10 research outputs found
Primary tumorâderived systemic nANGPTL4 inhibits metastasis
Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent
LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency
Background:
A poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tumors is vasculopathic and whether its inhibition has therapeutic utility.
Methods:
Tumor growth and vascular structure were analyzed in subcutaneous and genetically engineered mouse models in wild-type and Lrg1 knockout mice. The effects of LRG1 antibody blockade as monotherapy, or in combination with co-therapies, on vascular function, tumor growth, and infiltrated lymphocytes were investigated.
Findings:
In mouse models of cancer, Lrg1 expression was induced in tumor endothelial cells, consistent with an increase in protein expression in human cancers. The expression of LRG1 affected tumor progression as Lrg1 gene deletion, or treatment with a LRG1 function-blocking antibody, inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function, resulting in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy, and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent to immune active.
Conclusions:
LRG1 drives vascular abnormalization, and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics.
Funding:
Wellcome Trust (206413/B/17/Z), UKRI/MRC (G1000466, MR/N006410/1, MC/PC/14118, and MR/L008742/1), BHF (PG/16/50/32182), Health and Care Research Wales (CA05), CRUK (C42412/A24416 and A17196), ERC (ColonCan 311301 and AngioMature 787181), and DFG (CRC1366)
Angio-regulation of liver neovascularization and lung metastatic progression
BlutgefĂ€Ăe durchziehen den gesamten Körper und versorgen jede Zelle mit Sauerstoff und
NĂ€hrstoffen. Endothelzellen (EC) stellen die innerste Zellschicht von BlutgefĂ€Ăen dar, welche lange Zeit
ausschlieĂlich als inerte und passive GrenzflĂ€che betrachtet wurde. In der letzten Dekade haben
jedoch zahlreiche Forschungsergebnisse eine aktive Rolle von EC bei der Aufrechterhaltung einer
physiologischen Gewebshomöostase aufgezeigt. ZusÀtzlich spielen angiokrine Mediatoren aus EC, die
multidirektional Signale innerhalb der lokalen Gewebsmikroumgebung vermitteln, eine
ĂŒbergeordnete Rolle in der Wundheilung und zahlreicher pathologischer Prozesse, unter anderem bei
Krebserkrankungen. Die vorliegende Studie zielte darauf ab (i) zellulÀre Quellen zu ermitteln, die an
der Reparatur und Erneuerung von BlutgefĂ€Ăen in adulten MĂ€usen beteiligt sind, sowie (ii) die
dynamische Evolution des Genexpressionsmusters von EC wÀhrend der Progression von
Tumormetastasen zu untersuchen.
Um die unterschiedlichen zellulĂ€ren Quellen aufzuschlĂŒsseln, die an der vaskulĂ€ren Reparatur beteiligt
sind, wurde als Untersuchungsmodell eine partielle (zwei Drittel-) Hepatektomie (PHx) in adulten
MĂ€usen durchgefĂŒhrt. Die adulte Leber hat die einzigartige FĂ€higkeit ihre verlorene Gewebemasse
innerhalb von 10 Tagen nach PHx komplett zu regenerieren. Genetische
Abstammungsuntersuchungen (âlineage tracingâ) zeigten, dass unbeschĂ€digte, nach PHx verbliebene
LebergefĂ€Ăzellen effizient proliferieren um ein vollstĂ€ndig funktionelles vaskulĂ€res Netzwerk
wiederherzustellen. Im Gegensatz hierzu, fĂŒhrt eine Strahlenbelastung zu einer derartigen
BeschĂ€digung lokaler Leber-EC, dass Knochenmarkszellen fĂŒr die vaskulĂ€re Reparatur benötigt
werden. Daher können sowohl lokale EC sowie VorlÀuferzellen aus dem Knochenmark als potentielle
Quellen der LebergefĂ€Ăregeneration dienen, deren relative Beteiligung von der zellulĂ€ren Fitness der
verbliebenen Lebervaskulatur abhÀngt.
Um zu verstehen welche Rolle angiokrine Mediatoren bei der Etablierung einer metastatischen Nische
spielen, wurde in einem fortschrittlichen Maustumormodell vergleichend sowohl das Transkriptom
von Lungen-EC als auch das Serum-Proteom an verschiedenen Zeitpunkten der
Metastasenprogression bestimmt. Leucine Rich alpha-2-Glycoprotein 1 (LRG1) wurde hierbei als ein
EC-spezifisches Signal identifiziert, dessen Genexpressionsmuster die Abfolge einer Tumor-induzierten
systemischen EntzĂŒndungsreaktion widerspiegelt. Weitere Einzelzell-Analysen von Lungen-EC sowie
Multi-Organ-GefĂ€Ăanalysen offenbarten, dass LRG1 bei einer Tumorerkrankung in multiplen
GefĂ€Ăbetten hochreguliert wird. Funktionell erleichtert ein systemisch erhöhter LRG1-Spiegel die
metastatische Kolonisierung. Daher unterdrĂŒckt eine postoperative adjuvante Therapie mit einem
LRG1-neutralisierenden Antikörper Metastasierung und verlĂ€ngert das GesamtĂŒberleben, im
Vergleich zu Kontroll-IgG-behandelten MÀusen. Insgesamt reprÀsentieren die erstellten DatensÀtze
eine beispiellose Ressource um per intelligenter Datenanalyse angiokrine Mediatoren zu identifizieren,
die als mögliche Zielstrukturen dienen könnten, um eine metastatische Progression zu limitieren
Preclinical validation of a novel metastasisâinhibiting Tie1 functionâblocking antibody
Abstract The angiopoietin (Ang)âTie pathway has been intensely pursued as candidate secondâgeneration antiâangiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2âtargeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 remains therapeutically unexplored, although its endothelialâspecific genetic deletion has previously been shown to result in a strong reduction in metastatic growth. Here, we report a novel Tie1 functionâblocking antibody (ABâTie1â39), which suppressed postnatal retinal angiogenesis. During primary tumor growth, neoadjuvant administration of ABâTie1â39 strongly impeded systemic metastasis. Furthermore, the administration of ABâTie1â39 in a perioperative therapeutic window led to a significant survival advantage as compared to controlâIgGâtreated mice. Additional in vivo experimental metastasis and in vitro transmigration assays concurrently revealed that ABâTie1â39 treatment suppressed tumor cell extravasation at secondary sites. Taken together, the data phenocopy previous genetic work in endothelial Tie1 KO mice and thereby validate ABâTie1â39 as a Tie1 functionâblocking antibody. The study establishes Tie1 as a therapeutic target for metastasis in a perioperative or neoadjuvant setting
Sphingosine-1-Phosphate Recruits Macrophages and Microglia and Induces a Pro-Tumorigenic Phenotype That Favors Glioma Progression
Glioblastoma is the most aggressive brain tumor in adults. Treatment failure is predominantly caused by its high invasiveness and its ability to induce a supportive microenvironment. As part of this, a major role for tumor-associated macrophages/microglia (TAMs) in glioblastoma development was recognized. Phospholipids are important players in various fundamental biological processes, including tumorâstroma crosstalk, and the bioactive lipid sphingosine-1-phosphate (S1P) has been linked to glioblastoma cell proliferation, invasion, and survival. Despite the urgent need for better therapeutic approaches, novel strategies targeting sphingolipids in glioblastoma are still poorly explored. Here, we showed that higher amounts of S1P secreted by glioma cells are responsible for an active recruitment of TAMs, mediated by S1P receptor (S1PR) signaling through the modulation of Rac1/RhoA. This resulted in increased infiltration of TAMs in the tumor, which, in turn, triggered their pro-tumorigenic phenotype through the inhibition of NFkB-mediated inflammation. Gene set enrichment analyses showed that such an anti-inflammatory microenvironment correlated with shorter survival of glioblastoma patients. Inhibition of S1P restored a pro-inflammatory phenotype in TAMs and resulted in increased survival of tumor-bearing mice. Taken together, our results establish a crucial role for S1P in fine-tuning the crosstalk between glioma and infiltrating TAMs, thus pointing to the S1PâS1PR axis as an attractive target for glioma treatment
STAT3-YAP/TAZ signaling in endothelial cells promotes tumor angiogenesis
The nuclear translocation and activity of the cotranscriptional activators YAP and TAZ (YAP/TAZ) in endothelial cells (ECs) are crucial during developmental angiogenesis. Here, we studied the role of YAP/TAZ signaling in ECs in tumor angiogenesis and found that the expression of YAP/TAZ and downstream target genes in ECs correlated with tumor vascularization in human colorectal carcinomas and skin melanoma. Treatment with the YAP/TAZ inhibitor verteporfin reduced vessel density and tumor progression in a mouse colorectal cancer (CRC) model. Conditional deletion of YAP/TAZ in ECs reduced tumor angiogenesis and growth in a mouse B16-F10 melanoma model. Using cultured ECs and mice with EC-specific ablation, we showed that signal transducer and activator of transcription 3 (STAT3) was required for the activation of YAP/TAZ in tumor-associated ECs. Moreover, we showed that STAT3-mediated signaling promoted YAP/TAZ activity and that the nuclear shuttling machinery for STAT3 was also required for YAP/TAZ nuclear translocation. Together, our data highlight the role of YAP/TAZ as critical players in ECs during tumor angiogenesis and provide insight into the signaling pathways leading to their activation
Caspase-8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice
The gut has a specific vascular barrier that controls trafficking of antigens and microbiota into the bloodstream. However, the molecular mechanisms regulating the maintenance of this vascular barrier remain elusive. Here, we identified Caspase-8 as a pro-survival factor in mature intestinal endothelial cells that is required to actively maintain vascular homeostasis in the small intestine in an organ-specific manner. In particular, we find that deletion of Caspase-8 in endothelial cells results in small intestinal hemorrhages and bowel inflammation, while all other organs remained unaffected. We also show that Caspase-8 seems to be particularly needed in lymphatic endothelial cells to maintain gut homeostasis. Our work demonstrates that endothelial cell dysfunction, leading to the breakdown of the gut-vascular barrier, is an active driver of chronic small intestinal inflammation, highlighting the role of the intestinal vasculature as a safeguard of organ function