Nuclear FAK Controls Chemokine Transcription, Tregs, and Evasion of Anti-tumor Immunity

Serrels, Alan; Lund, Tom; Serrels, Bryan; Byron, Adam; McPherson, Rhoanne C.; Kriegsheim, Alex von; Gómez-Cuadrado, Laura; Canel, Marta; Muir, Morwenna; Ring, Jennifer E.; Maniati, Eleni; Sims, Andrew H.; Pachter, Jonathan A.; Brunton, Valerie G.; Gilbert, Nick; Anderton, Stephen M.; Nibbs, Robert J. B.

doi:10.1016/j.cell.2015.09.001

Cited by 315 publications

(370 citation statements)

References 48 publications

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“…However, in a murine breast cancer model with CCL5 knockdown in tumor cells only, no differences in tumor growth or metastasis occurred (63). However, in squamous cell carcinoma, knockdown of CCL5 leads to tumor regression and reduced numbers of recruited Treg cells (64). Further, knockdown of CCL5 in murine colorectal carcinoma cells delays tumor growth and decreases both Treg cell infiltration and CD8 ϩ T-cell apoptosis (65).…”

Section: Journal Of Biological Chemistry 4101mentioning

confidence: 99%

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Kretschmer

Freudenberger

Twarock

et al. 2016

Journal of Biological Chemistry

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The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less ␣-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4 ؉ but not CD8 ؉ cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response.

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Section: Journal Of Biological Chemistry 4101mentioning

confidence: 99%

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Kretschmer

Freudenberger

Twarock

et al. 2016

Journal of Biological Chemistry

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“…3E) that could be exploited in the treatment of GBM. For instance, targeting FAK, effectors of EMT or components of the glycocalyx, each of which are being examined as targets in clinical trials (Hingorani et al, 2016;Traber et al, 2013;Serrels et al, 2015), could improve disease outcome when combined with standard-of-care treatment. These findings also suggest that, similar to what has been shown for solid tumors (Acerbi et al, 2015), mechanical testing or assessment of mechanosignaling of gliomas can extend the repertoire of conventional molecular biomarkers, thereby improving predictions of response to therapy.…”

Section: Effects Of Mechanical Changes On Glioma Progressionmentioning

confidence: 99%

Tissue mechanics regulate brain development, homeostasis and disease

Barnes

Przybyla

Weaver

2017

Journal of Cell Science

252

245

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All cells sense and integrate mechanical and biochemical cues from their environment to orchestrate organismal development and maintain tissue homeostasis. Mechanotransduction is the evolutionarily conserved process whereby mechanical force is translated into biochemical signals that can influence cell differentiation, survival, proliferation and migration to change tissue behavior. Not surprisingly, disease develops if these mechanical cues are abnormal or are misinterpreted by the cells – for example, when interstitial pressure or compression force aberrantly increases, or the extracellular matrix (ECM) abnormally stiffens. Disease might also develop if the ability of cells to regulate their contractility becomes corrupted. Consistently, disease states, such as cardiovascular disease, fibrosis and cancer, are characterized by dramatic changes in cell and tissue mechanics, and dysregulation of forces at the cell and tissue level can activate mechanosignaling to compromise tissue integrity and function, and promote disease progression. In this Commentary, we discuss the impact of cell and tissue mechanics on tissue homeostasis and disease, focusing on their role in brain development, homeostasis and neural degeneration, as well as in brain cancer.

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“…One that stood out was FAK, a nonreceptor tyrosine kinase that is overexpressed and/or hyperactive in many different cancer cell types, where it has been shown to participate in the maintenance of the transformed phenotype, including the evasion of apoptosis and promotion of anchorage-independent growth (23)(24)(25)(26)(27). In fact, targeting FAK for inactivation is currently being used as a strategy to treat several different types of human cancer (28,29). Fig.…”

Section: Onco-dbl Expression In Mefs Induces Cellular Transformation-mentioning

confidence: 99%

Microvesicle Cargo and Function Changes upon Induction of Cellular Transformation

Kreger

Dougherty

Greene

et al. 2016

Journal of Biological Chemistry

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Extracellular vesicles (EVs), including exosomes and microvesicles (MVs), have emerged as a major form of intercellular communication, playing important roles in several physiological processes and diseases, including cancer. EVs generated by cancer cells contain a variety of proteins and RNA species that can be transferred between cancer cells as well as between cancer and non-transformed (normal) cells, thereby impacting a number of aspects of cancer progression. Here we show how oncogenic transformation influences the biogenesis and function of EVs using a mouse embryonic fibroblast (MEF) cell line that can be induced to express an oncogenic form of diffuse B cell lymphoma (Dbl). Although MEFs induced to express oncoDbl generated a similar amount of MVs as uninduced control cells, we found that MVs isolated from onco-Dbl-transformed cells contain a unique signaling protein, the ubiquitously expressed non-receptor tyrosine kinase focal adhesion kinase. The addition of MVs isolated from MEFs expressing onco-Dbl to cultures of fibroblasts strongly promoted their survival and induced their ability to grow under anchorage-independent conditions, outcomes that could be reversed by knocking down focal adhesion kinase and depleting it from the MVs or by inhibiting its kinase activity using a specific inhibitor. We then showed the same to be true for MVs isolated from aggressive MDAMB231 breast cancer cells. Together, these findings demonstrate that the induction of oncogenic transformation gives rise to MVs, which uniquely contain a signaling protein kinase that helps propagate the transformed phenotype and thus may offer a specific diagnostic marker of malignant disease.Classical intercellular signaling involves the secretion of growth factors, pro-inflammatory cytokines, and extracellular matrix proteins by a cell into its local environment (1, 2). These soluble factors then bind to their corresponding receptors expressed in a neighboring cell and induce the activation of intracellular signaling events that determine whether a cell grows, differentiates, migrates, or dies (3). These types of paracrine signaling activities are required throughout development and for tissue homeostasis, whereas deregulation of these events often leads to developmental abnormalities and the onset of diseases.The generation of EVs 3 by cells has quickly become appreciated as another major form of intercellular communication with important consequences in biology (4 -7). Cells generate two distinct types of EVs: MVs and exosomes. MVs typically range in size from 0.2-2.0 m in diameter and are formed via the budding and release (shedding) of membrane-enclosed packages from plasma membranes. Exosomes represent the second major class of EVs. They are significantly smaller than MVs, averaging only 0.03-0

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Nuclear FAK Controls Chemokine Transcription, Tregs, and Evasion of Anti-tumor Immunity

Cited by 315 publications

References 48 publications

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Tissue mechanics regulate brain development, homeostasis and disease

Microvesicle Cargo and Function Changes upon Induction of Cellular Transformation

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