Dataset Information

TRAIL-induced cancer secretome

ABSTRACT: To comprehensively determine which factors are secreted by cancer cells upon TRAIL stimulation, we conducted an unbiased mass spectrometric analysis of TRAIL’s secretome in resistant A549 cells.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell Of Lung

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: Silvia Surinova

LAB HEAD: Silvia Surinova

PROVIDER: PXD005664 | Pride | 2017-12-19

REPOSITORIES: Pride

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Publications

The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2.

Hartwig Torsten T Montinaro Antonella A von Karstedt Silvia S Sevko Alexandra A Surinova Silvia S Chakravarthy Ankur A Taraborrelli Lucia L Draber Peter P Lafont Elodie E Arce Vargas Frederick F El-Bahrawy Mona A MA Quezada Sergio A SA Walczak Henning H

Molecular cell 20170201 4

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether and to what extent TRAIL/TRAIL-R signaling in cancer cells can affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant cancer cells is FADD dependent and identify the TRAIL-induced secretome to drive monoc ...[more]

PMID: 28212753

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Project description:TRAIL cytotoxicity is exploited as anti-cancer therapy since many years, however incomplete knowledge is generating many obstacles. Here, we address whether the highly abundant extracellular matrix molecule tenascin-C (TNC) orchestrating an immune suppressive tumor microenvironment and binding TRAIL impacts TRAIL cytotoxicity. We used an immune competent autologous NT193 breast cancer model with a knockdown (KD) of Tnfsf10 (encoding TRAIL) and observed accelerated tumor growth marked by less apoptosis, more proliferation and less myeloid cell infiltration as seen by flow cytometry. Grafting the same Tnfsf10 KD cells into a TNC knockout host showed repressed tumor growth suggesting that TNC is involved in regulating TRAIL functions. In vitro, we saw reduced macrophage invasion and phagocytosis with conditioned medium from Tnfsf10 KD tumor cells proposing a role of TRAIL in counteracting tumor growth. We further demonstrated that TRAIL increases secretion of TGF2/3 inducing CXCR4 in macrophages. Here, we have discovered regulation of TRAIL cytotoxicity through cell plasticity orchestrated by TNC. The pro-tumorigenic effects of TNC, counteracting TRAIL cytotoxicity, entail repression of Tnfsf10 through integrin and, abolishing TRAIL-receptor DR5 and E-cadherin expression. As the MAREMO peptide MP5 inhibits TNC actions, we determined whether targeting TNC with MP5 has an impact on TRAIL cytotoxicity. Indeed, MP5 enforces an epithelial phenotype and elevates DR5 expression thus causing sensitization to TRAIL-induced cell death. Moreover, MP5 inhibited tumor growth that was less pronounced in Tnfsf10 KD tumors suggesting MP5 to empower endogenous TRAIL cytotoxicity. Kaplan-Meier analysis demonstrated that a high TRAIL expression correlates with favorable breast and gastric cancer patient survival which is abolished when TNC levels are also high. Our results predict that tumors with lower TNC might be more responsive to therapeutic TRAIL cytotoxicity and that MP5 could be a novel tool for enhancing TRAIL therapy.

			Action	DRS
	Hartwig-et-al.-Table-S1.xlsx	Xlsx
	evidence.txt	Txt
	mqpar.xml	Xml
	msms.txt	Txt
	proteinGroups.txt	Txt