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Research Article

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Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer
Changhao Chen, … , Rufu Chen, Tianxin Lin
Changhao Chen, … , Rufu Chen, Tianxin Lin
Published December 3, 2019; First published October 8, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI130892.
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Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer

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Abstract

Patients with bladder cancer (BCa) with clinical lymph node (LN) metastasis have an extremely poor prognosis. VEGF-C has been demonstrated to play vital roles in LN metastasis in BCa. However, approximately 20% of BCa with LN metastasis exhibits low VEGF-C expression, suggesting a VEGF-C–independent mechanism for LN metastasis of BCa. Herein, we demonstrate that BCa cell–secreted exosome-mediated lymphangiogenesis promoted LN metastasis in BCa in a VEGF-C–independent manner. We identified an exosomal long noncoding RNA (lncRNA), termed lymph node metastasis-associated transcript 2 (LNMAT2), that stimulated human lymphatic endothelial cell (HLEC) tube formation and migration in vitro and enhanced tumor lymphangiogenesis and LN metastasis in vivo. Mechanistically, LNMAT2 was loaded to BCa cell–secreted exosomes by directly interacting with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1). Subsequently, exosomal LNMAT2 was internalized by HLECs and epigenetically upregulated prospero homeobox 1 (PROX1) expression by recruitment of hnRNPA2B1 and increasing the H3K4 trimethylation level in the PROX1 promoter, ultimately resulting in lymphangiogenesis and lymphatic metastasis. Therefore, our findings highlight a VEGF-C–independent mechanism of exosomal lncRNA-mediated LN metastasis and identify LNMAT2 as a therapeutic target for LN metastasis in BCa.

Authors

Changhao Chen, Yuming Luo, Wang He, Yue Zhao, Yao Kong, Hongwei Liu, Guangzheng Zhong, Yuting Li, Jun Li, Jian Huang, Rufu Chen, Tianxin Lin

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U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation
Koji Haratani, … , Masaaki Miyazawa, Kazuhiko Nakagawa
Koji Haratani, … , Masaaki Miyazawa, Kazuhiko Nakagawa
Published December 3, 2019; First published October 29, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI126598.
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U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

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Abstract

Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3–targeting (HER3–targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti–PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor–resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.

Authors

Koji Haratani, Kimio Yonesaka, Shiki Takamura, Osamu Maenishi, Ryoji Kato, Naoki Takegawa, Hisato Kawakami, Kaoru Tanaka, Hidetoshi Hayashi, Masayuki Takeda, Naoyuki Maeda, Takashi Kagari, Kenji Hirotani, Junji Tsurutani, Kazuto Nishio, Katsumi Doi, Masaaki Miyazawa, Kazuhiko Nakagawa

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Chronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signaling
Heather A. Himburg, … , Gary Schiller, John P. Chute
Heather A. Himburg, … , Gary Schiller, John P. Chute
Published December 3, 2019; First published October 15, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI129061.
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Chronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signaling

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Abstract

Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but the persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. We report that CML stem cells upregulate the expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL+ mice. Constitutive PTN deletion substantially reduced the numbers of CML stem cells capable of initiating CML in vivo. Hematopoietic cell–specific deletion of PTN suppressed CML development in BCR/ABL+ mice, suggesting that cell-autonomous PTN signaling was necessary for CML disease evolution. Mechanistically, PTN promoted CML stem cell survival and TKI resistance via induction of Jun and the unfolded protein response. Human CML cells were also dependent on cell-autonomous PTN signaling, and anti-PTN antibody suppressed human CML colony formation and CML repopulation in vivo. Our results suggest that targeted inhibition of PTN has therapeutic potential to eradicate CML stem cells.

Authors

Heather A. Himburg, Martina Roos, Tiancheng Fang, Yurun Zhang, Christina M. Termini, Lauren Schlussel, Mindy Kim, Amara Pang, Jenny Kan, Liman Zhao, Hyung Suh, Joshua P. Sasine, Gopal Sapparapu, Peter M. Bowers, Gary Schiller, John P. Chute

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Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils
Karim Mahiddine, … , Clifford A. Lowell, Adrian Erlebacher
Karim Mahiddine, … , Clifford A. Lowell, Adrian Erlebacher
Published December 3, 2019; First published October 10, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI130952.
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Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils

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Abstract

Polymorphonuclear neutrophils (PMNs) are increasingly recognized to influence solid tumor development, but why their effects are so context dependent and even frequently divergent remains poorly understood. Using an autochthonous mouse model of uterine cancer and the administration of respiratory hyperoxia as a means to improve tumor oxygenation, we provide in vivo evidence that hypoxia is a potent determinant of tumor-associated PMN phenotypes and direct PMN–tumor cell interactions. Upon relief of tumor hypoxia, PMNs were recruited less intensely to the tumor-bearing uterus, but the recruited cells much more effectively killed tumor cells, an activity our data moreover suggested was mediated via their production of NADPH oxidase–derived reactive oxygen species and MMP-9. Simultaneously, their ability to promote tumor cell proliferation, which appeared to be mediated via their production of neutrophil elastase, was rendered less effective. Relieving tumor hypoxia thus greatly improved net PMN-dependent tumor control, leading to a massive reduction in tumor burden. Remarkably, this outcome was T cell independent. Together, these findings identify key hypoxia-regulated molecular mechanisms through which PMNs directly induce tumor cell death and proliferation in vivo and suggest that the contrasting properties of PMNs in different tumor settings may in part reflect the effects of hypoxia on direct PMN–tumor cell interactions.

Authors

Karim Mahiddine, Adam Blaisdell, Stephany Ma, Amandine Créquer-Grandhomme, Clifford A. Lowell, Adrian Erlebacher

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Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy
Nikita S. Sharma, … , Ashok Saluja, Sulagna Banerjee
Nikita S. Sharma, … , Ashok Saluja, Sulagna Banerjee
Published December 3, 2019; First published October 15, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI127515.
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Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.

Authors

Nikita S. Sharma, Vineet K. Gupta, Vanessa T. Garrido, Roey Hadad, Brittany C. Durden, Kousik Kesh, Bhuwan Giri, Anthony Ferrantella, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee

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Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury
Wenjing Sun, … , Juan Peng, Andrea Tedeschi
Wenjing Sun, … , Juan Peng, Andrea Tedeschi
Published December 3, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI130391.
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Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury

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Abstract

Axon regeneration failure causes neurological deficits and long-term disability after spinal cord injury (SCI). Here, we found that the α2δ2 subunit of voltage-gated calcium channels negatively regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased α2δ2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI. In contrast, α2δ2 pharmacological blockade through gabapentin administration promoted corticospinal structural plasticity and regeneration in adulthood. Using an optogenetic strategy combined with in vivo electrophysiological recording, we demonstrated that regenerating corticospinal axons functionally integrate into spinal circuits. Mice administered gabapentin recovered upper extremity function after cervical SCI. Importantly, such recovery relies on reorganization of the corticospinal pathway, as chemogenetic silencing of injured corticospinal neurons transiently abrogated recovery. Thus, targeting α2δ2 with a clinically relevant treatment strategy aids repair of motor circuits after SCI.

Authors

Wenjing Sun, Molly J.E. Larson, Conrad M. Kiyoshi, Alexander J. Annett, William A. Stalker, Juan Peng, Andrea Tedeschi

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Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus
Seong Su Kang, … , David Weinshenker, Keqiang Ye
Seong Su Kang, … , David Weinshenker, Keqiang Ye
Published December 3, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI130513.
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Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus

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Abstract

Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer’s disease–like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase–cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD.

Authors

Seong Su Kang, Xia Liu, Eun Hee Ahn, Jie Xiang, Fredric P. Manfredsson, Xifei Yang, Hongbo R. Luo, L. Cameron Liles, David Weinshenker, Keqiang Ye

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GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections
Magdalena B. Flak, … , Francesco Palmas, Jesmond Dalli
Magdalena B. Flak, … , Francesco Palmas, Jesmond Dalli
Published December 3, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI131609.
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GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections

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Abstract

N-3 docosapentaenoic acid–derived resolvin D5 (RvD5n-3 DPA) is diurnally regulated in peripheral blood and exerts tissue-protective actions during inflammatory arthritis. Here, using an orphan GPCR screening approach coupled with functional readouts, we investigated the receptor(s) involved in mediating the leukocyte-directed actions of RvD5n-3 DPA and identified GPR101 as the top candidate. RvD5n-3 DPA bound to GPR101 with high selectivity and stereospecificity, as demonstrated by a calculated KD of approximately 6.9 nM. In macrophages, GPR101 knockdown limited the ability of RvD5n-3 DPA to upregulate cyclic adenosine monophosphate, phagocytosis of bacteria, and efferocytosis. Inhibition of this receptor in mouse and human leukocytes abrogated the pro-resolving actions of RvD5n-3 DPA, including the regulation of bacterial phagocytosis in neutrophils. Knockdown of the receptor in vivo reversed the protective actions of RvD5n-3 DPA in limiting joint and gut inflammation during inflammatory arthritis. Administration of RvD5n-3 DPA during E. coli–initiated inflammation regulated neutrophil trafficking to the site of inflammation, increased bacterial phagocytosis by neutrophils and macrophages, and accelerated the resolution of infectious inflammation. These in vivo protective actions of RvD5n-3 DPA were limited when Gpr101 was knocked down. Together, our findings demonstrate a fundamental role for GPR101 in mediating the leukocyte-directed actions of RvD5n-3 DPA.

Authors

Magdalena B. Flak, Duco S. Koenis, Agua Sobrino, James Smith, Kimberly Pistorius, Francesco Palmas, Jesmond Dalli

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Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy
Catherine E. Willoughby, … , Anderson J. Ryan, Stephen R. Wedge
Catherine E. Willoughby, … , Anderson J. Ryan, Stephen R. Wedge
Published November 25, 2019; First published October 3, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI127483.
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Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy

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Abstract

Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.

Authors

Catherine E. Willoughby, Yanyan Jiang, Huw D. Thomas, Elaine Willmore, Suzanne Kyle, Anita Wittner, Nicole Phillips, Yan Zhao, Susan J. Tudhope, Lisa Prendergast, Gesa Junge, Luiza Madia Lourenco, M. Raymond V. Finlay, Paul Turner, Joanne M. Munck, Roger J. Griffin, Tommy Rennison, James Pickles, Celine Cano, David R. Newell, Helen L. Reeves, Anderson J. Ryan, Stephen R. Wedge

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Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity
Catriona A. Wagner, … , Denny Liggitt, Joan M. Goverman
Catriona A. Wagner, … , Denny Liggitt, Joan M. Goverman
Published November 25, 2019; First published October 1, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI132531.
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Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity

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Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS. Although CD4+ T cells are implicated in MS pathogenesis and have been the main focus of MS research using the animal model experimental autoimmune encephalomyelitis (EAE), substantial evidence from patients with MS points to a role for CD8+ T cells in disease pathogenesis. We previously showed that an MHC class I–restricted epitope of myelin basic protein (MBP) is presented in the CNS during CD4+ T cell–initiated EAE. Here, we investigated whether naive MBP-specific CD8+ T cells recruited to the CNS during CD4+ T cell–initiated EAE engaged in determinant spreading and influenced disease. We found that the MBP-specific CD8+ T cells exacerbated brain but not spinal cord inflammation. We show that a higher frequency of monocytes and monocyte-derived cells presented the MHC class I–restricted MBP ligand in the brain compared with the spinal cord. Infiltration of MBP-specific CD8+ T cells enhanced ROS production in the brain only in these cell types and only when the MBP-specific CD8+ T cells expressed Fas ligand (FasL). These results suggest that myelin-specific CD8+ T cells may contribute to disease pathogenesis via a FasL-dependent mechanism that preferentially promotes lesion formation in the brain.

Authors

Catriona A. Wagner, Pamela J. Roqué, Trevor R. Mileur, Denny Liggitt, Joan M. Goverman

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