Репозиторий Университета

© 2020 Elsevier B.V. Background: Photoimmunotherapy (PIT) is an emerging method of cancer treatment based on the use of a photosensitizer near-infrared dye IRDye700DX (IR700) conjugated to a monoclonal antibody. The antibody selectively delivers IR700 to cancer cells, which can then be killed after photoexcitation. Glypican-1 (GPC-1) is a novel target expressed specifically in malignant tumors. We aimed to investigate whether anti-GPC-1 antibody Miltuximab® (Glytherix Ltd., Sydney, Australia) can be conjugated with IR700 for PIT of solid tumors. Methods: The dye IR700 was conjugated with Miltuximab® and characterized by spectrophotometry and flow cytometry. Miltuximab®-IR700-mediated PIT was tested in prostate (DU-145), bladder (C3 and T-24), brain (U-87 and U-251) and ovarian (SKOV-3) cancer cell lines. After 1 h incubation with Miltuximab®-IR700, the cells were washed by PBS and illuminated using a 690-nm light-emitting diode. The viability of the cells was assessed by a CCK-8 viability kit 24 h later. Results: Miltuximab®-IR700-mediated PIT caused 67.3–92.3% reduction in viability of cells with medium-high GPC-1 expression and did not affect the viability of GPC-1-low cells. Cytotoxicity was attributed to the targeted binding of the conjugate with subsequent photoactivation, as the conjugate or light exposure alone had no effect on the cell viability. Miltuximab®-IR700 did not induce cytotoxicity in cells blocked by unconjugated Miltuximab®. Conclusions: PIT with Miltuximab®-IR700 appears to be highly specific and effective against GPC-1-expressing cancer cells, indicating that it holds promise for an effective and safe treatment of early stage solid tumors or as adjuvant therapy following surgical resection. These findings necessitate further investigation of PIT with Miltuximab®-IR700 in other GPC-1-expressing cancer cell lines in vitro and in vivo in xenograft tumor models.

© 2020 Elsevier B.V. Background: Photoimmunotherapy (PIT) is an emerging method of cancer treatment based on the use of a photosensitizer near-infrared dye IRDye700DX (IR700) conjugated to a monoclonal antibody. The antibody selectively delivers IR700 to cancer cells, which can then be killed after photoexcitation. Glypican-1 (GPC-1) is a novel target expressed specifically in malignant tumors. We aimed to investigate whether anti-GPC-1 antibody Miltuximab® (Glytherix Ltd., Sydney, Australia) can be conjugated with IR700 for PIT of solid tumors. Methods: The dye IR700 was conjugated with Miltuximab® and characterized by spectrophotometry and flow cytometry. Miltuximab®-IR700-mediated PIT was tested in prostate (DU-145), bladder (C3 and T-24), brain (U-87 and U-251) and ovarian (SKOV-3) cancer cell lines. After 1 h incubation with Miltuximab®-IR700, the cells were washed by PBS and illuminated using a 690-nm light-emitting diode. The viability of the cells was assessed by a CCK-8 viability kit 24 h later. Results: Miltuximab®-IR700-mediated PIT caused 67.3–92.3% reduction in viability of cells with medium-high GPC-1 expression and did not affect the viability of GPC-1-low cells. Cytotoxicity was attributed to the targeted binding of the conjugate with subsequent photoactivation, as the conjugate or light exposure alone had no effect on the cell viability. Miltuximab®-IR700 did not induce cytotoxicity in cells blocked by unconjugated Miltuximab®. Conclusions: PIT with Miltuximab®-IR700 appears to be highly specific and effective against GPC-1-expressing cancer cells, indicating that it holds promise for an effective and safe treatment of early stage solid tumors or as adjuvant therapy following surgical resection. These findings necessitate further investigation of PIT with Miltuximab®-IR700 in other GPC-1-expressing cancer cell lines in vitro and in vivo in xenograft tumor models.

© 2020 Elsevier B.V. Background: Photoimmunotherapy (PIT) is an emerging method of cancer treatment based on the use of a photosensitizer near-infrared dye IRDye700DX (IR700) conjugated to a monoclonal antibody. The antibody selectively delivers IR700 to cancer cells, which can then be killed after photoexcitation. Glypican-1 (GPC-1) is a novel target expressed specifically in malignant tumors. We aimed to investigate whether anti-GPC-1 antibody Miltuximab® (Glytherix Ltd., Sydney, Australia) can be conjugated with IR700 for PIT of solid tumors. Methods: The dye IR700 was conjugated with Miltuximab® and characterized by spectrophotometry and flow cytometry. Miltuximab®-IR700-mediated PIT was tested in prostate (DU-145), bladder (C3 and T-24), brain (U-87 and U-251) and ovarian (SKOV-3) cancer cell lines. After 1 h incubation with Miltuximab®-IR700, the cells were washed by PBS and illuminated using a 690-nm light-emitting diode. The viability of the cells was assessed by a CCK-8 viability kit 24 h later. Results: Miltuximab®-IR700-mediated PIT caused 67.3–92.3% reduction in viability of cells with medium-high GPC-1 expression and did not affect the viability of GPC-1-low cells. Cytotoxicity was attributed to the targeted binding of the conjugate with subsequent photoactivation, as the conjugate or light exposure alone had no effect on the cell viability. Miltuximab®-IR700 did not induce cytotoxicity in cells blocked by unconjugated Miltuximab®. Conclusions: PIT with Miltuximab®-IR700 appears to be highly specific and effective against GPC-1-expressing cancer cells, indicating that it holds promise for an effective and safe treatment of early stage solid tumors or as adjuvant therapy following surgical resection. These findings necessitate further investigation of PIT with Miltuximab®-IR700 in other GPC-1-expressing cancer cell lines in vitro and in vivo in xenograft tumor models.

© 2020 Elsevier B.V. In a recent computational study, we revealed some mechanistic aspects of TRPV1 (transient receptor potential channel 1) thermal activation and gating and proposed a set of probable functionally important residues — “hot spots” that have not been characterized experimentally yet. In this work, we analyzed TRPV1 point mutants G643A, I679A + A680G, and K688G/P combining molecular modeling, biochemistry, and electrophysiology. The substitution G643A reduced maximal conductivity that resulted in a normal response to moderate stimuli, but a relatively weak response to more intensive activation. I679A + A680G channel was severely toxic for oocytes most probably due to abnormally increased basal activity of the channel (“always open” gates). The replacement K688G presumably facilitated movements of TRP domain and disturbed its coupling to the pore, thus leading to spontaneous activation and enhanced desensitization of the channel. Finally, mutation K688P was suggested to impair TRP domain directed movement, and the mutated channel showed ~100-fold less sensitivity to the capsaicin, enhanced desensitization and weaker activation by the heat. Our results provide a better understanding of TRPV1 thermal and capsaicin-induced activation and gating. These observations provide a structural basis for understanding some aspects of TRPV1 channel functioning and depict potentially pathogenic mutations.

© 2020 Elsevier B.V. In a recent computational study, we revealed some mechanistic aspects of TRPV1 (transient receptor potential channel 1) thermal activation and gating and proposed a set of probable functionally important residues — “hot spots” that have not been characterized experimentally yet. In this work, we analyzed TRPV1 point mutants G643A, I679A + A680G, and K688G/P combining molecular modeling, biochemistry, and electrophysiology. The substitution G643A reduced maximal conductivity that resulted in a normal response to moderate stimuli, but a relatively weak response to more intensive activation. I679A + A680G channel was severely toxic for oocytes most probably due to abnormally increased basal activity of the channel (“always open” gates). The replacement K688G presumably facilitated movements of TRP domain and disturbed its coupling to the pore, thus leading to spontaneous activation and enhanced desensitization of the channel. Finally, mutation K688P was suggested to impair TRP domain directed movement, and the mutated channel showed ~100-fold less sensitivity to the capsaicin, enhanced desensitization and weaker activation by the heat. Our results provide a better understanding of TRPV1 thermal and capsaicin-induced activation and gating. These observations provide a structural basis for understanding some aspects of TRPV1 channel functioning and depict potentially pathogenic mutations.

© 2020 Elsevier B.V. Brain metastases manifest the advanced stage of breast cancer disease with poor prognosis for patient survival. Recent reports demonstrate that some therapeutic agents can activate the expression of several breast cancer-associated genes, whose products are involved in the onset and development of brain metastases. In this study, we discovered a functional link between KISS1 and E-cadherin that could be observed in both primary brain metastatic lesions and paired cell lines, such as parental CN34TGL and MDA-MB-231 and their respective brain metastatic subclones CN34Brm2Ctgl and MDA-MB-231Br. Remarkably, expression of KISS1 and E-cadherin genes consistently showed an inverse correlation in all of the above cell/tissue types. While E-cadherin expression was strongly upregulated in metastatic clones isolated from blood and brain, the levels of this protein in parental MDA-MB-231 cell line was low. Furthermore, E-cadherin upregulation can be artificially induced in MDA-MB-231Br and CN34Brm2Ctgl cell populations by knocking down KISS1 expression directly or through overexpressing the miR345 mimic. In the aggregate, our data suggest that the tumor microenvironment, which controls breast cancer spreading via miR345-regulated KISS1 expression, might modulate metastatic spreading by a mechanism(s) involving upregulation of E-cadherin production.

© 2020 A series of novel metal complexes of Cu(II), Ni(II), Zn(II), Cd(II), and Mg(II) with four N-heterocyclic derivatives of 2-arylhydrazono-1,3-dicarbonyl compounds were isolated and identified by FT IR, 1H NMR, EPR, and UV–Vis spectroscopy. The crystallographic data for two organic ligands as well as Mg(II) and Ni(II) complexes were obtained. It was indicated that the organic species exist in the form of hydrazo-tautomers. The Ni complex is monomeric and is characterized by the tridentate coordination of the ligand through a deprotonated N-atom of the hydrazo-fragment and two neighboring O-atoms of the carbonyl and deprotonated hydroxy-groups. In the case of the Mg complex the polymeric structure is observed with the additional coordination through the sulfamide group of the organic specie. Formation constants of the complexes in ethanol aqueous solutions were calculated and correlated with some physical characteristics of the metal cations. Structures of yet unstudied metal complexes were proposed based on quantum-chemical modeling at the DFT/B3LYP level.

© 2020 Elsevier Inc. This study reports the differences in toxic action between cadmium sulfide (CdS) and zinc sulfide (ZnS) nanoparticles (NPs) prepared by recently developed xanthate-mediated method. The aquatic toxicity of the synthesized NPs on four marine microalgae species was explored. Growth rate, esterase activity, membrane potential, and morphological changes of microalgae cells were evaluated using flow cytometry and optical microscopy. CdS and ZnS NPs demonstrated similar level of general toxicity and growth-rate inhibition to all used microalgae species, except the red algae P. purpureum. More specifically, CdS NPs caused higher inhibition of growth rate for C. muelleri and P. purpureum, while ZnS NPs were more toxic for A. ussuriensis and H. akashiwo species. Our findings suggest that the sensitivity of different microalgae species to CdS and ZnS NPs depends on the chemical composition of NPs and their ability to interact with the components of microalgal cell-wall. The red microalga was highly resistant to ZnS NPs most likely due to the presence of phycoerythrin proteins in the outer membrane bound Zn2+ cations defending their cells from further toxic influence. The treatment with CdS NPs caused morphological changes and biochemical disorder in all tested microalgae species. The toxicity of CdS NPs is based on their higher photoactivity under visible light irradiation and lower dissociation in water, which allows them to generate more reactive oxygen species and create a higher risk of oxidative stress to aquatic organisms. The results of this study contribute to our understanding of the parameters affecting the aquatic toxicity of semiconductor NPs and provide a basis for further investigations.

© 2020 A series of novel metal complexes of Cu(II), Ni(II), Zn(II), Cd(II), and Mg(II) with four N-heterocyclic derivatives of 2-arylhydrazono-1,3-dicarbonyl compounds were isolated and identified by FT IR, 1H NMR, EPR, and UV–Vis spectroscopy. The crystallographic data for two organic ligands as well as Mg(II) and Ni(II) complexes were obtained. It was indicated that the organic species exist in the form of hydrazo-tautomers. The Ni complex is monomeric and is characterized by the tridentate coordination of the ligand through a deprotonated N-atom of the hydrazo-fragment and two neighboring O-atoms of the carbonyl and deprotonated hydroxy-groups. In the case of the Mg complex the polymeric structure is observed with the additional coordination through the sulfamide group of the organic specie. Formation constants of the complexes in ethanol aqueous solutions were calculated and correlated with some physical characteristics of the metal cations. Structures of yet unstudied metal complexes were proposed based on quantum-chemical modeling at the DFT/B3LYP level.

© 2020 Elsevier Inc. This study reports the differences in toxic action between cadmium sulfide (CdS) and zinc sulfide (ZnS) nanoparticles (NPs) prepared by recently developed xanthate-mediated method. The aquatic toxicity of the synthesized NPs on four marine microalgae species was explored. Growth rate, esterase activity, membrane potential, and morphological changes of microalgae cells were evaluated using flow cytometry and optical microscopy. CdS and ZnS NPs demonstrated similar level of general toxicity and growth-rate inhibition to all used microalgae species, except the red algae P. purpureum. More specifically, CdS NPs caused higher inhibition of growth rate for C. muelleri and P. purpureum, while ZnS NPs were more toxic for A. ussuriensis and H. akashiwo species. Our findings suggest that the sensitivity of different microalgae species to CdS and ZnS NPs depends on the chemical composition of NPs and their ability to interact with the components of microalgal cell-wall. The red microalga was highly resistant to ZnS NPs most likely due to the presence of phycoerythrin proteins in the outer membrane bound Zn2+ cations defending their cells from further toxic influence. The treatment with CdS NPs caused morphological changes and biochemical disorder in all tested microalgae species. The toxicity of CdS NPs is based on their higher photoactivity under visible light irradiation and lower dissociation in water, which allows them to generate more reactive oxygen species and create a higher risk of oxidative stress to aquatic organisms. The results of this study contribute to our understanding of the parameters affecting the aquatic toxicity of semiconductor NPs and provide a basis for further investigations.

© 2020 Elsevier Inc. Dysfunction in the circadian system has been linked to emotion regulation and mood disorders with genetic variation in clock genes as likely contributors. Here, we focused on endophenotypes of affective processing and investigated in two independent samples of healthy individuals (n1=99, n2=108) whether genotypes of a functional single nucleotide polymorphism (SNP) in the gene encoding CLOCK (CLOCK T3111C, rs1801260) differed in physiological responses to emotional stimuli. Both samples underwent an emotional startle paradigm with startle responses being measured via EMG. In the second sample, skin conductance responses as well as corrugator and zygomaticus activity were also assessed. In both samples, CLOCK T3111C was associated with overall startle responses to loud noise bursts with T/T homozygotes showing consistently more marked responses. However, in the all-female second sample, the effects of CLOCK on skin conductance responses to the same loud noise bursts depended on hormone status: similar to the startle results, in free-cycling women T/T homozygotes showed more pronounced skin conductance response (SCR) compared to C allele carriers. The opposite was true for women using combined oral contraceptives (COC). A further CLOCK × hormone status interaction effect was found for corrugator activity. In free-cycling women, T/T homozygotes presented with less corrugator activity to affective pictures compared to C allele carriers, while the opposite pattern emerged for COC users. The findings emphasize the potential role of CLOCK for affect and mood.

© 2020 Elsevier Inc. Dysfunction in the circadian system has been linked to emotion regulation and mood disorders with genetic variation in clock genes as likely contributors. Here, we focused on endophenotypes of affective processing and investigated in two independent samples of healthy individuals (n1=99, n2=108) whether genotypes of a functional single nucleotide polymorphism (SNP) in the gene encoding CLOCK (CLOCK T3111C, rs1801260) differed in physiological responses to emotional stimuli. Both samples underwent an emotional startle paradigm with startle responses being measured via EMG. In the second sample, skin conductance responses as well as corrugator and zygomaticus activity were also assessed. In both samples, CLOCK T3111C was associated with overall startle responses to loud noise bursts with T/T homozygotes showing consistently more marked responses. However, in the all-female second sample, the effects of CLOCK on skin conductance responses to the same loud noise bursts depended on hormone status: similar to the startle results, in free-cycling women T/T homozygotes showed more pronounced skin conductance response (SCR) compared to C allele carriers. The opposite was true for women using combined oral contraceptives (COC). A further CLOCK × hormone status interaction effect was found for corrugator activity. In free-cycling women, T/T homozygotes presented with less corrugator activity to affective pictures compared to C allele carriers, while the opposite pattern emerged for COC users. The findings emphasize the potential role of CLOCK for affect and mood.

© 2020 The Authors Genome-wide screening approaches identified the cell adhesion molecule Cadherin-13 (CDH13) as a risk factor for neurodevelopmental disorders, nevertheless the contribution of CDH13 to the disease mechanism remains obscure. CDH13 is involved in neurite outgrowth and axon guidance during early brain development and we previously provided evidence that constitutive CDH13 deficiency influences the formation of the raphe serotonin (5-HT) system by modifying neuron-radial glia interaction. Here, we dissect the specific impact of CDH13 on 5-HT system development and function using a 5-HT neuron-specific Cdh13 knockout mouse model (conditional Cdh13 knockout, Cdh13 cKO). Our results show that exclusive inactivation of CDH13 in 5-HT neurons selectively increases 5-HT neuron density in the embryonic dorsal raphe, with persistence into adulthood, and serotonergic innervation of the developing prefrontal cortex. At the behavioral level, adult Cdh13 cKO mice display delayed acquisition of several learning tasks and a subtle impulsive-like phenotype, with decreased latency in a sociability paradigm alongside with deficits in visuospatial memory. Anxiety-related traits were not observed in Cdh13 cKO mice. Our findings further support the critical role of CDH13 in the development of dorsal raphe 5-HT circuitries, a mechanism that may underlie specific clinical features observed in neurodevelopmental disorders.

© 2020 The Authors Genome-wide screening approaches identified the cell adhesion molecule Cadherin-13 (CDH13) as a risk factor for neurodevelopmental disorders, nevertheless the contribution of CDH13 to the disease mechanism remains obscure. CDH13 is involved in neurite outgrowth and axon guidance during early brain development and we previously provided evidence that constitutive CDH13 deficiency influences the formation of the raphe serotonin (5-HT) system by modifying neuron-radial glia interaction. Here, we dissect the specific impact of CDH13 on 5-HT system development and function using a 5-HT neuron-specific Cdh13 knockout mouse model (conditional Cdh13 knockout, Cdh13 cKO). Our results show that exclusive inactivation of CDH13 in 5-HT neurons selectively increases 5-HT neuron density in the embryonic dorsal raphe, with persistence into adulthood, and serotonergic innervation of the developing prefrontal cortex. At the behavioral level, adult Cdh13 cKO mice display delayed acquisition of several learning tasks and a subtle impulsive-like phenotype, with decreased latency in a sociability paradigm alongside with deficits in visuospatial memory. Anxiety-related traits were not observed in Cdh13 cKO mice. Our findings further support the critical role of CDH13 in the development of dorsal raphe 5-HT circuitries, a mechanism that may underlie specific clinical features observed in neurodevelopmental disorders.

© 2020 The Authors Genome-wide screening approaches identified the cell adhesion molecule Cadherin-13 (CDH13) as a risk factor for neurodevelopmental disorders, nevertheless the contribution of CDH13 to the disease mechanism remains obscure. CDH13 is involved in neurite outgrowth and axon guidance during early brain development and we previously provided evidence that constitutive CDH13 deficiency influences the formation of the raphe serotonin (5-HT) system by modifying neuron-radial glia interaction. Here, we dissect the specific impact of CDH13 on 5-HT system development and function using a 5-HT neuron-specific Cdh13 knockout mouse model (conditional Cdh13 knockout, Cdh13 cKO). Our results show that exclusive inactivation of CDH13 in 5-HT neurons selectively increases 5-HT neuron density in the embryonic dorsal raphe, with persistence into adulthood, and serotonergic innervation of the developing prefrontal cortex. At the behavioral level, adult Cdh13 cKO mice display delayed acquisition of several learning tasks and a subtle impulsive-like phenotype, with decreased latency in a sociability paradigm alongside with deficits in visuospatial memory. Anxiety-related traits were not observed in Cdh13 cKO mice. Our findings further support the critical role of CDH13 in the development of dorsal raphe 5-HT circuitries, a mechanism that may underlie specific clinical features observed in neurodevelopmental disorders.

© 2019 The Authors Immunosuppressive chemoresistance is a major challenge in lung cancer treatment. Exosomes present in the tumor microenviroment are implicated in chemoresistant-related immune suppression, and metastasis but the exact pathogenic role of lung-derived exosomes is still uncertain. Recent reports reveal that lung cancer pathogenesis is strictly associated with a exosomal tumor supportive status and a dysfunctional immune system. In this study, we investigate the role of Kras-derived exosomes in chemoresistant immunosuppression in which neoplastic cells create a metabolic-sustained microenvironment. Findings reveal that Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice and consequently increase lung metastatic burden. Furthermore, exosomal Kras inhibition downregulated transcription factor BACH2/GATA-3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism, contributing to a tumor-restraining status. Further co-treatment with carboplatin triggered RIP3/TNFa dependent necroptosis in ex vivo cells accompanied by differential expression of immunosuppressive miR-146/miR-210 regulators in metastatic lung cancer patients. Overall, these findings demonstrate the multifaceted roles of Kras-derived exosomes in sustaining lung immunosuppressive metastasis and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

© 2019 The Authors Immunosuppressive chemoresistance is a major challenge in lung cancer treatment. Exosomes present in the tumor microenviroment are implicated in chemoresistant-related immune suppression, and metastasis but the exact pathogenic role of lung-derived exosomes is still uncertain. Recent reports reveal that lung cancer pathogenesis is strictly associated with a exosomal tumor supportive status and a dysfunctional immune system. In this study, we investigate the role of Kras-derived exosomes in chemoresistant immunosuppression in which neoplastic cells create a metabolic-sustained microenvironment. Findings reveal that Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice and consequently increase lung metastatic burden. Furthermore, exosomal Kras inhibition downregulated transcription factor BACH2/GATA-3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism, contributing to a tumor-restraining status. Further co-treatment with carboplatin triggered RIP3/TNFa dependent necroptosis in ex vivo cells accompanied by differential expression of immunosuppressive miR-146/miR-210 regulators in metastatic lung cancer patients. Overall, these findings demonstrate the multifaceted roles of Kras-derived exosomes in sustaining lung immunosuppressive metastasis and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

© 2019 The Authors Immunosuppressive chemoresistance is a major challenge in lung cancer treatment. Exosomes present in the tumor microenviroment are implicated in chemoresistant-related immune suppression, and metastasis but the exact pathogenic role of lung-derived exosomes is still uncertain. Recent reports reveal that lung cancer pathogenesis is strictly associated with a exosomal tumor supportive status and a dysfunctional immune system. In this study, we investigate the role of Kras-derived exosomes in chemoresistant immunosuppression in which neoplastic cells create a metabolic-sustained microenvironment. Findings reveal that Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice and consequently increase lung metastatic burden. Furthermore, exosomal Kras inhibition downregulated transcription factor BACH2/GATA-3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism, contributing to a tumor-restraining status. Further co-treatment with carboplatin triggered RIP3/TNFa dependent necroptosis in ex vivo cells accompanied by differential expression of immunosuppressive miR-146/miR-210 regulators in metastatic lung cancer patients. Overall, these findings demonstrate the multifaceted roles of Kras-derived exosomes in sustaining lung immunosuppressive metastasis and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

© 2019 The Authors Immunosuppressive chemoresistance is a major challenge in lung cancer treatment. Exosomes present in the tumor microenviroment are implicated in chemoresistant-related immune suppression, and metastasis but the exact pathogenic role of lung-derived exosomes is still uncertain. Recent reports reveal that lung cancer pathogenesis is strictly associated with a exosomal tumor supportive status and a dysfunctional immune system. In this study, we investigate the role of Kras-derived exosomes in chemoresistant immunosuppression in which neoplastic cells create a metabolic-sustained microenvironment. Findings reveal that Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice and consequently increase lung metastatic burden. Furthermore, exosomal Kras inhibition downregulated transcription factor BACH2/GATA-3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism, contributing to a tumor-restraining status. Further co-treatment with carboplatin triggered RIP3/TNFa dependent necroptosis in ex vivo cells accompanied by differential expression of immunosuppressive miR-146/miR-210 regulators in metastatic lung cancer patients. Overall, these findings demonstrate the multifaceted roles of Kras-derived exosomes in sustaining lung immunosuppressive metastasis and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

© 2019 The Authors Immunosuppressive chemoresistance is a major challenge in lung cancer treatment. Exosomes present in the tumor microenviroment are implicated in chemoresistant-related immune suppression, and metastasis but the exact pathogenic role of lung-derived exosomes is still uncertain. Recent reports reveal that lung cancer pathogenesis is strictly associated with a exosomal tumor supportive status and a dysfunctional immune system. In this study, we investigate the role of Kras-derived exosomes in chemoresistant immunosuppression in which neoplastic cells create a metabolic-sustained microenvironment. Findings reveal that Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice and consequently increase lung metastatic burden. Furthermore, exosomal Kras inhibition downregulated transcription factor BACH2/GATA-3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism, contributing to a tumor-restraining status. Further co-treatment with carboplatin triggered RIP3/TNFa dependent necroptosis in ex vivo cells accompanied by differential expression of immunosuppressive miR-146/miR-210 regulators in metastatic lung cancer patients. Overall, these findings demonstrate the multifaceted roles of Kras-derived exosomes in sustaining lung immunosuppressive metastasis and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.