Abstract:
:Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.
journal_name
Nat Medjournal_title
Nature medicineauthors
Cañadas I,Thummalapalli R,Kim JW,Kitajima S,Jenkins RW,Christensen CL,Campisi M,Kuang Y,Zhang Y,Gjini E,Zhang G,Tian T,Sen DR,Miao D,Imamura Y,Thai T,Piel B,Terai H,Aref AR,Hagan T,Koyama S,Watanabe M,Baba H,doi
10.1038/s41591-018-0116-5subject
Has Abstractpub_date
2018-08-01 00:00:00pages
1143-1150issue
8eissn
1078-8956issn
1546-170Xpii
10.1038/s41591-018-0116-5journal_volume
24pub_type
杂志文章相关文献
NATURE MEDICINE文献大全abstract::Autoimmune T-helper cells drive pathogenic autoantibody production in systemic lupus erythematosus (SLE), but the mechanisms maintaining those T cells are unknown. Autoreactive T cells are normally eliminated by functional inactivation (anergy) and activation-induced cell death (AICD) or apoptosis through death recept...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1005
更新日期:2004-04-01 00:00:00
abstract::Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear pre-osteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1514
更新日期:2006-12-01 00:00:00
abstract::Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery1. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive2,3. Moreover, interpretation of intraoperative histologic images is de...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-019-0715-9
更新日期:2020-01-01 00:00:00
abstract::Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells. V alpha 14-J alpha 15 natural killer T (NKT) cells recognize lipid antigens presented by the major histocompatibility complex class I-like protein CD1d...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0901-1052
更新日期:2001-09-01 00:00:00
abstract::Conceptual and practical advances in molecular medicine are changing our understanding of cancer pathogenesis. In time this should provide the opportunity to alter the natural history of many cancers. ...
journal_title:Nature medicine
pub_type: 杂志文章,评审
doi:10.1038/nm0495-309
更新日期:1995-04-01 00:00:00
abstract::Defects in major histocompatibility complex (MHC) class I-restricted antigen presentation are frequently observed in human cancers and result in escape of tumors from cytotoxic T lymphocyte (CTL) immune surveillance in mice. Here, we show the existence of a unique category of CTLs that can prevent this escape. The CTL...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1381
更新日期:2006-04-01 00:00:00
abstract::Adequate lipid secretion by mammary glands during lactation is essential for the survival of mammalian offspring. However, the mechanism governing this process is poorly understood. Here we show that Cidea is expressed at high levels in lactating mammary glands and its deficiency leads to premature pup death as a resu...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2614
更新日期:2012-01-15 00:00:00
abstract::The mechanism by which angiogenic factors recruit bone marrow (BM)-derived quiescent endothelial and hematopoietic stem cells (HSCs) is not known. Here, we report that functional vascular endothelial growth factor receptor-1 (VEGFR1) is expressed on human CD34(+) and mouse Lin(-)Sca-1(+)c-Kit(+) BM-repopulating stem c...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm740
更新日期:2002-08-01 00:00:00
abstract::Two big challenges of transplantation biology are controlling the reaction of the graft to the host after hematopoietic stem cell transplantation and preventing rejection of donor organs by the host. Raewyn Broady and Megan K. Levings discuss the first challenge, examining studies suggesting that statins might be help...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1108-1155
更新日期:2008-11-01 00:00:00
abstract::Recent years have seen an explosion in the rate of discovery of genetic defects linked to Parkinson's disease. These breakthroughs have not provided a direct explanation for the disease process. Nevertheless, they have helped transform Parkinson's disease research by providing tangible clues to the neurobiology of the...
journal_title:Nature medicine
pub_type: 杂志文章,评审
doi:10.1038/nm1068
更新日期:2004-07-01 00:00:00
abstract::Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with ins...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm727
更新日期:2002-07-01 00:00:00
abstract::A new investigation into Duchenne muscular dystrophy (DMD) pathogenesis suggests that at least part of the muscle degeneration observed in DMD patients may result from the reduced production of muscle membrane-associated neuronal nitric oxide synthase. This reduction may lead to impaired regulation of the vasoconstric...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/83309
更新日期:2001-01-01 00:00:00
abstract::Synthetic vascular prostheses are foreign bodies, so that blood coagulation can occur on their luminal surfaces, causing graft occlusion very frequently in prostheses of small diameter. A vascular prosthesis needs angiogenesis for endothelialization of the luminal surface, as endothelial cells have natural and permane...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0196-90
更新日期:1996-01-01 00:00:00
abstract::Advances in imaging are transforming our understanding of angiogenesis and the evaluation of drugs that stimulate or inhibit angiogenesis in preclinical models and human disease. Vascular imaging makes it possible to quantify the number and spacing of blood vessels, measure blood flow and vascular permeability, and an...
journal_title:Nature medicine
pub_type: 杂志文章,评审
doi:10.1038/nm0603-713
更新日期:2003-06-01 00:00:00
abstract::Azoospermia or oligozoospermia due to disruption of spermatogenesis are common causes of human male infertility. We used the technique of spermatogonial transplantation in two infertile mouse strains, Steel (Sl) and dominant white spotting (W), to determine if stem cells from an infertile male were capable of generati...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/71496
更新日期:2000-01-01 00:00:00
abstract::The 55-kilodalton (kDa) protein from the E1B-region of adenovirus binds to and inactivates the p53 gene, which is mutated in half of human cancers. We have previously shown that the replication and cytopathogenicity of an E1B, 55-kDa gene-attenuated adenovirus, ONYX-015, is blocked by functional p53 in RKO and U20S ca...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0697-639
更新日期:1997-06-01 00:00:00
abstract::CD23 is a low-affinity receptor for immunoglobulin E (IgE) expressed by a variety of haematopoietic cells. Proteolytic cleavage of the transmembrane receptor generates soluble forms, which can be detected in biological fluids. CD23 regulates many functional aspects of immune cells, both in its cell-associated and solu...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0895-781
更新日期:1995-08-01 00:00:00
abstract::Smallpox was eradicated without an adequate understanding of how vaccination induced protection. In response to possible bioterrorism with smallpox, the UK government vaccinated approximately 300 health care workers with vaccinia virus (VACV) strain Lister. Antibody responses were analyzed using ELISA for multiple sur...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1457
更新日期:2006-11-01 00:00:00
abstract::Retinal ischemia can cause vision-threatening pathological neovascularization. The mechanisms of retinal ischemia are not fully understood, however. Here we have shown that leukocytes prune the retinal vasculature during normal development and obliterate it in disease. Beginning at postnatal day 5 (P5) in the normal r...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm877
更新日期:2003-06-01 00:00:00
abstract::Sympathetic innervation is critical for effective cardiac function. However, the developmental and regulatory mechanisms determining the density and patterning of cardiac sympathetic innervation remain unclear, as does the role of this innervation in arrhythmogenesis. Here we show that a neural chemorepellent, Sema3a,...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1570
更新日期:2007-05-01 00:00:00
abstract::The androgen receptor (AR) is involved in the development, growth and progression of prostate cancer (CaP). CaP often progresses from an androgen-dependent to an androgen-independent tumor, making androgen ablation therapy ineffective. However, the mechanisms for the development of androgen-independent CaP are unclear...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/76287
更新日期:2000-06-01 00:00:00
abstract::Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to above-knee amputees, thereby reducing confidence and walking speed in the users that is associated with high mental and physical fatigue1-4. The lack of physiological feedback from the remaining extremity to th...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-019-0567-3
更新日期:2019-09-01 00:00:00
abstract::Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS)1,2, but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation3,4. To understand the basis of the ADA ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-019-0568-2
更新日期:2019-09-01 00:00:00
abstract::The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4(+) T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8(+) T cells are controve...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.1881
更新日期:2008-11-01 00:00:00
abstract::We determine here the functional integrity of auxiliary livers in containers fashioned from the small intestine. Liver microfragments from dipeptidyl peptidase 4 (DPP4)-deficient rats were transplanted into syngeneic normal animals with isolated intestinal segments characterized by mucosal denudation but intact vascul...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1057
更新日期:2004-07-01 00:00:00
abstract::To understand the integrin requirements of T-helper (T(H)) effector subsets, we investigated the contribution of CD18 (beta(2) integrin) to T(H)1 and T(H)2 function in vitro and in relevant disease models. CD18-deficient (Itgb2(-/-)) T cells showed largely normal in vitro function. Compared with wild-type mice, Itgb2(...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm932
更新日期:2003-10-01 00:00:00
abstract::Chlamydia trachomatis is the leading cause worldwide of preventable infectious blindness (trachoma) and sexually transmitted disease, including nongonoccocal urethritis and pelvic inflammatory disease. To date, no effective vaccine against C. trachomatis infection has been identified. A monoclonal anti-idiotypic antib...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1096-1116
更新日期:1996-10-01 00:00:00
abstract::Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopoly...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1663
更新日期:2007-11-01 00:00:00
abstract::Movement towards or away from a given stimulus guides the directional migration of prokaryotes, simple eukaryotes and neurons. As bi-directional cues may influence entry and exit of immune effector cells from tissue sites, we evaluated the migratory responses of T-cell subsets to varying concentrations of the chemokin...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/75022
更新日期:2000-05-01 00:00:00
abstract::Kidney transplantation has been one of the major medical advances of the past 30 years. However, tissue availability remains a major obstacle. This can potentially be overcome by the use of undifferentiated or partially developed kidney precursor cells derived from early embryos and fetal tissue. Here, transplantation...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm812
更新日期:2003-01-01 00:00:00