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1.
Cell Rep ; 43(6): 114260, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38838225

RESUMEN

Immunotherapy remains underexploited in acute myeloid leukemia (AML) compared to other hematological malignancies. Currently, gemtuzumab ozogamicin is the only therapeutic antibody approved for this disease. Here, to identify potential targets for immunotherapeutic intervention, we analyze the surface proteome of 100 genetically diverse primary human AML specimens for the identification of cell surface proteins and conduct single-cell transcriptome analyses on a subset of these specimens to assess antigen expression at the sub-population level. Through this comprehensive effort, we successfully identify numerous antigens and markers preferentially expressed by primitive AML cells. Many identified antigens are targeted by therapeutic antibodies currently under clinical evaluation for various cancer types, highlighting the potential therapeutic value of the approach. Importantly, this initiative uncovers AML heterogeneity at the surfaceome level, identifies several antigens and potential primitive cell markers characterizing AML subgroups, and positions immunotherapy as a promising approach to target AML subgroup specificities.


Asunto(s)
Inmunoterapia , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patología , Inmunoterapia/métodos , Proteínas de la Membrana/metabolismo
2.
Neuro Oncol ; 26(6): 1052-1066, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38271182

RESUMEN

BACKGROUND: Compared to minimally invasive brain metastases (MI BrM), highly invasive (HI) lesions form abundant contacts with cells in the peritumoral brain parenchyma and are associated with poor prognosis. Reactive astrocytes (RAs) labeled by phosphorylated STAT3 (pSTAT3) have recently emerged as a promising therapeutic target for BrM. Here, we explore whether the BrM invasion pattern is influenced by pSTAT3+ RAs and may serve as a predictive biomarker for STAT3 inhibition. METHODS: We used immunohistochemistry to identify pSTAT3+ RAs in HI and MI human and patient-derived xenograft (PDX) BrM. Using PDX, syngeneic, and transgenic mouse models of HI and MI BrM, we assessed how pharmacological STAT3 inhibition or RA-specific STAT3 genetic ablation affected BrM growth in vivo. Cancer cell invasion was modeled in vitro using a brain slice-tumor co-culture assay. We performed single-cell RNA sequencing of human BrM and adjacent brain tissue. RESULTS: RAs expressing pSTAT3 are situated at the brain-tumor interface and drive BrM invasive growth. HI BrM invasion pattern was associated with delayed growth in the context of STAT3 inhibition or genetic ablation. We demonstrate that pSTAT3+ RAs secrete Chitinase 3-like-1 (CHI3L1), which is a known STAT3 transcriptional target. Furthermore, single-cell RNA sequencing identified CHI3L1-expressing RAs in human HI BrM. STAT3 activation, or recombinant CHI3L1 alone, induced cancer cell invasion into the brain parenchyma using a brain slice-tumor plug co-culture assay. CONCLUSIONS: Together, these data reveal that pSTAT3+ RA-derived CHI3L1 is associated with BrM invasion, implicating STAT3 and CHI3L1 as clinically relevant therapeutic targets for the treatment of HI BrM.


Asunto(s)
Astrocitos , Neoplasias Encefálicas , Proteína 1 Similar a Quitinasa-3 , Invasividad Neoplásica , Factor de Transcripción STAT3 , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Humanos , Proteína 1 Similar a Quitinasa-3/metabolismo , Proteína 1 Similar a Quitinasa-3/genética , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/genética , Astrocitos/metabolismo , Astrocitos/patología , Ratones , Ratones Transgénicos , Proliferación Celular , Ensayos Antitumor por Modelo de Xenoinjerto , Células Tumorales Cultivadas
3.
Blood Adv ; 8(1): 112-129, 2024 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-37729615

RESUMEN

ABSTRACT: Acute megakaryoblastic leukemia (AMKL) is a rare, developmentally restricted, and highly lethal cancer of early childhood. The paucity and hypocellularity (due to myelofibrosis) of primary patient samples hamper the discovery of cell- and genotype-specific treatments. AMKL is driven by mutually exclusive chimeric fusion oncogenes in two-thirds of the cases, with CBFA2T3::GLIS2 (CG2) and NUP98 fusions (NUP98r) representing the highest-fatality subgroups. We established CD34+ cord blood-derived CG2 models (n = 6) that sustain serial transplantation and recapitulate human leukemia regarding immunophenotype, leukemia-initiating cell frequencies, comutational landscape, and gene expression signature, with distinct upregulation of the prosurvival factor B-cell lymphoma 2 (BCL2). Cell membrane proteomic analyses highlighted CG2 surface markers preferentially expressed on leukemic cells compared with CD34+ cells (eg, NCAM1 and CD151). AMKL differentiation block in the mega-erythroid progenitor space was confirmed by single-cell profiling. Although CG2 cells were rather resistant to BCL2 genetic knockdown or selective pharmacological inhibition with venetoclax, they were vulnerable to strategies that target the megakaryocytic prosurvival factor BCL-XL (BCL2L1), including in vitro and in vivo treatment with BCL2/BCL-XL/BCL-W inhibitor navitoclax and DT2216, a selective BCL-XL proteolysis-targeting chimera degrader developed to limit thrombocytopenia in patients. NUP98r AMKL were also sensitive to BCL-XL inhibition but not the NUP98r monocytic leukemia, pointing to a lineage-specific dependency. Navitoclax or DT2216 treatment in combination with low-dose cytarabine further reduced leukemic burden in mice. This work extends the cellular and molecular diversity set of human AMKL models and uncovers BCL-XL as a therapeutic vulnerability in CG2 and NUP98r AMKL.


Asunto(s)
Antineoplásicos , Leucemia Megacarioblástica Aguda , Humanos , Niño , Preescolar , Animales , Ratones , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/patología , Proteómica , Factores de Transcripción , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Represoras
4.
Front Oncol ; 12: 981927, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36052226

RESUMEN

The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor mediating the clearance of various molecules from the extracellular matrix. LRP1 also regulates cell surface expression of matrix receptors by modulating both extracellular and intracellular signals, though current knowledge of the underlying mechanisms remains partial in the frame of cancer cells interaction with matricellular substrates. In this study we identified that LRP1 downregulates calpain activity and calpain 2 transcriptional expression in an invasive thyroid carcinoma cell model. LRP1-dependent alleviation of calpain activity limits cell-matrix attachment strength and contributes to FTC133 cells invasive abilities in a modified Boyden chamber assays. In addition, using enzymatic assays and co-immunoprecipitation experiments, we demonstrated that LRP1 exerts post-translational inhibition of calpain activity through PKA-dependent phosphorylation of calpain-2. This LRP-1 dual mode of control of calpain activity fine-tunes carcinoma cell spreading. We showed that LRP1-mediated calpain inhibition participates in talin-positive focal adhesions dissolution and limits ß1-integrin expression at carcinoma cell surface. In conclusion, we identified an additional and innovative intracellular mechanism which demonstrates LRP-1 pro-motile action in thyroid cancer cells. LRP-1 ability to specifically control calpain-2 expression and activity highlights a novel facet of its de-adhesion receptor status.

5.
Oncotarget ; 8(45): 78614-78632, 2017 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-29108253

RESUMEN

LRP-1 is a large endocytic receptor mediating the clearance of various molecules from the extracellular matrix. LRP-1 was reported to control focal adhesion turnover to optimize the adhesion-deadhesion balance to support invasion. To better understand how LRP-1 coordinates cell-extracellular matrix interface, we explored its ability to regulate cell surface integrins in thyroid carcinomas. Using an antibody approach, we demonstrated that ß1-integrin levels were increased at the plasma membrane under LRP1 silencing or upon RAP treatment, used as LRP-1 antagonist. Our data revealed that LRP-1 binds with both inactive and active ß1-integrin conformations and identified the extracellular ligand-binding domains II or IV of LRP-1 as sufficient to bind ß1-integrin. Using a recombinant ß1-integrin, we demonstrated that LRP-1 acts as a regulator of ß1-integrin intracellular traffic. Moreover, RAP or LRP-1 blocking antibodies decreased up to 36% the number of ß1-integrin-containing endosomes. LRP-1 blockade did not significantly affect the levels of ß1-integrin-containing lysosomes while decreasing localization of ß1-integrin within Rab-11 positive vesicles. Overall, we identified an original molecular process in which LRP-1 acts as a main regulator of ß1-integrin internalization and recycling in thyroid cancer cells.

6.
Clin Exp Metastasis ; 33(7): 637-49, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27349907

RESUMEN

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.


Asunto(s)
Antígeno CD47/genética , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Péptidos Cíclicos/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Trombospondina 1/genética , Animales , Antígeno CD47/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Melanoma/genética , Melanoma/patología , Melanoma Experimental/genética , Melanoma Experimental/patología , Ratones , Metástasis de la Neoplasia , Neovascularización Patológica , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Trombospondina 1/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Melanoma Cutáneo Maligno
7.
Oncotarget ; 6(20): 17981-8000, 2015 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-26046793

RESUMEN

The multi-modular glycoprotein thrombospondin-1 (TSP-1) is considered as a key actor within the tumor microenvironment. Besides, TSP-1 binding to CD47 is widely reported to regulate cardiovascular function as it promotes vasoconstriction and angiogenesis limitation. Therefore, many studies focused on targeting TSP-1:CD47 interaction, aiming for up-regulation of physiological angiogenesis to enhance post-ischemia recovery or to facilitate engraftment. Thus, we sought to identify an innovative selective antagonist for TSP-1:CD47 interaction. Protein-protein docking and molecular dynamics simulations were conducted to design a novel CD47-derived peptide, called TAX2. TAX2 binds TSP-1 to prevent TSP-1:CD47 interaction, as revealed by ELISA and co-immunoprecipitation experiments. Unexpectedly, TAX2 inhibits in vitro and ex vivo angiogenesis features in a TSP-1-dependent manner. Consistently, our data highlighted that TAX2 promotes TSP-1 binding to CD36-containing complexes, leading to disruption of VEGFR2 activation and downstream NO signaling. Such unpredicted results prompted us to investigate TAX2 potential in tumor pathology. A multimodal imaging approach was conducted combining histopathological staining, MVD, MRI analysis and µCT monitoring for tumor angiography longitudinal follow-up and 3D quantification. TAX2 in vivo administrations highly disturb syngeneic melanoma tumor vascularization inducing extensive tumor necrosis and strongly inhibit growth rate and vascularization of human pancreatic carcinoma xenografts in nude mice.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Carcinoma/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Péptidos Cíclicos/farmacología , Péptidos/farmacología , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/metabolismo , Animales , Antígenos CD36/metabolismo , Carcinoma/irrigación sanguínea , Carcinoma/metabolismo , Carcinoma/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diseño Asistido por Computadora , Diseño de Fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Imagen por Resonancia Magnética , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Terapia Molecular Dirigida , Necrosis , Neovascularización Patológica , Óxido Nítrico/metabolismo , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Péptidos/química , Péptidos/metabolismo , Péptidos Cíclicos/química , Péptidos Cíclicos/metabolismo , Unión Proteica , Transducción de Señal/efectos de los fármacos , Trombospondina 1/metabolismo , Factores de Tiempo , Transfección , Carga Tumoral/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Microtomografía por Rayos X , Ensayos Antitumor por Modelo de Xenoinjerto
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