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The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-beta into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-beta signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy., Funding Agencies|European Research Council (ERC) advanced grant ANGIOFAT [250021]; Swedish Research Council; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grant; NOVO Nordisk Foundation; Knut and Alice Wallenbergs Foundation; Robert Lundberg Memorial Foundation [2021-00668]; National Key R & D Program of China [2020YFC0846600]; Volkswagen Stiftung

The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-beta into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-beta signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy., Funding Agencies|European Research Council (ERC) advanced grant ANGIOFAT [250021]; Swedish Research Council; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grant; NOVO Nordisk Foundation; Knut and Alice Wallenbergs Foundation; Robert Lundberg Memorial Foundation [2021-00668]; National Key R & D Program of China [2020YFC0846600]; Volkswagen Stiftung

Ocular surface neovascularization and its resulting pathological changes significantly alter corneal refraction and obstruct the light path to the retina, and hence is a major cause of vision loss. Various factors such as infection, irritation, trauma, dry eye, and ocular surface surgery trigger neovascularization via angiogenesis and lym-phangiogenesis dependent on VEGF-related and alternative mechanisms. Recent advances in antiangiogenic drugs, nanotechnology, gene therapy, surgical equipment and techniques, animal models, and drug delivery strategies have provided a range of novel therapeutic options for the treatment of ocular surfaceneovascularization. In this review article, we comprehensively discuss the etiology and mechanisms of corneal neovascularization and other types of ocular surface neovascularization, as well as emerging animal models and drug delivery strategies that facilitate its management., Funding Agencies|National Program on Key Research [2021YFA0804703]; National Youth Talent Support Program; Innovation Research Team of High-level Local Universities in Shanghai; Program for Professor of Special Appointment in Shanghai (Eastern Scholar) [TP2018007]; Longyan City Science and Technology Plan Project [2022LYF19075]; European Union [101007931]

Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases., Funding Agencies|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou P. R. China [510060]; National Natural Science Foundation of China [82150710555, 82220108016, 81970823, 81830013]; Key Research and Development Plan of Shandong Province [2016GSF201100]; Fundamental Research Funds for the Central Universities [19ykpy151]; long-term structural Methusalem; Flemish Government, Belgium; Deutsche Forschungsgemeinschaft [394046768 - SFB1366]; DZHK partner site Mannheim/Heidelberg; ERA PerMed 2020 JTC

The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-beta into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-beta signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy., Funding Agencies|European Research Council (ERC) advanced grant ANGIOFAT [250021]; Swedish Research Council; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grant; NOVO Nordisk Foundation; Knut and Alice Wallenbergs Foundation; Robert Lundberg Memorial Foundation [2021-00668]; National Key R & D Program of China [2020YFC0846600]; Volkswagen Stiftung

Ocular surface neovascularization and its resulting pathological changes significantly alter corneal refraction and obstruct the light path to the retina, and hence is a major cause of vision loss. Various factors such as infection, irritation, trauma, dry eye, and ocular surface surgery trigger neovascularization via angiogenesis and lym-phangiogenesis dependent on VEGF-related and alternative mechanisms. Recent advances in antiangiogenic drugs, nanotechnology, gene therapy, surgical equipment and techniques, animal models, and drug delivery strategies have provided a range of novel therapeutic options for the treatment of ocular surfaceneovascularization. In this review article, we comprehensively discuss the etiology and mechanisms of corneal neovascularization and other types of ocular surface neovascularization, as well as emerging animal models and drug delivery strategies that facilitate its management., Funding Agencies|National Program on Key Research [2021YFA0804703]; National Youth Talent Support Program; Innovation Research Team of High-level Local Universities in Shanghai; Program for Professor of Special Appointment in Shanghai (Eastern Scholar) [TP2018007]; Longyan City Science and Technology Plan Project [2022LYF19075]; European Union [101007931]

Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases., Funding Agencies|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou P. R. China [510060]; National Natural Science Foundation of China [82150710555, 82220108016, 81970823, 81830013]; Key Research and Development Plan of Shandong Province [2016GSF201100]; Fundamental Research Funds for the Central Universities [19ykpy151]; long-term structural Methusalem; Flemish Government, Belgium; Deutsche Forschungsgemeinschaft [394046768 - SFB1366]; DZHK partner site Mannheim/Heidelberg; ERA PerMed 2020 JTC

Ocular surface neovascularization and its resulting pathological changes significantly alter corneal refraction and obstruct the light path to the retina, and hence is a major cause of vision loss. Various factors such as infection, irritation, trauma, dry eye, and ocular surface surgery trigger neovascularization via angiogenesis and lym-phangiogenesis dependent on VEGF-related and alternative mechanisms. Recent advances in antiangiogenic drugs, nanotechnology, gene therapy, surgical equipment and techniques, animal models, and drug delivery strategies have provided a range of novel therapeutic options for the treatment of ocular surfaceneovascularization. In this review article, we comprehensively discuss the etiology and mechanisms of corneal neovascularization and other types of ocular surface neovascularization, as well as emerging animal models and drug delivery strategies that facilitate its management., Funding Agencies|National Program on Key Research [2021YFA0804703]; National Youth Talent Support Program; Innovation Research Team of High-level Local Universities in Shanghai; Program for Professor of Special Appointment in Shanghai (Eastern Scholar) [TP2018007]; Longyan City Science and Technology Plan Project [2022LYF19075]; European Union [101007931]

Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating beta-hydroxybutyrate (beta-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-beta-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked beta-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a non-toxic, low-cost dietary intervention for combating CIT., Funding Agencies|National Key Research and Development Program, Ministry of Science and Technology of China [2021YFA0804700]; National Youth Talent Support Program (Ten Thousand Talent Program); Zhengyou Program of Fudan University; Innovation Research Team of High-level Local Universities in Shanghai; Program for Professor of Special Appointment in Shanghai (Eastern Scholar) [TP2018007]; Fujian provincial health technology project [2017-2-86]; Startup Fund For Scientific Research, Fujian Medical University [2017XQ1186]; National Natural Science Foundation of China [81600839, 82204857]; Swedish Research Council [2021-06122]; Swedish Cancer Foundation [200734PjF]

Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy., Funding Agencies|European Research Council (ERC) advanced grant ANGIOFATEuropean Research Council (ERC) [250021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute FoundationKarolinska Institutet; Karolinska Institute distinguished professor awardKarolinska Institutet; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grantNovo Nordisk; NOVO Nordisk FoundationNovo Nordisk Foundation; Knut and Alice Wallenbergs FoundationKnut & Alice Wallenberg Foundation; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81801163, 81703617]; Jinan clinical medical science and technology innovation plan [202019099]; China Scholarship CouncilChina Scholarship Council [201906225024]; Karolinska InstituteKarolinska Institutet

Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy., Funding Agencies|European Research Council (ERC) advanced grant ANGIOFATEuropean Research Council (ERC) [250021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute FoundationKarolinska Institutet; Karolinska Institute distinguished professor awardKarolinska Institutet; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grantNovo Nordisk; NOVO Nordisk FoundationNovo Nordisk Foundation; Knut and Alice Wallenbergs FoundationKnut & Alice Wallenberg Foundation; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81801163, 81703617]; Jinan clinical medical science and technology innovation plan [202019099]; China Scholarship CouncilChina Scholarship Council [201906225024]; Karolinska InstituteKarolinska Institutet

Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy., Funding Agencies|European Research Council (ERC) advanced grant ANGIOFATEuropean Research Council (ERC) [250021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute FoundationKarolinska Institutet; Karolinska Institute distinguished professor awardKarolinska Institutet; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grantNovo Nordisk; NOVO Nordisk FoundationNovo Nordisk Foundation; Knut and Alice Wallenbergs FoundationKnut & Alice Wallenberg Foundation; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81801163, 81703617]; Jinan clinical medical science and technology innovation plan [202019099]; China Scholarship CouncilChina Scholarship Council [201906225024]; Karolinska InstituteKarolinska Institutet

Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy., Funding Agencies|European Research Council (ERC) advanced grant ANGIOFATEuropean Research Council (ERC) [250021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute FoundationKarolinska Institutet; Karolinska Institute distinguished professor awardKarolinska Institutet; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grantNovo Nordisk; NOVO Nordisk FoundationNovo Nordisk Foundation; Knut and Alice Wallenbergs FoundationKnut & Alice Wallenberg Foundation; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81801163, 81703617]; Jinan clinical medical science and technology innovation plan [202019099]; China Scholarship CouncilChina Scholarship Council [201906225024]; Karolinska InstituteKarolinska Institutet

Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy., Funding Agencies|European Research Council (ERC) advanced grant ANGIOFATEuropean Research Council (ERC) [250021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute FoundationKarolinska Institutet; Karolinska Institute distinguished professor awardKarolinska Institutet; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grantNovo Nordisk; NOVO Nordisk FoundationNovo Nordisk Foundation; Knut and Alice Wallenbergs FoundationKnut & Alice Wallenberg Foundation; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81801163, 81703617]; Jinan clinical medical science and technology innovation plan [202019099]; China Scholarship CouncilChina Scholarship Council [201906225024]; Karolinska InstituteKarolinska Institutet

High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKC alpha pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a plateletadoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKC alpha pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. Significance: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75., Funding Agencies|National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81600839, 81773203, 81773059]; General Program of Shandong Natural Science Foundation [ZR2019MH086]; Shanghai Pujiang ProgramShanghai Pujiang Program [18PJ1400600]; Original Research Program of Fudan University; Innovation Research Team of High-level Local Universities in Shanghai; Program for Professor of Special Appointment in Shanghai (Eastern Scholar) [TP2018007]

The choriocapillaris is an exceptionally high density, two-dimensional, sheet-like capillary network, characterized by the highest exchange rate of nutrients for waste products per area in the organism. These unique morphological and physiological features are critical for supporting the extreme metabolic requirements of the outer retina needed for vision. The developmental mechanisms and processes responsible for generating this unique vascular network remain, however, poorly understood. Here we take advantage of the zebrafish as a model organism for gaining novel insights into the cellular dynamics and molecular signaling mechanisms involved in the development of the choriocapillaris. We show for the first time that zebrafish have a choriocapillaris highly similar to that in mammals, and that it is initially formed by a novel process of synchronized vasculogenesis occurring simultaneously across the entire outer retina. This initial vascular network expands by un-inhibited sprouting angiogenesis whereby all endothelial cells adopt tip-cell characteristics, a process which is sustained throughout embryonic and early post-natal development, even after the choriocapillaris becomes perfused. Ubiquitous sprouting was maintained by continuous VEGF-VEGFR2 signaling in endothelial cells delaying maturation until immediately before stages where vision becomes important for survival, leading to the unparalleled high density and lobular structure of this vasculature. Sprouting was throughout development limited to two dimensions by Bruchs membrane and the sclera at the anterior and posterior surfaces respectively. These novel cellular and molecular mechanisms underlying choriocapillaris development were recapitulated in mice. In conclusion, our findings reveal novel mechanisms underlying the development of the choriocapillaris during zebrafish and mouse development. These results may explain the uniquely high density and sheet-like organization of this vasculature., Funding Agencies|Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Eva och Oscar Ahrens Stiftelse; Ollie och Elof Ericssons Stiftelse; Stiftelsen Sigurd och Elsa Goljes Minne; Magnus Bergvalls Stiftelse; Ogonfonden; Jeanssons Stiftelser; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81773059]; Shanghai Pujiang ProgramShanghai Pujiang Program [18PJ1400600]; VetenskapsradetSwedish Research Council

The choriocapillaris is an exceptionally high density, two-dimensional, sheet-like capillary network, characterized by the highest exchange rate of nutrients for waste products per area in the organism. These unique morphological and physiological features are critical for supporting the extreme metabolic requirements of the outer retina needed for vision. The developmental mechanisms and processes responsible for generating this unique vascular network remain, however, poorly understood. Here we take advantage of the zebrafish as a model organism for gaining novel insights into the cellular dynamics and molecular signaling mechanisms involved in the development of the choriocapillaris. We show for the first time that zebrafish have a choriocapillaris highly similar to that in mammals, and that it is initially formed by a novel process of synchronized vasculogenesis occurring simultaneously across the entire outer retina. This initial vascular network expands by un-inhibited sprouting angiogenesis whereby all endothelial cells adopt tip-cell characteristics, a process which is sustained throughout embryonic and early post-natal development, even after the choriocapillaris becomes perfused. Ubiquitous sprouting was maintained by continuous VEGF-VEGFR2 signaling in endothelial cells delaying maturation until immediately before stages where vision becomes important for survival, leading to the unparalleled high density and lobular structure of this vasculature. Sprouting was throughout development limited to two dimensions by Bruchs membrane and the sclera at the anterior and posterior surfaces respectively. These novel cellular and molecular mechanisms underlying choriocapillaris development were recapitulated in mice. In conclusion, our findings reveal novel mechanisms underlying the development of the choriocapillaris during zebrafish and mouse development. These results may explain the uniquely high density and sheet-like organization of this vasculature., Funding Agencies|Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Eva och Oscar Ahrens Stiftelse; Ollie och Elof Ericssons Stiftelse; Stiftelsen Sigurd och Elsa Goljes Minne; Magnus Bergvalls Stiftelse; Ogonfonden; Jeanssons Stiftelser; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81773059]; Shanghai Pujiang ProgramShanghai Pujiang Program [18PJ1400600]; VetenskapsradetSwedish Research Council

The choriocapillaris is an exceptionally high density, two-dimensional, sheet-like capillary network, characterized by the highest exchange rate of nutrients for waste products per area in the organism. These unique morphological and physiological features are critical for supporting the extreme metabolic requirements of the outer retina needed for vision. The developmental mechanisms and processes responsible for generating this unique vascular network remain, however, poorly understood. Here we take advantage of the zebrafish as a model organism for gaining novel insights into the cellular dynamics and molecular signaling mechanisms involved in the development of the choriocapillaris. We show for the first time that zebrafish have a choriocapillaris highly similar to that in mammals, and that it is initially formed by a novel process of synchronized vasculogenesis occurring simultaneously across the entire outer retina. This initial vascular network expands by un-inhibited sprouting angiogenesis whereby all endothelial cells adopt tip-cell characteristics, a process which is sustained throughout embryonic and early post-natal development, even after the choriocapillaris becomes perfused. Ubiquitous sprouting was maintained by continuous VEGF-VEGFR2 signaling in endothelial cells delaying maturation until immediately before stages where vision becomes important for survival, leading to the unparalleled high density and lobular structure of this vasculature. Sprouting was throughout development limited to two dimensions by Bruchs membrane and the sclera at the anterior and posterior surfaces respectively. These novel cellular and molecular mechanisms underlying choriocapillaris development were recapitulated in mice. In conclusion, our findings reveal novel mechanisms underlying the development of the choriocapillaris during zebrafish and mouse development. These results may explain the uniquely high density and sheet-like organization of this vasculature., Funding Agencies|Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Eva och Oscar Ahrens Stiftelse; Ollie och Elof Ericssons Stiftelse; Stiftelsen Sigurd och Elsa Goljes Minne; Magnus Bergvalls Stiftelse; Ogonfonden; Jeanssons Stiftelser; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81773059]; Shanghai Pujiang ProgramShanghai Pujiang Program [18PJ1400600]; VetenskapsradetSwedish Research Council

The choriocapillaris is an exceptionally high density, two-dimensional, sheet-like capillary network, characterized by the highest exchange rate of nutrients for waste products per area in the organism. These unique morphological and physiological features are critical for supporting the extreme metabolic requirements of the outer retina needed for vision. The developmental mechanisms and processes responsible for generating this unique vascular network remain, however, poorly understood. Here we take advantage of the zebrafish as a model organism for gaining novel insights into the cellular dynamics and molecular signaling mechanisms involved in the development of the choriocapillaris. We show for the first time that zebrafish have a choriocapillaris highly similar to that in mammals, and that it is initially formed by a novel process of synchronized vasculogenesis occurring simultaneously across the entire outer retina. This initial vascular network expands by un-inhibited sprouting angiogenesis whereby all endothelial cells adopt tip-cell characteristics, a process which is sustained throughout embryonic and early post-natal development, even after the choriocapillaris becomes perfused. Ubiquitous sprouting was maintained by continuous VEGF-VEGFR2 signaling in endothelial cells delaying maturation until immediately before stages where vision becomes important for survival, leading to the unparalleled high density and lobular structure of this vasculature. Sprouting was throughout development limited to two dimensions by Bruchs membrane and the sclera at the anterior and posterior surfaces respectively. These novel cellular and molecular mechanisms underlying choriocapillaris development were recapitulated in mice. In conclusion, our findings reveal novel mechanisms underlying the development of the choriocapillaris during zebrafish and mouse development. These results may explain the uniquely high density and sheet-like organization of this vasculature., Funding Agencies|Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Eva och Oscar Ahrens Stiftelse; Ollie och Elof Ericssons Stiftelse; Stiftelsen Sigurd och Elsa Goljes Minne; Magnus Bergvalls Stiftelse; Ogonfonden; Jeanssons Stiftelser; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81773059]; Shanghai Pujiang ProgramShanghai Pujiang Program [18PJ1400600]; VetenskapsradetSwedish Research Council

Automatically extracting Protein-Protein Interactions (PPI) from biomedical literature provides additional support for precision medicine efforts. This paper proposes a novel memory network-based model (MNM) for PPI extraction, which leverages prior knowledge about protein-protein pairs with memory networks. The proposed MNM captures important context clues related to knowledge representations learned from knowledge bases. Both entity embeddings and relation embeddings of prior knowledge are effective in improving the PPI extraction model, leading to a new state-of-the-art performance on the BioCreative VI PPI dataset. The paper also shows that multiple computational layers over an external memory are superior to long short-term memory networks with the local memories., Comment: Published on Database-The Journal of Biological Databases and Curation, 11 pages, 5 figures

Chemical-disease relation (CDR) extraction is significantly important to various areas of biomedical research and health care. Nowadays, many large-scale biomedical knowledge bases (KBs) containing triples about entity pairs and their relations have been built. KBs are important resources for biomedical relation extraction. However, previous research pays little attention to prior knowledge. In addition, the dependency tree contains important syntactic and semantic information, which helps to improve relation extraction. So how to effectively use it is also worth studying. In this paper, we propose a novel convolutional attention network (CAN) for CDR extraction. Firstly, we extract the shortest dependency path (SDP) between chemical and disease pairs in a sentence, which includes a sequence of words, dependency directions, and dependency relation tags. Then the convolution operations are performed on the SDP to produce deep semantic dependency features. After that, an attention mechanism is employed to learn the importance/weight of each semantic dependency vector related to knowledge representations learned from KBs. Finally, in order to combine dependency information and prior knowledge, the concatenation of weighted semantic dependency representations and knowledge representations is fed to the softmax layer for classification. Experiments on the BioCreative V CDR dataset show that our method achieves comparable performance with the state-of-the-art systems, and both dependency information and prior knowledge play important roles in CDR extraction task., Comment: Published on Journal of Biomedical Informatics, 13 pages

The choriocapillaris is an exceptionally high density, two-dimensional, sheet-like capillary network, characterized by the highest exchange rate of nutrients for waste products per area in the organism. These unique morphological and physiological features are critical for supporting the extreme metabolic requirements of the outer retina needed for vision. The developmental mechanisms and processes responsible for generating this unique vascular network remain, however, poorly understood. Here we take advantage of the zebrafish as a model organism for gaining novel insights into the cellular dynamics and molecular signaling mechanisms involved in the development of the choriocapillaris. We show for the first time that zebrafish have a choriocapillaris highly similar to that in mammals, and that it is initially formed by a novel process of synchronized vasculogenesis occurring simultaneously across the entire outer retina. This initial vascular network expands by un-inhibited sprouting angiogenesis whereby all endothelial cells adopt tip-cell characteristics, a process which is sustained throughout embryonic and early post-natal development, even after the choriocapillaris becomes perfused. Ubiquitous sprouting was maintained by continuous VEGF-VEGFR2 signaling in endothelial cells delaying maturation until immediately before stages where vision becomes important for survival, leading to the unparalleled high density and lobular structure of this vasculature. Sprouting was throughout development limited to two dimensions by Bruchs membrane and the sclera at the anterior and posterior surfaces respectively. These novel cellular and molecular mechanisms underlying choriocapillaris development were recapitulated in mice. In conclusion, our findings reveal novel mechanisms underlying the development of the choriocapillaris during zebrafish and mouse development. These results may explain the uniquely high density and sheet-like organization of this vasculature., Funding Agencies|Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Eva och Oscar Ahrens Stiftelse; Ollie och Elof Ericssons Stiftelse; Stiftelsen Sigurd och Elsa Goljes Minne; Magnus Bergvalls Stiftelse; Ogonfonden; Jeanssons Stiftelser; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81773059]; Shanghai Pujiang ProgramShanghai Pujiang Program [18PJ1400600]; VetenskapsradetSwedish Research Council

Automatically extracting the relationships between chemicals and diseases is significantly important to various areas of biomedical research and health care. Biomedical experts have built many large-scale knowledge bases (KBs) to advance the development of biomedical research. KBs contain huge amounts of structured information about entities and relationships, therefore plays a pivotal role in chemical-disease relation (CDR) extraction. However, previous researches pay less attention to the prior knowledge existing in KBs. This paper proposes a neural network-based attention model (NAM) for CDR extraction, which makes full use of context information in documents and prior knowledge in KBs. For a pair of entities in a document, an attention mechanism is employed to select important context words with respect to the relation representations learned from KBs. Experiments on the BioCreative V CDR dataset show that combining context and knowledge representations through the attention mechanism, could significantly improve the CDR extraction performance while achieve comparable results with state-of-the-art systems., Comment: Published on IEEE/ACM Transactions on Computational Biology and Bioinformatics, 11 pages, 5 figures

Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor is at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAF) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes. Experimental Design: Multicolor-coded cancer cells and CAFs were coimplanted into the transparent zebrafish body and metastasis at a single-cell level was monitored in living animals. Healthy fibroblasts, tumor factor-educated fibroblasts, and CAFs isolated from various tumors were tested for their ability to facilitate metastasis. Results: We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor was at the microscopic size consisting of a few hundred cells, CAFs were able to hijack cancer cells for dissemination from the primary site. Surprisingly, a majority of metastatic cancer cells remained in tight association with CAFs in the circulation. Furthermore, stimulation of non-metastasis-promoting normal fibroblasts with TGF-B, FGF-2, HGF, and PDGF-BB led to acquisition of their metastatic capacity. Conclusions: Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred cells. CAFs are the key cellular determinant for metastasis. Our findings provide novel mechanistic insights on CAFs in promoting cancer metastasis and targeting CAFs for cancer therapy should be aimed at the early stage during cancer development. (C) 2017 AACR., Funding Agencies|European Research Council (ERC) advanced grant ANGIOFAT [250021]; Swedish Research Council [K2012-67X-21130-04-5, 2015-02410]; Swedish Cancer Foundation [140659]; Karolinska Institute Foundation [C166658073]; Karolinska Institute distinguished professor award [C166646352]; Torsten Soderbergs Foundation [M144/12]; Maud and Birger Gustavsson Foundation [C166655073]; NOVO Nordisk Foundation (BtN/AIR); Knut and Alice Wallenbergs Foundation [C166646483]; Swedish Cancer Society [15 0591]; Cancer Research Institute, New York; Fund for High Level University Construction of Medical Discipline, China [2016031638]

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33–ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain- and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33–ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain-and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs foundation; Tore Nilsons foundation; Martin Rinds foundation; European Research Council (ERC) advanced grant ANGIOFAT [250021]; NOVO Nordisk Foundation

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain-and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs foundation; Tore Nilsons foundation; Martin Rinds foundation; European Research Council (ERC) advanced grant ANGIOFAT [250021]; NOVO Nordisk Foundation

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing similar to 57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing similar to 57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing similar to 57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain-and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs foundation; Tore Nilsons foundation; Martin Rinds foundation; European Research Council (ERC) advanced grant ANGIOFAT [250021]; NOVO Nordisk Foundation

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing similar to 57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing similar to 57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain-and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs foundation; Tore Nilsons foundation; Martin Rinds foundation; European Research Council (ERC) advanced grant ANGIOFAT [250021]; NOVO Nordisk Foundation

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain- and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.

Anti-VEGF-based antiangiogenic drugs are designed to block tumor angiogenesis for treatment of cancer patients. However, anti-VEGF drugs produce off-tumor target effects on multiple tissues and organs and cause broad adverse effects. Here, we show that vasculatures in endocrine organs were more sensitive to anti-VEGF treatment than tumor vasculatures. In thyroid, adrenal glands, and pancreatic islets, systemic treatment with low doses of an anti-VEGF neutralizing antibody caused marked vascular regression, whereas tumor vessels remained unaffected. Additionally, a low dose of VEGF blockade significantly inhibited the formation of thyroid vascular fenestrae, leaving tumor vascular structures unchanged. Along with vascular structural changes, the low dose of VEGF blockade inhibited vascular perfusion and permeability in thyroid, but not in tumors. Prolonged treatment with the low-dose VEGF blockade caused hypertension and significantly decreased circulating levels of thyroid hormone free-T3 and -T4, leading to functional impairment of thyroid. These findings show that the fenestrated microvasculatures in endocrine organs are more sensitive than tumor vasculatures in response to systemic anti-VEGF drugs. Thus, our data support the notion that clinically nonbeneficial treatments with anti-VEGF drugs could potentially cause adverse effects., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Swedish Diabetes Research Foundation; Swedish Childhood Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute Distinguished Professor award; Torsten Soderbergs Foundation; European Research Council Advanced Grant ANGIOFAT [250021]; Knut Alice Wallenberg Foundation; Program of Introducing Talents of Discipline to Universities [B07035]; State Program of National Natural Science Foundation of China for Innovative Research Group [81321061]; NOVO Nordisk Foundation for the advanced grant

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain-and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs foundation; Tore Nilsons foundation; Martin Rinds foundation; European Research Council (ERC) advanced grant ANGIOFAT [250021]; NOVO Nordisk Foundation

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick–host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host ‘questing’, prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain- and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.

The impact of discontinuation of anti-VEGF cancer therapy in promoting cancer metastasis is unknown. Here we show discontinuation of anti-VEGF treatment creates a time-window of profound structural changes of liver sinusoidal vasculatures, exhibiting hyper-permeability and enlarged open-pore sizes of the fenestrated endothelium and loss of VE-cadherin. The drug cessation caused highly leaky hepatic vasculatures permit tumour cell intravasation and extravasation. Discontinuation of an anti-VEGF antibody-based drug and sunitinib markedly promotes liver metastasis. Mechanistically, host hepatocyte, but not tumour cell-derived vascular endothelial growth factor (VEGF), is responsible for cancer metastasis. Deletion of hepatocyte VEGF markedly ablates the 'off-drug'-induced metastasis. These findings provide mechanistic insights on anti-VEGF cessation-induced metastasis and raise a new challenge for uninterrupted and sustained antiangiogenic therapy for treatment of human cancers.

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.

Inhibition of Dll4 (delta-like ligand 4)-Notch signaling-mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti-Dll4-Notch-associated antitumor activity. We show that human and mouse tumor cell-derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch-induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderberg Foundation; European Research Council (ERC) [250021]; NOVO Nordisk Foundation; Royal Alice Wallenberg Foundation; International Research Fund for Subsidy of Kyushu University School of Medicine Alumni

Inhibition of Dll4 (delta-like ligand 4)-Notch signaling-mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti-Dll4-Notch-associated antitumor activity. We show that human and mouse tumor cell-derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch-induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderberg Foundation; European Research Council (ERC) [250021]; NOVO Nordisk Foundation; Royal Alice Wallenberg Foundation; International Research Fund for Subsidy of Kyushu University School of Medicine Alumni

The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A-null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk(-/-) mice and mice treated with anti-VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Torsten Soderberg Foundation; European Research Council Advanced Grant ANGIOFAT [250021]; Novo Nordisk Foundation advanced grant; Karolinska Institute distinguished professor award

Inhibition of Dll4 (delta-like ligand 4)-Notch signaling-mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti-Dll4-Notch-associated antitumor activity. We show that human and mouse tumor cell-derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch-induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderberg Foundation; European Research Council (ERC) [250021]; NOVO Nordisk Foundation; Royal Alice Wallenberg Foundation; International Research Fund for Subsidy of Kyushu University School of Medicine Alumni

The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A-null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk(-/-) mice and mice treated with anti-VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Torsten Soderberg Foundation; European Research Council Advanced Grant ANGIOFAT [250021]; Novo Nordisk Foundation advanced grant; Karolinska Institute distinguished professor award

Inhibition of Dll4 (delta-like ligand 4)-Notch signaling-mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti-Dll4-Notch-associated antitumor activity. We show that human and mouse tumor cell-derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch-induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderberg Foundation; European Research Council (ERC) [250021]; NOVO Nordisk Foundation; Royal Alice Wallenberg Foundation; International Research Fund for Subsidy of Kyushu University School of Medicine Alumni

Although inflammation and metastasis are two well-known hallmarks of malignant disease, the relationship between inflammation and lymphatic metastasis is an unexplored research area. We recently elucidated a sophisticated mechanism by which TNF alpha-induced tumor inflammation conscripts macrophage-mediated VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis.

Inhibition of Dll4 (delta-like ligand 4)-Notch signaling-mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti-Dll4-Notch-associated antitumor activity. We show that human and mouse tumor cell-derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch-induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors., Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderberg Foundation; European Research Council (ERC) [250021]; NOVO Nordisk Foundation; Royal Alice Wallenberg Foundation; International Research Fund for Subsidy of Kyushu University School of Medicine Alumni