Type 2 Innate Lymphoid Cells Protect against Colorectal Cancer Progression and Predict Improved Patient Survival.

Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define the role of ILCs in CRC we employed complementary heterotopic and chemically-induced CRC mouse models. We discovered that ILCs were abundant in CRC tumours and contributed to anti-tumour immunity. We focused on ILC2 and showed that ILC2-deficient mice developed a higher tumour burden compared with littermate wild-type controls. We generated an ILC2 gene signature and using machine learning models revealed that CRC patients with a high intratumor ILC2 gene signature had a favourable clinical prognosis. Collectively, our results highlight a critical role for ILC2 in CRC, suggesting a potential new avenue to improve clinical outcomes through ILC2-agonist based therapeutic approaches

A transcriptional program for detecting TGFbeta-induced EMT in cancer

Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. Transforming growth factor beta (TGFbeta) is one of the best-studied drivers of EMT, and many drugs are available to target this signalling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGFbeta-induced EMT which can be used to score TGFbeta-driven EMT in cells and clinical specimens. Considering this signature in pan-cancer cell and tumour datasets, a number of cell lines (including Basal B breast cancer and cancers of the central nervous system) show evidence for TGFbeta-driven EMT and carry a low mutational burden across the TGFbeta signalling pathway. Further, significant variation is observed in the response of high scoring cell lines to some common cancer drugs. Finally, this signature was applied to pan-cancer data from The Cancer Genome Atlas to identify tumour types with evidence of TGFbeta-induced EMT. Tumour types with high scores showed significantly lower survival rates compared to those with low scores, and also carry a lower mutational burden in the TGFbeta pathway. The current transcriptomic signature demonstrates reproducible results across independent cell line and cancer datasets and identifies samples with strong mesenchymal phenotypes likely to be driven by TGFbeta. Implications: The TGFbeta-induced EMT signature may be useful to identify patients with mesenchymal-like tumours that could benefit from targeted therapeutics to inhibit pro-mesenchymal TGFbeta signalling and disrupt the metastatic cascade

A transcriptional program for detecting TGFbeta-induced EMT in cancer

Most cancer deaths are due to metastasis, and <i>epithelial-to-mesenchymal transition</i> (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. <i>Transforming growth factor beta</i> (TGFbeta) is one of the best-studied drivers of EMT, and many drugs are available to target this signalling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGFbeta-induced EMT which can be used to score TGFbeta-driven EMT in cells and clinical specimens. Considering this signature in pan-cancer cell and tumour datasets, a number of cell lines (including Basal B breast cancer and cancers of the central nervous system) show evidence for TGFbeta-driven EMT and carry a low mutational burden across the TGFbeta signalling pathway. Further, significant variation is observed in the response of high scoring cell lines to some common cancer drugs. Finally, this signature was applied to pan-cancer data from The Cancer Genome Atlas to identify tumour types with evidence of TGFbeta-induced EMT. Tumour types with high scores showed significantly lower survival rates compared to those with low scores, and also carry a lower mutational burden in the TGFbeta pathway. The current transcriptomic signature demonstrates reproducible results across independent cell line and cancer datasets and identifies samples with strong mesenchymal phenotypes likely to be driven by TGFbeta. Implications: The TGFbeta-induced EMT signature may be useful to identify patients with mesenchymal-like tumours that could benefit from targeted therapeutics to inhibit pro-mesenchymal TGFbeta signalling and disrupt the metastatic cascade

Molecular insight into targeting the NK cell immune response to cancer

Natural Killer (NK) cells have long been considered an important part of the anti-tumor immune response due to their potent cytolytic and cytokine-secreting abilities. To date, a clear demonstration of the role NK cells play in human cancer is lacking, and there are still very few examples of therapies that efficiently exploit or enhance the spontaneous ability of NK cells to destroy the autologous cancer cells. Given the paradigm shift toward cancer immunotherapy over the past decade, there is a renewed push to understand how NK cell homeostasis and function are regulated in order to therapeutically harness these cells to treat cancer. This review will highlight recent advancements in our understanding of how growth factors impact on NK cell development, differentiation, survival and function with an emphasis on how these pathways may influence NK cell activity in the tumor microenvironment and control of cancer metastasis

comBat_corrected_Foroutan_et_al_2017

<div>Methods used to correct the combined data for batch effects and the original datasets are described in the paper by Foroutan <i>et al.</i> (2017) <i>Molecular Cancer Research.</i></div><div><br></div>PMID: 28119430<div>DOI: 10.1158/<a>1541-7786</a>.MCR-16-0313</div

A gene signature predicting natural killer cell infiltration and improved survival in melanoma patients

Natural killer (NK) cell activity is essential for initiating (TCGA), we show that patients with metastatic cutaneous antitumor responses and may be linked to immunotherapy melanoma have an improved survival rate if their tumor success. NK cells and other innate immune components shows evidence of NK cell infiltration. Furthermore, these could be exploitable for cancer treatment, which drives the survival effects are enhanced in tumors that show higher need for tools and methods that identify therapeutic ave-expression of genes that encode NK cell stimuli such as the nues. Here, we extend our gene-set scoring method singscore cytokine IL15. Using this signature, we then examine tran-to investigate NK cell infiltration by applying RNA-seq scriptomic data to identify tumor and stromal components analysis to samples from bulk tumors. Computational that may influence the penetrance of NK cells into solid methods have been developed for the deconvolution of tumors. Our results provide evidence that NK cells play a immune cell types within solid tumors. We have taken the role in the regulation of human tumors and highlight NK cell gene signatures from several such tools, then curated potential survival effects associated with increased NK cell the gene list using a comparative analysis of tumors and activity. Our computational analysis identifies putative gene immune cell types. Using a gene-set scoring method to targets that may be of therapeutic value for boosting NK cell investigate RNA-seq data from The Cancer Genome Atlas antitumor immunity

Snail induces epithelial cell extrusion by regulating RhoA contractile signalling and cell–matrix adhesion

Cell extrusion is a morphogenetic process that is implicated in epithelial homeostasis and elicited by stimuli ranging from apoptosis to oncogenic transformation. To explore whether the morphogenetic transcription factor Snail (SNAI1) induces extrusion, we inducibly expressed a stabilized Snail transgene in confluent MCF-7 monolayers. When expressed in small clusters (less than three cells) within otherwise wild-type confluent monolayers, Snail expression induced apical cell extrusion. In contrast, larger clusters or homogenous cultures of Snail cells did not show enhanced apical extrusion, but eventually displayed sporadic basal delamination. Transcriptomic profiling revealed that Snail did not substantively alter the balance of epithelial and mesenchymal genes. However, we identified a transcriptional network that led to upregulated RhoA signalling and cortical contractility in cells expressing Snail. Enhanced contractility was necessary, but not sufficient, to drive extrusion, suggesting that Snail collaborates with other factors. Indeed, we found that the transcriptional downregulation of cell–matrix adhesion cooperates with contractility to mediate basal delamination. This provides a pathway for Snail to influence epithelial morphogenesis independently of classic epithelial-to-mesenchymal transition

MicroRNA-21 is immunosuppressive and pro-metastatic via separate mechanisms

Abstract MiR-21 was identified as a gene whose expression correlated with the extent of metastasis of murine mammary tumours. Since miR-21 is recognised as being associated with poor prognosis in cancer, we investigated its contribution to mammary tumour growth and metastasis in tumours with capacity for spontaneous metastasis. Unexpectedly, we found that suppression of miR-21 activity in highly metastatic tumours resulted in regression of primary tumour growth in immunocompetent mice but did not impede growth in immunocompromised mice. Analysis of the immune infiltrate of the primary tumours at the time when the tumours started to regress revealed an influx of both CD4+ and CD8+ activated T cells and a reduction in PD-L1+ infiltrating monocytes, providing an explanation for the observed tumour regression. Loss of anti-tumour immune suppression caused by decreased miR-21 activity was confirmed by transcriptomic analysis of primary tumours. This analysis also revealed reduced expression of genes associated with cell cycle progression upon loss of miR-21 activity. A second activity of miR-21 was the promotion of metastasis as shown by the loss of metastatic capacity of miR-21 knockdown tumours established in immunocompromised mice, despite no impact on primary tumour growth. A proteomic analysis of tumour cells with altered miR-21 activity revealed deregulation of proteins known to be associated with tumour progression. The development of therapies targeting miR-21, possibly via targeted delivery to tumour cells, could be an effective therapy to combat primary tumour growth and suppress the development of metastatic disease

NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

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