Showing papers by "C. Shad Thaxton published in 2017"
TL;DR: It is demonstrated that pre-metastatic tumors produce exosomes, which elicit a broad range of PMo-reliant innate immune responses via trigger(s) of immune surveillance, causing cancer cell clearance at the pre- metastatic niche.
Abstract: Metastatic cancers produce exosomes that condition pre-metastatic niches in remote microenvironments to favor metastasis. In contrast, here we show that exosomes from poorly metastatic melanoma cells can potently inhibit metastasis to the lung. These "non-metastatic" exosomes stimulate an innate immune response through the expansion of Ly6Clow patrolling monocytes (PMo) in the bone marrow, which then cause cancer cell clearance at the pre-metastatic niche, via the recruitment of NK cells and TRAIL-dependent killing of melanoma cells by macrophages. These events require the induction of the Nr4a1 transcription factor and are dependent on pigment epithelium-derived factor (PEDF) on the outer surface of exosomes. Importantly, exosomes isolated from patients with non-metastatic primary melanomas have a similar ability to suppress lung metastasis. This study thus demonstrates that pre-metastatic tumors produce exosomes, which elicit a broad range of PMo-reliant innate immune responses via trigger(s) of immune surveillance, causing cancer cell clearance at the pre-metastatic niche.
221 citations
TL;DR: In this article, the authors measured HDL particle size, HDL particle number, and LDL particle number with NMR spectroscopy, as well as HDL efflux capacity, and quantified associations between the presence of LRNC and HDL and LDL particles number, HDL and efflux capacities using adjusted logistic regression models.
59 citations
TL;DR: It is shown, for the first time, that scavenger receptor type B-1 (SCARB1), a high-affinity receptor for spherical high-density lipoprotein (HDL), is expressed by MDSCs, and it is demonstrated that SCARB1 is specifically targeted by synthetic high- density lipop Protein-like nanoparticles ( HDL NP), which reduce MDSC activity.
Abstract: Myeloid derived suppressor cells (MDSCs) are innate immune cells that potently inhibit T cells. In cancer, novel therapies aimed to activate T cells can be rendered ineffective due to the activity of MDSCs. Thus, targeted inhibition of MDSCs may greatly enhance T cell-mediated anti-tumor immunity, but targeted mechanisms remain obscure. Here we show, for the first time, that scavenger receptor type B-1 (SCARB1), a high-affinity receptor for spherical high-density lipoprotein (HDL), is expressed by MDSCs. Furthermore, we demonstrate that SCARB1 is specifically targeted by synthetic high-density lipoprotein-like nanoparticles (HDL NP), which reduces MDSC activity. Using in vitro T cell proliferation assays, data show that HDL NPs specifically bind SCARB1 to inhibit MDSC activity. In murine cancer models, HDL NP treatment significantly reduces tumor growth, metastatic tumor burden, and increases survival due to enhanced adaptive immunity. Flow cytometry and immunohistochemistry demonstrate that HDL NP-mediated suppression of MDSCs increased CD8+ T cells and reduced Treg cells in the metastatic tumor microenvironment. Using transgenic mice lacking SCARB1, in vivo data clearly show that the HDL NPs specifically target this receptor for suppressing MDSCs. Ultimately, our data provide a new mechanism and targeted therapy, HDL NPs, to modulate a critical innate immune cell checkpoint to enhance the immune response to cancer.
48 citations
TL;DR: The development of potential theranostic agents for cardiovascular disease that are based on high-density lipoprotein-like magnetic nanostructures (HDL-MNS) offer prospects for diagnosis via noninvasive magnetic resonance imaging for anatomic detection and also serve as effective cholesterol efflux agents to address atherosclerotic vascular lesions.
Abstract: We report the development of potential theranostic agents for cardiovascular disease that are based on high-density lipoprotein-like magnetic nanostructures (HDL-MNS). The HDL-MNS offer prospects for diagnosis via noninvasive magnetic resonance imaging for anatomic detection and also serve as effective cholesterol efflux agents to address atherosclerotic vascular lesions. The HDL-MNS are synthesized by adding phospholipids and the HDL-defining apolipoprotein A1 to the surface of magnetic nanostructures (MNS) to mimic some aspects of natural HDL particles. From a diagnostic perspective, HDL-MNS show a 5 times higher contrast (r2 relaxivity up to 383 mM–1 s–1) in magnetic resonance imaging (MRI) than commercially available T2 MRI contrast agents (e.g., Ferumoxytol). Internalization of HDL-MNS by macrophage cells was confirmed by transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDX), inductive-coupled plasma mass spectrometry (ICP-MS), and successfully imaged via MRI. Also, the H...
34 citations
TL;DR: Reduction of cellular cholesterol is a powerful mechanism to induce apoptosis in otherwise resistant ABC DLBCL cell lines, providing a new paradigm for rationally targeting cholesterol metabolism as therapy for cancer.
Abstract: Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). As we previously reported, GC DLBCL are exquisitely sensitive to HDL NP as monotherapy, while ABC DLBCL are less sensitive. Herein, we report that enhanced BCR signaling and resultant de novo cholesterol synthesis in ABC DLBCL ...
34 citations
TL;DR: It is demonstrated that DISE induction occurs in cancer cells in vivo after introducing a lentiviral CD95L derived shRNA (shL3) into HeyA8 ovarian cancer cells grown as i.p. xenografts in mice, when compared to a scrambled shRNA.
Abstract: // Andrea E. Murmann 1 , Kaylin M. McMahon 3,6 , Ashley Haluck-Kangas 1 , Nandini Ravindran 1 , Monal Patel 1 , Calvin Y. Law 1 , Sonia Brockway 1 , Jian-Jun Wei 4 , C. Shad Thaxton 3,5,6,7 and Marcus E. Peter 1,2,5 1 Department of Medicine/Division of Hematology/Oncology, Feinberg School of Medicine, Chicago, IL, USA 2 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Chicago, IL, USA 3 Department of Urology, Feinberg School of Medicine, Chicago, IL, USA 4 Department of Pathology and Obstetrics and Gynecology, Feinberg School of Medicine, Chicago, IL, USA 5 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, IL, USA 6 Simpson Querrey Institute (SQI) for BioNanotechnology, Chicago, IL, USA 7 International Institute for Nanotechnology, Evanston, IL, USA Correspondence to: Marcus E. Peter, email: // Keywords : RNAi, Fas, ovarian cancer, TLP nanoparticles, cell death Received : January 23, 2017 Accepted : September 13, 2017 Published : October 04, 2017 Abstract The death receptor CD95/Fas can be activated by immune cells to kill cancer cells. shRNAs and siRNAs derived from CD95 or CD95 ligand (CD95L) are highly toxic to most cancer cells. We recently found that these sh/siRNAs kill cancer cells in the absence of the target by targeting the 3’UTRs of critical survival genes through canonical RNAi. We have named this unique form of off-target effect DISE (for death induced by survival gene elimination). DISE preferentially kills transformed cells and cancer stem cells. We demonstrate that DISE induction occurs in cancer cells in vivo after introducing a lentiviral CD95L derived shRNA (shL3) into HeyA8 ovarian cancer cells grown as i.p. xenografts in mice, when compared to a scrambled shRNA. To demonstrate the possibility of therapeutically inducing DISE, we coupled siRNAs to templated lipoprotein nanoparticles (TLP). In vitro , TLPs loaded with a CD95L derived siRNA (siL3) selectively silenced a biosensor comprised of Venus and CD95L ORF and killed ovarian cancer cells. In vivo , two siRNA-TLPs (siL2-TLP and siL3-TLP) reduced tumor growth similarly as observed for cells expressing the shL3 vector. These data suggest that it is possible to kill ovarian cancer cells in vivo via DISE induction using siRNA-TLPs.
33 citations
TL;DR: Evidence suggests that targeting cholesterol metabolism in CLL cells may have therapeutic benefit, and evidence suggests cholesterol-poor synthetic HDL nanoparticles (HDL NP), known for targeting SR-B1, as a therapy for CLL, implicate SR- B1 as a target in Cll and HDL NPs as targeted monotherapy for Cll.
Abstract: // Kaylin M. McMahon 1, * , Cristina Scielzo 2, 3, * , Nicholas L. Angeloni 1 , Elad Deiss-Yehiely 1 , Lydia Scarfo 2, 3 , Pamela Ranghetti 2, 3 , Shuo Ma 4 , Jason Kaplan 4, 5 , Federica Barbaglio 3 , Leo I. Gordon 4 , Francis J. Giles 4, 5 , C. Shad Thaxton 1, 4, 6, 7 , Paolo Ghia 2, 3 1 Department of Urology, Feinberg School of Medicine, Northwestern University, Tarry, Chicago, IL, USA 2 Universita Vita-Salute San Raffaele, Milan, Italy 3 Strategic Research Program On CLL and Unit of B cell Neoplasia, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy 4 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 5 Developmental Therapeutics Program of The Division of Hematology Oncology, Feinberg School of Medicine, Chicago, IL, USA 6 Simpson Querrey Institute (SQI) for BioNanotechnology, Chicago, IL, USA 7 International Institute for Nanotechnology, Evanston, IL, USA * These authors equally contributed to this work Correspondence to: C. Shad Thaxton, email: cthaxton003@md.northwestern.edu Paolo Ghia, email: ghia.paolo@hsr.it Keywords: lipoprotein, leukemia, scavenger receptor type B-I, nanoparticle, biomaterials Received: June 29, 2016 Accepted: December 26, 2016 Published: January 04, 2017 ABSTRACT Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new drugs. Therapies targeting receptors and pathways active specifically in malignant B cells might provide better treatment options. For instance, in B cell lymphoma, our group has previously shown that scavenger receptor type B-1 (SR-B1), the high-affinity receptor for cholesterol-rich high-density lipoproteins (HDL), is a therapeutic target. As evidence suggests that targeting cholesterol metabolism in CLL cells may have therapeutic benefit, we examined SR-B1 expression in primary CLL cells from patients. Unlike normal B cells that do not express SR-B1, CLL cells express the receptor. As a result, we evaluated cholesterol-poor synthetic HDL nanoparticles (HDL NP), known for targeting SR-B1, as a therapy for CLL. HDL NPs potently and selectively induce apoptotic cell death in primary CLL cells. HDL NPs had no effect on normal peripheral blood mononuclear cells from healthy individuals or patients with CLL. These data implicate SR-B1 as a target in CLL and HDL NPs as targeted monotherapy for CLL.
21 citations
TL;DR: The most recent developments, current challenges and future possibilities of nanomedicine approaches are discussed.
20 citations
TL;DR: X-ray photoelectron spectroscopy and lecithin/cholesterol acyltransferase activation experiments together with coarse-grained and all-atom molecular dynamics simulations are used to model the structure and cholesterol uptake properties of the HDL AuNP construct.
Abstract: High-density lipoprotein (HDL) plays an important role in the transport and metabolism of cholesterol. Mimics of HDL are being explored as potentially powerful therapeutic agents for removing excess cholesterol from arterial plaques. Gold nanoparticles (AuNPs) functionalized with apolipoprotein A-I and with the lipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate] have been demonstrated to be robust acceptors of cellular cholesterol. However, detailed structural information about this functionalized HDL AuNP is still lacking. In this study, we have used X-ray photoelectron spectroscopy and lecithin/cholesterol acyltransferase activation experiments together with coarse-grained and all-atom molecular dynamics simulations to model the structure and cholesterol uptake properties of the HDL AuNP construct. By simulating different apolipoprotein-loaded AuNPs, we find that lipids are oriented differently in regions with and with...
16 citations
TL;DR: In this paper, a form of off-target effect DISE (for death induced by survival gene elimination) was proposed for cancer cells in the absence of the target by targeting the 3′UTRs of critical survival genes through canonical RNAi.
Abstract: The death receptor CD95/Fas can be activated by immune cells to kill cancer cells. shRNAs and siRNAs derived from CD95 or CD95 ligand (CD95L) are highly toxic to most cancer cells. We recently found that these sh/siRNAs kill cancer cells in the absence of the target by targeting the 3′UTRs of critical survival genes through canonical RNAi. We have named this unique form of off-target effect DISE (for death induced by survival gene elimination). DISE preferentially kills transformed cells and cancer stem cells. We demonstrate that DISE induction occurs in cancer cells in vivo after introducing a lentiviral CD95L derived shRNA (shL3) into HeyA8 ovarian cancer cells grown as i.p. xenografts in mice, when compared to a scrambled shRNA. To demonstrate the possibility of therapeutically inducing DISE, we coupled siRNAs to templated lipoprotein nano particles (TLP). In vitro, TLPs loaded with a CD95L derived siRNA (siL3) selectively silenced a biosensor comprised of Venus and CD95L ORF and killed ovarian cancer cells. In vivo, two siRNA-TLPs (siL2-TLP and siL3-TLP) reduced tumor growth similarly as observed for cells expressing the shL3 vector. These data suggest that it is possible to kill ovarian cancer cells in vivo via DISE induction using siRNA-TLPs.
5 citations
Patent•
27 Apr 2017TL;DR: In this article, the authors proposed a system for the systemic delivery of nucleic acids, such as RNA, using templated lipoprotein nanoparticles (TLPs) composed of a core decorated with proteins, a lipid bilayer and hydrophobic molecules.
Abstract: Nanostructures for the systemic delivery of nucleic acids, such as RNA, are provided herein. The nanostructures include templated lipoprotein nanoparticles (TLPs) composed of a core decorated with proteins, a lipid bilayer and hydrophobic molecules that self-assemble with nucleic acids, such as RNA. The nanostructures are useful for research, therapeutic and diagnostic applications.
Patent•
15 Sep 2017TL;DR: In this article, an inorganic core and a lipid layer capable of binding a lecithinxholesterol acyltransferase (LCAT) activator such as an apolipoprotein are provided.
Abstract: Nanostructures having an inorganic core and a lipid layer capable of binding a lecithinxholesterol acyltransferase (LCAT) activator such as an apolipoprotein are provided herein. Methods of using the nanostructures and related devices and compositions for assessing the risk of developing a disease or condition or treating the disease or condition are also provided.
TL;DR: The HDL AuNP is able to efficiently activate LCAT and form esterified cholesterol from free cholesterol and phospholipid, and the distribution of cholesteryl ester maintains a reverse concentration gradient that is similar to the gradient found in native HDL.