Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Rautela, Jai; Baschuk, Nikola; Slaney, Clare Y.; Jayatilleke, Krishnath M.; Xiao, Kun; Bidwell, Bradley N.; Lucas, Erin C.; Hawkins, Edwin D.; Lock, Peter; Wong, Christina S.F.; Chen, Weisan; Anderson, Robin L.; Hertzog, Paul J.; Andrews, Daniel M.; Möller, Andreas; Parker, Belinda S.

doi:10.1158/2326-6066.cir-15-0065

Cited by 69 publications

(64 citation statements)

References 41 publications

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“…S1 C-G), indicating that phosphorylation of eIF4E was dispensable for normal hematopoiesis. In the context of 66cl4 mammary tumors, previous studies have found neutrophils, natural killer (NK) cells, and the ratio of CD8 + T cells to T regulatory (CD8 + /T reg ) cells to be important for metastasis (20)(21)(22). However, analysis of dissociated primary mammary tumors indicated that the CD8 + /T reg ratio was the same in WT and eIF4E S209A mice (Fig.…”

Section: Resultsmentioning

confidence: 96%

Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils

Robichaud

Hsu

Istomine

et al. 2018

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

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The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in the translational control of cancer is the eukaryotic translation initiation factor 4E (eIF4E). We and others have shown that eIF4E availability and phosphorylation promote metastasis in mouse models of breast cancer by selectively augmenting the translation of mRNAs involved in invasion and metastasis. However, the impact of translational control in cell types within the tumor microenvironment (TME) is unknown. Here, we demonstrate that regulatory events affecting translation in cells of the TME impact cancer progression. Mice bearing a mutation in the phosphorylation site of eIF4E (S209A) in cells comprising the TME are resistant to the formation of lung metastases in a syngeneic mammary tumor model. This is associated with reduced survival of prometastatic neutrophils due to decreased expression of the antiapoptotic proteins BCL2 and MCL1. Furthermore, we demonstrate that pharmacological inhibition of eIF4E phosphorylation prevents metastatic progression in vivo, supporting the development of phosphorylation inhibitors for clinical use.

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Section: Resultsmentioning

confidence: 96%

Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils

Robichaud

Hsu

Istomine

et al. 2018

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

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“…Tumor cell decreases in JAK2 target genes (Socs3, Egfr) were reported, which indicated that target inhibition was achieved, along with decreases in activated STAT3, which was high at trial commencement in all patients. However, significant decreases in GZMB + CD8 + T cells were observed in metastatic lesions compared to primary tumors, suggesting that JAK2 inhibition, which is critical in IFN responses and immune induction, particularly in a metastatic setting [206,207], might abrogate immune-mediated antitumor effects, as others have proposed. The trial was subsequently terminated due to progressive disease in all surviving enrolled patients.…”

Section: Jak Inhibitionmentioning

confidence: 88%

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

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458

326

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Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.2 of 26 role in pathogenesis [3]. Yet, despite the seemingly linear order of events, the impact of mutations, selective dimerization, negative pathway regulation, and post-translational modifications of pathway members has branded the JAK-STAT axis a complex signaling cascade, of which many regulatory processes are still poorly understood.STATs have emerged as somewhat of a double-edged sword, being widely explored in the context of cancer. While several members of the STAT family, which encompasses STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 as a whole, have been linked to tumor initiation and progression (STAT3 and STAT5), others are integral in antitumor defense and the maintenance of an effective and long-term immune response (STAT1 and STAT2) through evolutionarily conserved programs [1]. With increasing emphasis on immune-based agents as important therapeutics in the fight against solid tumor growth and spread, understanding the function of STAT specificity, redundancy, and connectedness in cancer is a critical component of achieving immunotherapeutic augmentation and success.Here, we investigate the good and the bad of STAT signaling in the context of immune regulation and cancer, and discuss how STATs can be targeted to bolster antitumor immune defense. JAK-STAT Signaling and InterferonsThe presence of stimulatory or inhibitory signals governs the innate and adaptive immune activity that controls both effective immune surveillance and facilitates escape. Such signals determine the fate of plastic immune cells, such as T lymphocytes, and regulate their recruitment, survival, status, and eventual death ...

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“…In mice lacking IFNAR1, loss of type-1 interferon signaling is sufficient to promote metastasis of breast cancer to lung, independently of the growth of primary tumors (159). Reduced expression of CD69 and IFNγ, two primary biomarkers of Natural Killer (NK) cells, also showed that the homeostasis of the NK population in the immune system which is dependent on signaling through IFNAR1 receptors was impaired in the process (159). The cytokine IL-2 is used as an immunotherapeutic agent to induce anti-metastatic and cytotoxic effects in cancer cells and has been approved for the treatment of metastatic renal cell carcinoma and melanoma.…”

Section: Novel Interactions Of Ifnar1 and Gart May Point At The Influmentioning

confidence: 99%

Mesothelioma Interactome with 367 Novel Protein-Protein Interactions

Yanamala

Boyce

et al. 2018

Preprint

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Malignant pleural mesothelioma (MPM) is an aggressive cancer of the thorax with a median survival of one year. We constructed an 'MPM interactome' with over 300 computationally predicted PPIs and over 1300 known PPIs of 62 literature-curated genes whose activity affects MPM. Known PPIs of the 62 MPM associated genes were derived from BioGRID and HPRD databases. Novel PPIs were predicted by applying the HiPPIP algorithm, which computes features of protein pairs such as cellular localization, molecular function, biological process membership, genomic location of the gene, gene expression in microarray experiments, protein domains and tissue membership, and classifies the pairwise features as interacting or non-interacting based on a random forest model. To our satisfaction, the interactome is significantly enriched with genes differentially expressed in MPM tumors compared with normal pleura, and with other thoracic tumors. The interactome is also significantly enriched with genes whose high expression has been correlated with unfavorable prognosis in lung cancer, and with genes differentially expressed on crocidolite exposure. 28 of the interactors of MPM proteins are targets of 147 FDA-approved drugs. By comparing differential expression profiles induced by drug to profiles induced by MPM, potentially repurposable drugs are identified from this drug list. Development of PPIs of disease-specific set of genes is a powerful approach with high translational impactthe interactome is a vehicle to piece together an integrated view on how genes associated with MPM through various high throughput studies are functionally linked, leading to clinically translatable results such as clinical trials with repurposed drugs. The PPIs are made available on a webserver, called Wiki-Pi MPM at http://severus.dbmi.pitt.edu/wiki-MPM with advanced search capabilities.Recently, twenty four germline mutations were identified in 13 genes from 198 patients with malignant mesothelioma of pleural or peritoneal origin (11). Non-invasive pre-malignant phase is not seen in mesothelioma unlike other tumors, which necessitates expeditious discovery of genetic predispositions, molecular mechanisms and therapeutics for the disease (12).60% of the disease-associated missense mutations perturb protein-protein interactions (PPIs) in human genetic disorders (13). PPIs are intricately involved in biological functions and disease mechanisms, and may be exploited for drug-discovery (13). The molecular mechanisms of disease are often revealed by the PPIs of diseaseassociated genes. For example, the involvement of transcriptional deregulation in the pathogenesis of MPM was identified through mutations detected in BAP1 and its interactions with several proteins including BRCA1 revealed by co-immunoprecipitation (14). The PPI of BRCA1 with BAP1 was also central in understanding its role in growth-control pathways and cancer (15). Studies on BAP1 and BRCA1 later provided the basis for several clinical trials including testing of the drug Vinorelbine as a second...

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Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Cited by 69 publications

References 41 publications

Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils

Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Mesothelioma Interactome with 367 Novel Protein-Protein Interactions

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