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Effect of therapy-induced secretomes on the proteome of ovarian cancer cells

ABSTRACT: Exogenous signals from drug-stressed cancer cells promote acquisition of a more aggressive phenotype of neighboring tumor cells. Recently, we examined how cancer cell secretome changes in response to chemotherapy. Moreover, therapy-induced secretomes significantly increased resistance of cancer cells to subsequent cisplatin treatment. To elucidate how therapy-induced secretomes affect the proteomic profiles of recipient tumor cells, we incubated SKOV3 cells for 3 days with secretomes from control or dying cancer cells. Enrichment analysis of differentially abundant proteins revealed that therapy-induced secretomes provoked increase abundance of proteins involved in DNA repair and cell cycle regulation. These findings demonstrate that under stress condition cancer cells can secrete signaling molecules into the extracellular space and contribute to the emergence of tumor chemoresistance during short time period.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Georgij Arapidi

LAB HEAD: Georgij Pavlovich

PROVIDER: PXD027794 | Pride | 2024-05-29

REPOSITORIES: Pride

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			Action	DRS
	Sh-408-1.dat	Other
	Sh-408-1.mgf	Mgf
	Sh-408-1.mzid	Mzid
	Sh-408-1.mzid_Sh-408-1.MGF	Mzid
	Sh-408-1.raw	Raw

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Cisplatin-Induced Changes in Proteomic Profiles of Ovarian Cancer Cell and Fibroblast Secretomes

Project description:Exogenous signals from drug-stressed cancer cells promote acquisition of a more aggressive phenotype of neighboring tumor cells. To identify extracellular signaling molecules that potentially contribute to the development of therapy resistance, we examined how cancer cell secretome changes in response to chemotherapy. We performed LC-MS/MS analysis of conditioned media (CM) from ovarian cancer cells SKOV3 before and 48 hours after cisplatin treatment. We identified 1,820 and 784 proteins in secretomes of cancer cells treated or untreated with cisplatin, respectively. Functional annotation of proteins which secretion increased after cisplatin showed that these proteins were mainly associated with cluster of spliceosome. To investigate whether secretion of spliceosomal proteins during induction of apoptosis is a specific property of tumor cells, we compared proteomes of CM from primary culture of normal human skin fibroblasts before and 48 hours after exposure to cisplatin (IC50). A LC-MS/MS analysis revealed that most of the proteins in the CM of fibroblasts and cancer cells under normal conditions overlap, while the secretomes after therapy demonstrate much more pronounced differences. GO and KEGG enrichment analysis revealed higher abundance of cell adhesion and extracellular matrix proteins in CM of fibroblasts before chemotherapy; while lysosomal proteins and growth factors, associated with wound healing were increased after cisplatin treatment. Spliceosomal proteins were only slightly present in fibroblast CM and did not show any changes in a response to chemotherapy. We suggest that the acquisition of ovarian cancer chemoresistance might be partially mediated by extracellular spliceosomal components.

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Cisplatin-Induced Changes in Proteomic Profiles of Ovarian Cancer Cell and HaCaT Secretomes

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SILAC Strategy for Analysis of Proteins Released To the Extracellular Medium and Penetrated

Project description:Exogenous signals from drug-stressed cancer cells accelerate the proliferation of neighboring tumor cells and promote them to acquire a more aggressive phenotype. We have recently found an exciting phenomenon: drug-stressed cancer cells secrete various spliceosomal proteins. We have observed this phenomenon both in vitro (culture media from cancer cell lines [Pavluykov M. et al.//Cancer Cell, 2018]) and in vivo (ovarian cancer ascites after chemotherapy [Shender V. et al//Mol. Сell. Proteomics, 2014]). The aim of this study was to elucidate which proteins from the extracellular vesicles can penetrate into recipient cells. SKOV3 donor cells were cultured on special medium containing isotope labeled lysine and arginine. When label inclusion was more than 98%, the cells were treated or untreated (control) with cisplatin. After 48 h, extracellular vesicles containing labeled proteins were isolated. These vesicles were added to unlabeled SKOV3 recipient cells and, after 10 or 48 h, the cells were lysed and subjected to LC-MS/MS to identify labeled proteins. We found that at least 189 heavy-labeled proteins entered recipient cells from the vesicles at 10-hour of incubation. Among them, 101 proteins were present at a higher level in cells incubated with apoptotic vesicles, and 29 proteins were present at a higher level in cells incubated with vesicles from non-apoptotic cells. Functional annotation of heavy-labeled proteins elevated in samples incubated with apoptotic vesicles revealed the highest enrichment in a cluster of spliceosome-related proteins. We suggest that the acquisition of a more aggressive phenotype of recipient cancer cells might be partially mediated by extracellular spliceosomal components.

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Evaluation of secretomes derived from human dermal and adipose tissue mesenchymal stem/stromal cells for skin wound healing: Not as effective as cells

Project description:Although the paracrine effects of mesenchymal stem/stromal cells (MSCs) have been recognized as crucial mediators of their regenerative effects on tissue repair, the potential of MSC secretomes as effective substitutes for cellular therapies remains underexplored. In this study, we compared MSCs from the human dermis (DSCs) and adipose tissue (ASCs) with their secretomes regarding their efficacy for skin wound healing using a translationally-relevant murine model. Proteomic analysis revealed that while there was a substantial overlap in protein composition between DSC and ASC secretomes, specific proteins associated with wound healing and angiogenesis were differentially expressed. Despite a similar angiogenic potential in vivo, DSC- and ASC-secretomes were found to be less effective than cells in accelerating wound closure and promoting tissue remodeling. Overall, secretome-treated groups showed intermediary results between cells and control (empty scaffold) treated groups. These findings highlight that although secretomes possess therapeutic potential, their efficacy might be limited compared to cellular therapies. This study contributes to the growing understanding of MSC secretomes, emphasizes the need for further protocol optimization, and offers insights into their potential applications in regenerative medicine.

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Human melanoma cell lines secretome analysis

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2018-01-02 | PXD007265 | Pride

Mesenchymal stem cell secretome

Project description:Adult neural stem cells (aNSCs) show multilineage differentiation potential influenced by intrinsic and extrinsic signaling cues. We and others have shown that stimulation of aNSCs with bone marrow mesenchymal stem cell (MSC) secreted factors substantially enhances in vitro oligodendrogenesis at an expense of astrogenesis by yet unknown mechanisms (Rivera et al. 2006, Jadasz et al. 2013; 2018, Rivera et al., 2019). In the present study, we demonstrate that aNSCs pre-treated with MSC secretomes for different periods in vitro preferentially differentiate to oligodendrocytic cells in vivo after transplantation into the adult rat spinal cord. Analysis of different time points after transplantation revealed a stable survival rate of transplanted aNSCs and an emphasized pro-oligodendroglial differentiation in response to MSC secreted factors. MSC derived secretomes were then analyzed by mass spectrometry-based proteomics and label-free quantification to identify secreted proteins contributing to oligodendroglial lineage fate determination. To exclude possible contaminants derived from dead cells or serum, our approach includes a comparison of the abundances of proteins present in MSC derived secretomes with corresponding proteins in cell lysates (Grube et al., 2018, Schira-Heinen et al., 2019).

2020-06-18 | PXD018231 | Pride

Differential gene expression profiles between SKOV3.ip1-S116A cells (Ser116 of PEA-15 substituted with alanine) and SKOV3.ip1-S116D cells (Ser116 of PEA-15 substituted with aspartic acid).

Project description:To dissect the molecular mechanisms of PEA-15-mediated paclitaxel sensitization in ovarian cancer cells, we performed cDNA microarray analysis using SKOV3.ip1-S116A cells (Ser116 of PEA-15 substituted with alanine) and SKOV3.ip1-S116D cells (Ser116 of PEA-15 substituted with aspartic acid). cDNA microarray data analysis showed that SCLIP (SCG10-like protein), also known as STMN3, was highly expressed in SKOV3.ip1-S116D cells and was involved in pPEA-15-mediated paclitaxel sensitization in ovarian cancer cells. SKOV3.ip1-S116A cells (Ser116 of PEA-15 substituted with alanine) and SKOV3.ip1-S116D cells (Ser116 of PEA-15 substituted with aspartic acid) were used. Total RNA was extracted and purified using RNeasy mini kit (Qiagen, Inc.) according to the manufacturerM-bM-^@M-^Ys instructions. The integrity of the obtained RNA was assessed using an Agilent 2100 BioAnalyzer (Agilent Technologies). The Affymetrix HGU133 plus platform was used for hybridization, staining, and imaging of the arrays by following the manufacturerM-bM-^@M-^Ys instructions. Gene expression analysis was performed in triplicate.

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Proteomic profiling of the proteolytic events in the secretome of the transformed phenotype of melanocyte-derived cells using Terminal Amine Isotopic Labeling of Substrates

Project description:The comprehensive profiling of the repertoire of secreted proteins from cancer cells and/or tissue samples provides information on the signaling events that take place during oncogenesis as well as on the cross-talk between normal and tumoral cells. Moreover, the analysis of post translational modifications in secreted proteins may unravel biological circuits regulated by irreversible modifications such as, for example, proteolytic processing. In this context, we used Terminal Amine Isotopic Labeling of Substrates (TAILS) to perform a system-wide investigation on the N-terminome of the secretomes derived from a paired set of mouse melanocyte cell lines: Melan-a (a normal melanocyte) and Tm1 (its transformed phenotype). TAILS analysis allowed the profiling of co-translational modifications such as acetylated N-termini as well as proteolytic events in both secretomes. Although no significant difference has been found in the proportion of acetylated natural N-termini in both cell line secretomes, when evaluating amino acid identities at the scissile bond in internal peptides it was possible to detect significant differences, suggesting distinct proteolytic processes acting in the normal and tumoral secretomes. The mapping and annotation of cleavage sites in the tumoral secretome suggested functional roles of active proteases in central biological processes related to oncogenesis, such as the processing of growth factors, cleavage of extracellular matrix proteins and the shedding of ectopic domains from the cell surface, some of which may represent novel processed forms of the corresponding proteins. In the context of the tumor microenvironment, these results suggest important biological roles of proteolytic processing in murine melanoma secreted proteins.

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Project description:Exogenous signals from drug-stressed cancer cells promote acquisition of a more aggressive phenotype of neighboring tumor cells. Recently, we examined how cancer cell secretome changes in response to chemotherapy. We showed that tumor therapy-induced secretomes significantly increased resistance of cancer cells to subsequent cisplatin treatment but we did not observed the same phenomenon on normal fibroblasts. To elucidate how therapy-induced secretomes affect the transcriptomic profiles of recipient tumor cells, we incubated SKOV3 cells for 3 days with secretomes from control or dying cancer cells. The same conditions were used for normal fibroblasts. Enrichment analysis of differentially expressed genes in SKOV3 cells incubated with therapy-induced secretomes identified prominent up-regulation of genes involved in coordination of mitotic processes, G2/M transition checkpoints and DNA repair. These findings demonstrate that under stress condition cancer but not normal cells can secrete signaling molecules into the exracellular space and contribute to the emergence of tumor chemoresistance during short time period.

2024-04-24 | GSE241910 | GEO

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