) in a mouse stroma background.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Pancreas

DISEASE(S): Pancreatic Ductal Carcinoma

SUBMITTER: Sander Piersma

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD017393 | Pride | 2021-09-09

REPOSITORIES: Pride

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Microdissected pancreatic cancer proteomes reveal tumor heterogeneity and therapeutic targets.

Le Large Tessa Ys TY Mantini Giulia G Meijer Laura L LL Pham Thang V TV Funel Niccola N van Grieken Nicole Ct NC Kok Bart B Knol Jaco J van Laarhoven Hanneke Wm HW Piersma Sander R SR Jimenez Connie R CR Kazemier G G Giovannetti Elisa E Bijlsma Maarten F MF

JCI insight 20200806 15

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a relative paucity of cancer cells that are surrounded by an abundance of nontumor cells and extracellular matrix, known as stroma. The interaction between stroma and cancer cells contributes to poor outcome, but how proteins from these individual compartments drive aggressive tumor behavior is not known. Here, we report the proteomic analysis of laser-capture microdissected (LCM) PDAC samples. We isolated stroma, tumor, and bulk sample ...[more]

PMID: 32634123

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Stromal and epithelial proteome landscapes of pancreatic cancer predict poor prognosis and identify therapeutic options

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of relatively few tumor cells surrounded a heterocellular non-cancerous cell population embedded in extracellular matrix, collectively named stroma. Despite the recognition that the stroma is an important contributor to the typically poor outcome of PDAC, its analysis has been hampered by the analysis of bulk tissue. Similar issues have precluded meaningful analysis of the epithelial compartment. Here, we present the proteome analysis of a set of sixteen lasercapture microdissected PDAC samples, investigating tumor and stroma, together with bulk tumor samples, yielding the deepest PDAC proteomic to date.

2021-09-08 | PXD011289 | Pride

Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma

Project description:Aberrant tyrosine kinase activity can influence tumor growth and is regulated by phosphorylation. Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options. We investigated phosphorylated kinases as target in PDAC. Mass spectrometry-based phosphoproteomic analysis was performed of PDAC cell lines to evaluate active kinases. Pathway analysis and inferred kinase activity was performed to identify novel targets. We investigated targeting of focal adhesion kinase in vitro with drug perturbations in combination with chemotherapeutics used against PDAC. Phosphoproteome analysis upon treatment was performed to evaluate signaling..PDAC cell lines portrayed high activity of multiple receptor tyrosine kinases. Non-receptor kinase, focal adhesion kinase (FAK), was identified in all cell lines by our phosphoproteomic screen and pathway analysis. Targeting of this kinase with defactinib validated reduced phosphorylation profiles. Additionally, FAK inhibition had anti-proliferative and anti-migratory effects. Combination with (nab-)paclitaxel had a synergistic effect on cell proliferation in vitro and reduced tumor growth in vivo. In conclusion, our study shows a high phosphorylation of several oncogenic receptor tyrosine kinases in PDAC cells and validated FAK inhibition as potential synergistic target with Nab-paclitaxel

2021-09-10 | PXD024548 | Pride

Co-expression analysis of label-free proteomics data reveals prognostic biomarkers in pancreatic ductal adenocarcinoma

Project description:Despite extensive biological and clinical studies, including comprehensive genomics and transcriptomics analysis, pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease, with poor survival and no effective therapies to date. Correlation networks are emerging as a powerful approach to infer tumor biology and to prioritize candidate genes as biomarkers or drug targets. In this study we applied a weighted co-expression analysis to the functionally relevant proteome of 20 surgically resected patients with PDAC. We obtained twelve modules with overlapping yet distinct biology, which implicated metabolism and ECM complexes in several modules. Notably, one module enriched for metabolic processes and epithelial-mesenchymal-transition (EMT) was significantly associated with overall survival (p=0.01) and was validated in public RNA data (p=0.02). The prognostic value of three proteins (SPTBN1, KHSRP and PYGL) belonging to this module was confirmed using immunohistochemistry in a cohort of 82 radically resected patients.

2020-09-01 | PXD015744 | Pride

Combined expression of plasma CA19-9 and thrombospondin-2 for accurate diagnosis of pancreatic cancer and distal cholangiocarcinoma– A proteome approach

Project description:Minimally- invasive diagnostic biomarkers for patients with pancreatic ductal adenocarcinoma (PDAC) and distal cholangiocarcinoma (CCA) are warranted to enhance early and accurate diagnosis. This study identified tumor tissue secreted proteins, the “secretome”, which was analysed for differential candidate diagnostic plasma proteins. Secretome of tumor and normal tissue was collected directly after resection of the primary tumor from 4 patients with PDAC and distal CCA. The tissue secretome was investigated by label-free LC-MSMS, and database searching identified a total of 5179 proteins. 696 proteins were differentially enriched in tumor secretome compared to normal tissue. Thrombospondin-2 (THBS2) emerged as most promising candidate diagnostic biomarker. Subsequent analysis of THBS2 in plasma samples of patients with PDAC and distal CCA by ELISA showed significantly higher abundance compared to healthy individuals (p<0.001) and resulted in an AUC of 0.844.

2020-05-26 | PXD012480 | Pride

Omics Analysis of Pancreatic Cancer Platelets Reveals Active “Education”, including Dysregulation of Splicing Signature and Inhibition of SPARC by Modified Forms of miRNAs

Project description:Pancreatic ductal adenocarcinoma (PDAC) is associated with hypercoagulation, but molecular mechanisms underlying PDAC/platelets interaction remain controversial. PDAC cells can activate platelets and change their RNA and protein content, thus, we performed an integrative study investigating the biological processes of differentially spliced mRNAs and expressed miRNAs, as well as proteins. To focus on these “dangerous liaisons”, we used benign disease as a background noise correction for putative inflammatory signals. Gene set enrichment analysis on differential miRNAs, RNA transcripts and proteins revealed an enrichment of RNA splicing, mRNA processing and translation initiation on miRNAs and proteins and depletion on RNA transcripts, as previously described. Moreover, correlation analyses revealed a specific regulation on SPARC RNA transcripts by isomiRs involved in cancer signaling, suggesting a specific modulation/”education” in PDAC platelets. We identified HBA1, HBD, CA1 and AGT as protein markers in PDAC platelets. In conclusion, our data show that platelets change their biological repertoire in the presence of PDAC, through dysregulation of miRNAs and splicing factors, supporting the presence of a clear de novo protein machinery that can “educate” the platelet.

2021-09-09 | PXD022514 | Pride

(Phospho-)proteomic analysis of gemcitabine resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment response

Project description:Chemoresistance hampers the treatment of patients suffering from pancreatic ductal adenocarcinoma (PDAC). The present study aimed to evaluate the proteome and phosphoproteome of gemcitabine-sensitive and -resistant PDAC cells to identify novel targets and predictive biomarkers.The oncogenic capabilities of sensitive and resistant PDAC cells were evaluated in vitro and in vivo. Cultured cells were subsequently analysed by label-free mass spectrometry. Differential proteins and phosphopeptides were evaluated for Gene Ontology and predictive and / or prognostic biomarker potential by immunohistochemistry of tissue microarrays (TMAs). Differential analyses showed that resistant proteins are associated with membrane organization and microtubule regulation. Importantly, resistant cells displayed an increased sensitivity for paclitaxel treatment in vitro (p < 0.001) and nab-paclitaxel had a strong anti-tumour efficacy in vivo. Microtubule-associated protein 2 (MAP2) was found to be highly upregulated and phosphorylated in resistant cells. The identified resistance marker MAP2 emerged as a novel prognostic marker in PDAC patients treated with gemcitabine.

2019-06-19 | PXD010112 | Pride

Proteomic analysis upon miR195/497 replacement reveals potential chemo sensitizing candidates for colorectal cancer

Project description:Patients with advanced colorectal cancer (CRC) are commonly treated with systemic combination therapy but suffer eventually from drug resistance. MicroRNAs (miRNAs) are suggested to play a role in treatment resistance of CRC. We studied whether restoring downregulated miR-195-5p and 497-5p sensitize CRC cells to currently used chemotherapeutics 5-fluorouracil, oxaliplatin and irinotecan. Sensitivity to 5-FU, oxaliplatin and irinotecan before and after transfection with miR-195-5p and miR-497-5p mimics was analyzed in CRC cell lines HCT116, RKO, DLD-1 and SW480. Mass spectrometry based proteomic analysis of transfected and wild-type cells was used to identify targets involved in sensitivity to chemotherapy. Proteomic analysis revealed 181 proteins with significantly altered expression after transfection with miR-195-5p mimic in HCT116 and RKO, including 118 downregulated and 63 upregulated proteins. After transfection with miR-497-5p mimic, 130 proteins were significantly downregulated and 102 were upregulated in HCT116 and RKO (P<0.05 and FC<-3 or FC>3). CHUK and LUZP1 were coinciding downregulated proteins in sensitized CRC cells after transfection with either mimic. Resistance mechanisms of these two proteins may be related to nuclear factor kappa-B signaling and G1 cell cycle arrest, respectively. Restoring miR-195-5p and miR-497-5p expression enhanced sensitivity to chemotherapy, mainly oxaliplatin, in CRC cells and could be a promising treatment strategy for patients with mCRC. Proteomics revealed potential targets of these miRNAs involved in sensitivity to chemotherapy.

2019-09-27 | PXD015369 | Pride

Tumor heterogeneity underlies differential cisplatin sensitivity in mouse models of small cell lung cancer

Project description:SCLC is the most aggressive subtype of lung cancer characterized by a remarkable response to chemotherapy followed by development of resistance. Mechanisms of initial sensitivity and of subsequent resistance are not understood. Here we highlight a broad tumor heterogeneity in mouse models of SCLC, which includes a CDH1 high primary cisplatin-resistant peripheral neuroendocrine lesion with unique metabolic and structural profile. Cisplatin treatment preferentially eliminates CDH1 negative secondary tumor leaving behind CDH1 high primary lesions, thus revealing a striking differential response. We profile global protein and messenger RNA levels in vehicle and cisplatin treated lung tumor populations and find a marked reduction in proliferation and a pronounced metabolic shift following cisplatin-treatment. Our proteo-transcriptomic analysis gives insight into gene expression alterations that characterize cisplatin resistance and uncovers potential novel targets to overcome resistance of distinct populations. SCLC tumors in the mouse show heterogeneity which appears, as might be the case in humans, to be one of the underlying mechanisms of differential sensitivity to cisplatin.

2019-11-12 | PXD010680 | Pride

Lipopolysaccharide-regulated secretion of soluble and vesicle-based colorectal cancer cell proteins

Project description:Colorectal cancer (CRC), among the major cancer types in western world is responsible for 10% of cancer related deaths, often due to late detection when the tumor has already spread out of the colon. Surgery is the mainstay curative treatment for CRC. Nevertheless, between 15-30% of stage II and III patients develop hepatic metastasis within 5 years. Paradoxically, tumor surgery can contribute to the metastatic process, due to inflammatory mediator release in response to surgery, which promotes the metastatic ability of cancer cells. During surgery, bacterial products, such as LPS, from commensal bacteria translocate across the bowel wall, reach systemic circulation and induce an inflammatory response through to the activation of the Nuclear Factor-ĸB (NF-ĸB) pathway. Inflammation promotes malignant transformation by inducing chromosomal and microsatellite instability or CpG island methylation [14], but its direct effect on cancer cells and contribution to metastasis development remains to be elucidated. In this experiment we mimic the perioperative microenvironment where bacterial products get in contact with CRC cancer cells. We assessed the identity of the secreted proteins, including those released through extracellular vesicles (EV), of six CRC cell lines once exposed to lipopolysaccharide (LPS).

2022-02-28 | PXD011611 | Pride

Loss of FLCN-FNIP1/2 Induces a Non-Canonical Interferon 1 Response in Human Renal Tubular Epithelial Cells

Project description:Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene that has been linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown Here we show that FLCN loss activates E-box target genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD, yet without modifying mTORC1 activity. Surprisingly, inactivation of FLCN or its binding partners FNIP1/FNIP2 activates interferon response genes but independently of interferon. Mechanistically, FLCN loss promotes recruitment of STAT2 to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence the immune response. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint novel prognostic biomarkers.

2021-02-11 | PXD021346 | Pride

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