Tissue-based map of the human proteome

Uhlén, Mathias; Fagerberg, Linn; Hallström, Björn M.; Lindskog, Cecilia; Oksvold, Per; Mardinoğlu, Adil; Sivertsson, Åsa; Kampf, Caroline; Sjöstedt, Evelina; Asplund, Anna; Olsson, Ing-Marie; Edlund, Karolina; Lundberg, Emma; Navani, Sanjay; Szigyarto, Cristina Al‐Khalili; Odeberg, Jacob; Djureinovic, Dijana; Takanen, Jenny Ottosson; Hober, Sophia; Alm, Tove; Edqvist, Per‐Henrik; Berling, Holger; Tegel, Hanna; Mulder, Jan; Rockberg, Johan; Nilsson, Peter; Schwenk, Jochen M.; Hamsten, Marica; Feilitzen, Kalle von; Forsberg, Maud; Persson, Lukas; Johansson, Fredric; Zwahlén, Martin; Heijne, Gunnar von; Nielsen, Jens; Pontén, Fredrik

doi:10.1126/science.1260419

Cited by 12,166 publications

(11,310 citation statements)

References 52 publications

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“…As readout for oncogenic transformation we monitored clonal growth in 3D anchorage‐independent settings, which we have previously shown to correlate with in vivo tumor growth (Fig 1 b ) 25. In total, we have screened 13 secreted factors, of which seven factors passed the preselection criteria, including detectable expression of the cognate receptor as judged by RNAseq data (Human Protein Atlas http://www.proteinatlas.org) 33 and the ability to induce the activation of established downstream effectors (Supporting Information, Table S5). As positive control for the integrity of the screen, we monitored cellular transformation by concomitant epidermal growth factor (EGF) signaling and GLI1 expression, which we have previously shown to have potent synergistic transformation capacity (Fig 1 b′ ) 25.…”

Section: Resultsmentioning

confidence: 99%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

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Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin‐6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis‐regulatory sequences by co‐binding of GLI and STAT3 to common HH‐IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI‐driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH‐IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

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Section: Resultsmentioning

confidence: 99%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

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“…These features were able to separate the advanced cancer sample population from non-cancer patient in either the cross-validation model or by un-supervised hierarchical cluster method. Interestingly, according to the information from The Human Protein Atlas database [49–51], as shown in Table 1, the expression of over 70% of these features (43 out of 60) have been confirmed by immunohistochemistry on the breast cancer tissues slides, only 17 proteins are yet to be confirmed, partially because lacking of suitable antibodies, consistent to our expectation by screening the initial features from enriched plasma EVs with features from EVs generated by breast cancer cell lines. …”

Section: Discussionmentioning

confidence: 99%

Profiling plasma extracellular vesicle by pluronic block‐copolymer based enrichment method unveils features associated with breast cancer aggression, metastasis and invasion

Zhong

Rosenow

Xiao

et al. 2018

J of Extracellular Vesicle

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Extracellular vesicle (EV)-based liquid biopsies have been proposed to be a readily obtainable biological substrate recently for both profiling and diagnostics purposes. Development of a fast and reliable preparation protocol to enrich such small particles could accelerate the discovery of informative, disease-related biomarkers. Though multiple EV enrichment protocols are available, in terms of efficiency, reproducibility and simplicity, precipitation-based methods are most amenable to studies with large numbers of subjects. However, the selectivity of the precipitation becomes critical. Here, we present a simple plasma EV enrichment protocol based on pluronic block copolymer. The enriched plasma EV was able to be verified by multiple platforms. Our results showed that the particles enriched from plasma by the copolymer were EV size vesicles with membrane structure; proteomic profiling showed that EV-related proteins were significantly enriched, while high-abundant plasma proteins were significantly reduced in comparison to other precipitation-based enrichment methods. Next-generation sequencing confirmed the existence of various RNA species that have been observed in EVs from previous studies. Small RNA sequencing showed enriched species compared to the corresponding plasma. Moreover, plasma EVs enriched from 20 advanced breast cancer patients and 20 age-matched non-cancer controls were profiled by semi-quantitative mass spectrometry. Protein features were further screened by EV proteomic profiles generated from four breast cancer cell lines, and then selected in cross-validation models. A total of 60 protein features that highly contributed in model prediction were identified. Interestingly, a large portion of these features were associated with breast cancer aggression, metastasis as well as invasion, consistent with the advanced clinical stage of the patients. In summary, we have developed a plasma EV enrichment method with improved precipitation selectivity and it might be suitable for larger-scale discovery studies.

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“…The second filter is based on mRNA expression from the Human Protein Atlas 50,51,84 from the three methods (HPA, GTEx, FANTOM5), in the spleen and lymph node. Again, no obvious threshold emerged from these data.…”

Section: Methodsmentioning

confidence: 99%

Impact of chemotactic factors and receptors on the cancer immune infiltrate: a bioinformatics study revealing homogeneity and heterogeneity among patient cohorts

et al. 2018

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Multiple soluble factors including proteins (in particular chemokines), non-proteinaceous factors released by dead cells, as well as receptors for such factors (in particular chemokine receptors, formyl peptide receptors and purinergic receptors), influence the recruitment of distinct cell subsets into the tumor microenvironment. We performed an extensive bioinformatic analysis on tumor specimens from 5953 cancer patients to correlate the mRNA expression levels of chemotactic factors/receptors with the density of immune cell types infiltrating the malignant lesions. This meta-analysis, which included specimens from breast, colorectal, lung, ovary and head and neck carcinomas as well as melanomas, revealed that a subset of chemotactic factors/receptors exhibited a positive and reproducible correlation with several infiltrating cell types across various solid cancers, revealing a universal pattern of association. Hence, this meta-analysis distinguishes between homogeneous associations that occur across different cancer types and heterogeneous correlations, that are specific of one organ. Importantly, in four out of five breast cancer cohorts for which clinical data were available, the levels of expression of chemotactic factors/receptors that exhibited universal (rather than organ-specific) positive correlations with the immune infiltrate had a positive impact on the response to neoadjuvant chemotherapy. These results support the notion that general (rather than organ-specific) rules governing the recruitment of immune cells into the tumor bed are particularly important in determining local immunosurveillance and response to therapy.

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Tissue-based map of the human proteome

Cited by 12,166 publications

References 52 publications

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Profiling plasma extracellular vesicle by pluronic block‐copolymer based enrichment method unveils features associated with breast cancer aggression, metastasis and invasion

Impact of chemotactic factors and receptors on the cancer immune infiltrate: a bioinformatics study revealing homogeneity and heterogeneity among patient cohorts

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