A transcriptome-based global map of signaling pathways in the ovarian cancer microenvironment associated with clinical outcome

Reinartz, Silke; Finkernagel, Florian; Adhikary, Till; Rohnalter, Verena; Schumann, Tim; Schober, Yvonne; Nockher, Wolfgang Andreas; Nist, Andrea; Stiewe, Thorsten; Jansen, Julia M.; Wagner, Uwe; Müller‐Brüsselbach, Sabine; Müller, Rolf

doi:10.1186/s13059-016-0956-6

Cited by 85 publications

(170 citation statements)

References 86 publications

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“…These observations are in perfect agreement with the flow cytometry analysis described above (Figure 1A–1C). Similar observations were made for genes encoding pro-tumorigenic cytokines or growth factor (Figure 3B), previously found to be mainly expressed by TAMs within the ovarian cancer microenvironment [38]. These results indicate that ovarian carcinoma ascites-associated TAMs closely resemble pMPHs not only with respect to their activation state but also with regard to some of their pro-tumorigenic functions.…”

Section: Resultssupporting

confidence: 87%

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The transcriptional signature of human ovarian carcinoma macrophages is associated with extracellular matrix reorganization

Finkernagel

Reinartz²,

Lieber

et al. 2016

Oncotarget

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Macrophages occur as resident cells of fetal origin or as infiltrating blood monocyte-derived cells. Despite the critical role of tumor-associated macrophages (TAMs) in tumor progression, the contribution of these developmentally and functionally distinct macrophage subsets and their alteration by the tumor microenvironment are poorly understood. We have addressed this question by comparing TAMs from human ovarian carcinoma ascites, resident peritoneal macrophages (pMPHs) and monocyte-derived macrophages (MDMs). Our study revealed striking a similarity between TAMs and pMPHs, which was considerably greater that the resemblance of TAMs and MDMs, including their transcriptomes, their inflammation-related activation state, the presence of receptors mediating immune functions and the expression of tumor-promoting mediators. Consistent with these results, TAMs phagocytized bacteria, presented peptide antigens and activated cytotoxic T cells within their pathophysiological environment. These observations support the notion that tumor-promoting properties of TAMs may reflect, at least to some extent, normal features of resident macrophages rather than functions induced by the tumor microenvironment. In spite of these surprising similarities between TAMs and pMPHs, bioinformatic analyses identified a TAM-selective signature of 30 genes that are upregulated relative to both pMPHs and MDMs. The majority of these genes is linked to extracellular matrix (ECM) remodeling, supporting a role for TAMs in cancer cell invasion and ovarian cancer progression.

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Section: Resultssupporting

confidence: 87%

“…Tumor cells and CD3 + T cells were isolated as described [38]. MDMs were generated from monocytes (6-day differentiation for RNA experiments, 10-day cultures for flow cytometry) from healthy donors as described [75] and in RPMI with human AB serum.…”

Section: Methodsmentioning

confidence: 99%

The transcriptional signature of human ovarian carcinoma macrophages is associated with extracellular matrix reorganization

Finkernagel

Reinartz²,

Lieber

et al. 2016

Oncotarget

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“…T cell from peripheral blood were isolated as described for ascites [21]. Buffy coats were obtained from the blood bank at UKGM Giessen, Germany.…”

Section: Methodsmentioning

confidence: 99%

Interferon signaling in ascites-associated macrophages is linked to a favorable clinical outcome in a subgroup of ovarian carcinoma patients

et al. 2017

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BackgroundAlthough tumor-associated macrophages (TAMs) are essential for cancer progression, connections between different clinical outcomes and transcriptional networks have not been reported. We have addressed this issue by analyzing global expression patterns of TAMs isolated from the ascites of ovarian cancer patients.ResultsTAMs isolated from different ovarian cancer patients can be stratified by coexpression or principal component analysis into subgroups with specific biological features and associated with distinct clinical outcomes. A hallmark of subgroup A is a high expression of clinically unfavorable markers, including (i) high CD163 expression, a surface receptor characteristic of an anti-inflammatory activation state, (ii) increased PCOLCE2 expression, indicative of enhanced extracellular matrix organization, and (iii) elevated ascites levels of IL-6 and IL-10, linked to the aggressiveness of ovarian cancer and immune suppression. In contrast, subgroup B TAMs are characterized by the upregulation of genes linked to immune defense mechanisms and interferon (IFN) signaling. Intriguingly, analysis of published data for 1763 ovarian cancer patients revealed a strong association of this transcriptional signature with a longer overall survival. Consistent with these results, IFNγ was able to abrogate the suppressive effect of ovarian cancer ascites on the inducibility of IL12B expression and IL-12 secretion, a key determinant of a cytotoxic immune response.ConclusionsThe survival of ovarian cancer patients is linked to the presence of TAMs with a transcriptional signature that is characterized by a low expression of protumorigenic and immunosuppressive markers and an upregulation of genes linked to interferon signaling. The observed IFNγ-mediated restoration of the inducibility of IL-12 in the presence of ascites provides a possible explanation for the association of an interferon signaling-associated signature with a favorable clinical outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3630-9) contains supplementary material, which is available to authorized users.

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“…For mRNA‐level risk results, the overexpression of retinol binding protein 4 (RBP4) in OvCa cells promoted cancer cell migration and proliferation, and an adipokine secreted by adipose tissue also induced cell invasion and metastasis, which showed the potential risk roles of path: 04920_2 (Adipocykine signalling pathway, top 1). For path: 04360_5 (Axon guidance, top 2), a previous transcriptome‐based study also revealed the axon guidance molecules were related with OvCa clinical prognosis . Furthermore, CaMKK2 (one key kinase in calcium signalling) knockdown potentiated the effects of the chemotherapeutic drugs carboplatin and PX‐866 to reduce OvCa survival .…”

Section: Discussionmentioning

confidence: 96%

Comprehensive analysis of mRNA‐level and miRNA‐level subpathway activities for identifying robust ovarian cancer prognostic signatures

Tian

Zhang

et al. 2020

J Cellular Molecular Medi

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Ovarian cancer (OvCa) causes the highest mortality among all gynaecologic cancers. A large number of mRNA‐ or miRNA‐based signatures were identified for OvCa patient prognosis. However, the comprehensive analysis of function‐level prognostic signatures is currently not considered in OvCa. In the present study, we respectively inferred subpathway activities from mRNA and miRNA levels based on high‐throughput expression profiles and reconstructed subpathways. Firstly, the activities of two tumour pathways were calculated and the difference between normal and tumour samples were analysed using multiple tumour types. Then, we calculated subpathway activities for OvCa based on the expression profiles from both mRNA and miRNA levels. Furthermore, based on these subpathway activity matrices, we performed bootstrap analysis to obtain sub‐training sets and utilized univariate method to identify robust OvCa prognostic subpathways. A comprehensive comparison of subpathway results between these two levels was performed. As a result, we observed subpathway mutual exclusion trend between the levels of mRNA and miRNA, which indicated the necessary of combining mRNA‐miRNA levels. Finally, by using ICGC data as testing sets, we utilized two strategies to verify survival predictive power of the mRNA‐miRNA combined subpathway signatures and performed comparisons with results from individual levels. It was confirmed that our framework displayed application to identify robust and efficient prognostic signatures for OvCa, and the combined signatures indeed exhibited advantages over individual ones. In the study, we took a step forward in relevant novel integrated functional signatures for OvCa prognosis.

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A transcriptome-based global map of signaling pathways in the ovarian cancer microenvironment associated with clinical outcome

Cited by 85 publications

References 86 publications

The transcriptional signature of human ovarian carcinoma macrophages is associated with extracellular matrix reorganization

The transcriptional signature of human ovarian carcinoma macrophages is associated with extracellular matrix reorganization

Interferon signaling in ascites-associated macrophages is linked to a favorable clinical outcome in a subgroup of ovarian carcinoma patients

Comprehensive analysis of mRNA‐level and miRNA‐level subpathway activities for identifying robust ovarian cancer prognostic signatures

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