SECRETOME IN PANCREATIC DUCTUAL ADENOCARCINOMA
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
DISEASE(S): Pancreas Adenocarcinoma
SUBMITTER: 
Luc Camoin
LAB HEAD: Luc Camoin - Stephane Audebert
PROVIDER: PXD068001 | Pride | 2026-06-25
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| 10_Secretome.raw | Raw | |||
| 10_Secretome_170426004037.raw | Raw | |||
| 11_Secretome_170428221237.raw | Raw | |||
| 11_Secretome_170429004828.raw | Raw | |||
| 12_Secretome.raw | Raw |
Items per page: 5 1 - 5 of 112 |
Similar Datasets
Project description:Background. Pancreatic Ductal AdenoCarcinoma (PDAC), the most frequent pancreatic cancer, is a deadly cancer since often diagnosed late and resistant to current therapies. A high proportion of PDAC patients are affected by cachexia induced by the tumor. This cachexia, characterized by loss of muscle mass and strength, contributes to patient frailty and poor therapeutic response. We showed that mitochondrial metabolism is reprogrammed in PDAC tumor cell and constitutes a vulnerability, opening novel therapeutic avenues. The objective of the present work was to investigate the molecular mechanisms underlying mitochondrial remodeling in PDAC cachectic skeletal muscle. Methods. Our study focused on the gastrocnemius muscle of genetically-engineered mice developing spontaneously a PDAC associated with cachexia (KIC GEMM). We compared KIC mice developing a pancreatic tumor in 9-10 weeks to control littermates. We did an integrative study combining in vivo functional analyses by non-invasive Magnetic Resonance, and ex-vivo histology, Seahorse, RNA-sequencing, and proteomic mass spectrometry and western blotting analyses. Results. The cachectic KIC PDAC mice show a severe sarcopenia with loss of muscle mass and strength associated with a diminution in muscle fiber’s size and induction of protein degradation processes. Mitochondria in PDAC atrophic muscles show decreased respiratory capacities and structural alterations (“hyperfused” mitochondria), associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways at the molecular level. Increased expression of multiple reactive oxygen species (ROS) defense genes suggests oxidative stress prone to affect mitochondrial macromolecules and homeostasis. Interestingly, multiple genes and proteins involved in DNA metabolism pathways, such as DNA damage, degradation of DNA, nucleotide synthesis, and folate pathway were found altered in sarcopenic mitochondria. While the number of mitochondria was not changed, the mitochondrial mass was decreased by a factor of 2 and the mitochondrial DNA by a factor of 3, suggesting a defect in mitochondrial genome homeostasis. Conclusions. We unveiled that mitochondrial alterations in skeletal muscle play a central role in PDAC-induced cachexia. Muscle atrophy is associated with strong mitochondrial metabolic defects that are not limited to carbohydrates and protein, but concern also lipids, ROS and nucleic acids. Our data provide a frame to guide towards the most relevant molecular markers that would be affected at the start of tumor development and could be targets in the clinic to limit PDAC-induced cachexia at early stages of the pathology.
2024-04-09 | PXD036752 | Pride
Project description:Human pancreatic stellate cells (HPSCs) are an essential stromal component and are the mediators of pancreatic ductal adenocarcinoma (PDAC) progression. Small extracellular vesicles (sEVs) are membrane-enclosed nanoparticles released from stellate cells adjacent to the PDAC. sEVs are believed to play a key role in cell-cell communications and may play a critical role in disease progression. The role of membrane proteins of HPSC sEVs in the PDAC tumor microenvironment is unclear and to date, there has not been a quantitative proteomic comparison of sEVs from normal pancreatic stellate cells (HPaStec) and from PDAC-associated stellate cells (HPSCs). We hypothesized there would be differences in sEVs secretion and membrane protein expression between the 2 conditions that might contribute to PDAC biology. To test these hypotheses, we isolated sEVs using ultracentrifugation followed by characterization by electron microscopy and Nanoparticle Tracking Analysis. HPSCs secreted more sEVs compared to HPaStec, and these sEVs were enriched with exosomal markers, which was confirmed by Western blotting and flow cytometry. HPSC-sEVs also restore the activation of normal stellate cells. Next, we showed that intact membrane-associated proteins may be essential for sufficient uptake of stellate cell sEVs by both normal epithelial and cancer cells. Importantly, we demonstrated that stellate cells in general modulate the cellular proliferations of pancreatic cancer cells although stellate cell sEVs did not change the proliferation of cancer cells. We then compared sEV proteins isolated from HPSCs and HPaStecs cells using liquid chromatography–tandem mass spectrometry. Most of the 1,481 protein groups identified were shared with the exosome database, ExoCarta (http://exocarta.org/; curated by the Mathivanan Lab). Eighty-seven protein groups were differentially expressed (selected by 2-fold difference and adjusted P value ≤ 0.05) between HPSC and HPaStec sEVs. HPSC sEVs contained dramatically more CSE1L, a poor prognostic marker for pancreatic cancer. In conclusion, our findings using mass spectrometry–based proteomics may direct further studies to understand the biology and role of protein composition of HPSC sEVs in PDAC progression or to develop novel strategies based on delivery of exosome cargo to PDAC tumor cells.
2023-03-11 | PXD030077 | Pride
Project description:Mapping of dystrophin-lipid interactions by mass spectrometry
2019-11-14 | PXD007716 | Pride
Project description:Oncogenic KrasG12D, a driver mutation of pancreatic ductal adenocarcinoma (PDAC), induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). Here, we show that both functional complexes of mTOR (mechanistic target of rapamycin kinase, mTORC1 and mTORC2) are specifically activated in ADM. Murine models uncover that mTORC1 and mTORC2 cooperate to promote KrasG12D-driven ADM development. Proteomic analyses identify Arp2/3 complex, an actin nucleator, as the common downstream effector: mTORC1 is responsible for the protein synthesis of Rac1 and Arp3 while mTORC2 promotes the Arp2/3 complex activity via Akt/Rac1 signalling. Genetic ablation of Arp2/3 complex completely arrests KrasG12D-driven ADM development. The Arp2/3 complex-mediated y-branching of actin network promotes the basolateral spread of filamentous actin, which is indispensable for acinar cells-initiated carcinogenesis. Induced by oncogenic KrasG12D, ADM is a metaplastic phenotype of acinar cells that requires extensive actin rearrangements. mTORC1 and mTORC2, downstream targets of KrasG12D, have well-established oncogenic functions in PDAC development. The actin-related protein 2/3 (Arp2/3) complex is the first identified actin nucleator. Regarded as textbook knowledge, it is activated by EGFR/Rac1 signalling to promote the polymerisation of branched actin filaments from pre-existing filaments in numerous biological contexts. Hereby, we identify that mTORC1 and mTORC2 attain a dual, yet non-redundant, regulatory role in promoting Arp2/3 complex function, which is responsible for generating basolateral filamentous actin in ADM. Thus, the role of Arp2/3 complex fills up the missing gap between putative oncogenic signals and actin dynamics underlying PDAC initiation.
2021-01-07 | PXD018296 | Pride
Project description:A Cartes d'Identit des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net): Pancreatic adenocarcinoma (PDAC) is one of the most lethal human malignancies and a major health problem. Patient-derived xenografts (PDX) are appearing as a prime approach for preclinical studies despite being insufficiently characterized as a model of the human disease and its diversity. We generated subcutaneous PDX from PDAC samples obtained either surgically or using diagnostic biopsies (endoscopic ultrasound guided fine needle aspirate). The extensive multiomics characterization of the xenografts demonstrated that PDX is a suitable model for preclinical studies, representing the diversity of the primary cancers. the MultiOmicClassification variable indicates groups resulting from the analysis, and the CIMPclass, the CpG Island Methylator Phenotype as estimated by the methylation analysis. This dataset, describes the miRNA-Seq data used in the multiOmics analysis.
2017-12-12 | E-MTAB-5018 | biostudies-arrayexpress
Project description:In vitro ADP-ribosylated Src-K295M was separated by SDS-PAGE and the Coomassie stained protein band excised and digested with either trypsin, thermolysin or elastase. All digests were analysed by nanoLC-MS/MS using Higher-energy C-trap Dissociation (HCD) as well as Electron-Transfer Dissociation (ETD) fragmentation.
2014-12-19 | PXD001461 | Pride
Project description:The pathogen Mycobacterium tuberculosis employs a range of ESX-1 substrates to manipulate the host and build a successful infection. Although the importance of ESX-1 secretion in virulence is well established, the characterization of its individual components and the role of individual substrates is far from complete. Here, we describe the functional characterization of the accessory ESX-1 proteins EccA1, EspG1 and EspH, i.e. proteins that are not present in all five ESX system of mycobacteria. Proteomic analysis revealed that EspG1 is crucial for ESX-1 secretion, since all detectable ESX-1 substrates were absent from the cell surface and culture supernatant in an espG1 mutant. Deletion of eccA1 resulted in minor secretion defects, but interestingly, the severity of these secretion defects was dependent on the culture conditions. Finally, espH deletion showed a partial secretion defect, only secretion of EspE, EspF and EsxA/EsxB was blocked.
2018-08-02 | PXD008905 | Pride
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
Project description:E-cadherin is known as an epithelial marker often associated with tumour suppressive function. However, several studies revealed that some tumours cells, such as pancreatic cancer cells, with epithelial traits and high E-cadherin expression can undergo metastasis and form secondary tumours. These observations suggest an important role of E-cadherin in early stages of tumour cells invasion. Pancreatic ductal adenocarcinoma (PDAC) are highly metastatic with poor prognosis cancer and therefore provide an useful model to clarify E-cadherin function on tumour progression. To address the molecular function of E-cadherin regarding PDAC aggressivity, we knock-down E-cadherin expression in a pancreatic cancer cell line and analysed the consequences of E-cadherin depletion on the capacity of cells to form invasive structures called invadopodia. We then deciphered the molecular mechanisms by which E-cadherin regulates invadopodia formation by performing analysis of proteomes from control and E-cadh depleted cells.
2025-05-14 | PXD021795 | Pride
Project description:Growing evidence indicates that metabolism is a key driver of T cell functions. A switch from oxidative phosphorylation to aerobic glycolysis is a hallmark of T cell activation and is required to meet metabolic demands of proliferation and effector functions. However, the mechanisms underlying the metabolic switch in T cells remain unclear. Here, we identify Sirt2 as a crucial immune checkpoint coordinating metabolic and functional fitness of T cells. Sirt2 is induced upon T cell activation and increases in late maturation stages. Sirt2 negatively regulates glycolysis by targeting key glycolytic enzymes. Remarkably, Sirt2 knockout T cells exhibit profound upregulation of aerobic glycolysis with enhanced proliferation and effector function and thus effectively reject tumor challenge in vivo. Furthermore, pharmacologic inhibition of Sirt2 in human tumor infiltrating lymphocytes demonstrated a similar phenotype. Taken together, our results demonstrate Sirt2 as an actionable target to reprogram T cell metabolism to augment immunotherapy.
2020-06-15 | PXD012811 | Pride