Tenascin-C: Exploitation and collateral damage in cancer management

Spenlé, Caroline; Saupe, Falk; Midwood, Kim S.; Burckel, Hélène; Noël, G.; Orend, Gertraud

doi:10.1080/19336918.2014.1000074

Cited by 59 publications

(50 citation statements)

References 110 publications

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“…SepA shares homology with human MSTs and PAKs, known tumor supressors that are currently being investigated as therapeutic targets (84,85). Human Tenascin-C is reported to play a role in the progression and metastasis of breast cancer and as a potential target (86,87). The human DUSP proteins have been reported to play numerous roles in oncogenesis and cancer progression, are useful diagnostic markers, and are promising drug targets (88)(89)(90).…”

Section: Regulators Of Adhesion and Motility Reveal Multiple Points Ofmentioning

confidence: 99%

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Lampert

Kamprad

Edwards

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The model organism Dictyostelium discoideum has greatly facilitated our understanding of the signal transduction and cytoskeletal pathways that govern cell motility. Cell-substrate adhesion is downstream of many migratory and chemotaxis signaling events. Dictyostelium cells lacking the tumor suppressor PTEN show strongly impaired migratory activity and adhere strongly to their substrates. We reasoned that other regulators of migration could be obtained through a screen for overly adhesive mutants. A screen of restriction enzyme-mediated integration mutagenized cells yielded numerous mutants with the desired phenotypes, and the insertion sites in 18 of the strains were mapped. These regulators of adhesion and motility mutants have increased adhesion and decreased motility. Characterization of seven strains demonstrated decreased directed migration, flatness, increased filamentous actin-based protrusions, and increased signal transduction network activity. Many of the genes share homology to human genes and demonstrate the diverse array of cellular networks that function in adhesion and migration

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Section: Regulators Of Adhesion and Motility Reveal Multiple Points Ofmentioning

confidence: 99%

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Lampert

Kamprad

Edwards

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Because Tnc expression is absent in normal adult tissues but highly up-regulated in many solid cancers, it represents an ideal diagnostic marker and therapeutic target in cancers (40). In several compounds currently in clinical trials, antibodies against Tnc have been conjugated to either radioactive compounds that can inhibit tumor growth or IL-2, aimed at improving the efficacy of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival

Gocheva

Naba

Bhutkar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

124

130

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The extracellular microenvironment is an integral component of normal and diseased tissues that is poorly understood owing to its complexity. To investigate the contribution of the microenvironment to lung fibrosis and adenocarcinoma progression, two pathologies characterized by excessive stromal expansion, we used mouse models to characterize the extracellular matrix (ECM) composition of normal lung, fibrotic lung, lung tumors, and metastases. Using quantitative proteomics, we identified and assayed the abundance of 113 ECM proteins, which revealed robust ECM protein signatures unique to fibrosis, primary tumors, or metastases. These analyses indicated significantly increased abundance of several S100 proteins, including Fibronectin and Tenascin-C (Tnc), in primary lung tumors and associated lymph node metastases compared with normal tissue. We further showed that Tnc expression is repressed by the transcription factor Nkx2-1, a well-established suppressor of metastatic progression. We found that increasing the levels of Tnc, via CRISPR-mediated transcriptional activation of the endogenous gene, enhanced the metastatic dissemination of lung adenocarcinoma cells. Interrogation of human cancer gene expression data revealed that high TNC expression correlates with worse prognosis for lung adenocarcinoma, and that a three-gene expression signature comprising TNC, S100A10, and S100A11 is a robust predictor of patient survival independent of age, sex, smoking history, and mutational load. Our findings suggest that the poorly understood ECM composition of the fibrotic and tumor microenvironment is an underexplored source of diagnostic markers and potential therapeutic targets for cancer patients.

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“…Indeed, amongst 11 highly immunogenic peptides that have been delivered within an immunization cocktail to glioblastoma patients (clinical trial phase I), one represented tenascin-C (Dutoit et al, 2012;Rampling et al, 2016). Moreover, aptamers and antibodies that specifically bind to tenascin-C were applied to deliver drugs or immune stimulatory chemokines, such as IL2, into the tumor microenvironment of patients with different cancers (Catania et al, 2015;Gutbrodt et al, 2013 ; reviewed in Spenle et al, 2015b). Furthermore, tenascin-C gene expression negatively influences the cytotoxicity of doxorubicin in breast cancer and melanoma spheroids, as well as pancreatic cancer cells (Fukunaga-Kalabis et al, 2010;Oskarsson et al, 2011), suggesting that tenascin-C is a good target for adjuvant chemotherapy.…”

Section: Tenascin-c In Tissuesmentioning

confidence: 99%

Tenascin-C at a glance

Midwood

Chiquet

Tucker

et al. 2016

Journal of Cell Science

Self Cite

358

357

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Tenascin-C (TNC) is a hexameric, multimodular extracellular matrix protein with several molecular forms that are created through alternative splicing and protein modifications. It is highly conserved amongst vertebrates, and molecular phylogeny indicates that it evolved before fibronectin. Tenascin-C has many extracellular binding partners, including matrix components, soluble factors and pathogens; it also influences cell phenotype directly through interactions with cell surface receptors. Tenascin-C protein synthesis is tightly regulated, with widespread protein distribution in embryonic tissues, but restricted distribution of tenascin-C in adult tissues. Tenascin-C is also expressed de novo during wound healing or in pathological conditions, including chronic inflammation and cancer. First described as a modulator of cell adhesion, tenascin-C also directs a plethora of cell signaling and gene expression programs by shaping mechanical and biochemical cues within the cellular microenvironment. Exploitment of the pathological expression and function of tenascin-C is emerging as a promising strategy to develop new diagnostic, therapeutic and bioengineering tools. In this Cell Science at a Glance article and the accompanying poster we provide a succinct and comprehensive overview of the structural and functional features of tenascin-C and its potential roles in developing embryos and under pathological conditions.

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Tenascin-C: Exploitation and collateral damage in cancer management

Cited by 59 publications

References 110 publications

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival

Tenascin-C at a glance

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