Glioblastoma (GBM) remains among the deadliest of human malignancies, and the emergence of the cancer stem cell (CSC) phenotype represents a major challenge to durable treatment response. Because the environmental and lifestyle factors that impact CSC populations are not clear, we sought to understand the consequences of diet on CSC enrichment. We evaluated disease progression in mice fed an obesity-inducing high-fat diet (HFD) versus a low-fat, control diet. HFD resulted in hyper-aggressive disease accompanied by CSC enrichment and shortened survival. HFD drove intracerebral accumulation of saturated fats, which inhibited the production of the cysteine metabolite and gasotransmitter, hydrogen sulfide (H2S). H2S functions principally through protein S-sulfhydration and regulates multiple programs including bioenergetics and metabolism. Inhibition of H2S increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to death of cultured GBM cells and stasis of GBM tumors in vivo. Syngeneic GBM models and GBM patient specimens present an overall reduction in protein S-sulfhydration, primarily associated with proteins regulating cellular metabolism. These findings provide clear evidence that diet modifiable H2S signaling serves to suppress GBM by restricting metabolic fitness, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.
Daniel J. Silver, Gustavo A. Roversi, Nazmin Bithi, Sabrina Z. Wang, Katie M. Troike, Chase K.A. Neumann, Grace K. Ahuja, Ofer Reizes, J. Mark Brown, Christopher Hine, Justin D. Lathia
Macrophages deploy numerous strategies to combat invasion by microbes. One tactic is to restrict acquisition of diverse nutrients including trace metals, a process termed nutritional immunity. Intracellular pathogens adapt to a resource poor environment by marshalling mechanisms to harvest nutrients. Carbon acquisition is crucial for pathogen survival; compounds that reduce availability are a potential strategy to control intracellular replication. Treatment of macrophages with the glucose analog, 2-deoxy-D-glucose (2-DG), armed phagocytes to eliminate the intracellular fungal pathogen Histoplasma capsulatum in vitro and in vivo. Killing did not rely on altering access to carbon-containing molecules, or changes in ATP, ER stress, or autophagy. Unexpectedly, 2-DG undermined import of exogenous zinc into macrophages decreasing the quantity of cytosolic and phagosomal zinc. The fungus perished as a result of zinc starvation. This change in metal ingress was not ascribed to a defect in a single importer; rather, there was a collective impairment in transporter activity. This undescribed effect promotes the antifungal machinery of macrophages and expands the complexity of 2-DG activities far beyond manipulating glycolysis. Mechanistic metabolic studies employing 2-DG will have to consider its effect on zinc transport. Our preclinical data support consideration of this agent as a possible adjunctive therapy for histoplasmosis.
Diego C.P. Rossi, Julio A. Landero Figueroa, William R. Buesing, Kathleen Candor, Logan T. Blancett, Heather M. Evans, Rena Lenchitz, Bradford L. Crowther, Waleed Elsegeiny, Peter R. Williamson, Jan Rupp, George S. Deepe Jr.
BACKGROUND. Molecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecular targeted therapies for progressive 131I-refractory PTC. METHODS. PTC samples from 106 pediatric patients (age: 4.3–19.8 years; 21 boys) who attended Seoul National University Hospital (January 1983–March 2020) were available for genomic profiling. Previous transcriptome data from 125 adult PTCs were used for comparison. RESULTS. Genetic drivers were found in 80 tumors; 31 with fusion oncogenes (RET in 21, ALK in 6, and NTRK1/3 in 4), 47 with point mutations (BRAFV600E in 41, TERTC228T in 2, and DICER1 variants in 5), and 2 with amplifications. Fusion-oncogene PTCs, predominantly detected in younger patients, presented with a more advanced stage and showed more recurrent or persistent disease than BRAFV600E PTCs, which were detected mostly in adolescents. Pediatric fusion PTCs (in those aged < 10 years) showed lower expression of thyroid differentiation genes, including SLC5A5, than adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion received fusion-targeted therapy; larotrectinib and selpercatinib decreased the tumor extent and restored radioiodine uptake. The girl with the CCDC6-RET fusion received 131I therapy combined with selpercatinib, leading to a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited growth and restored radioiodine avidity. CONCLUSIONS. In pediatric fusion-oncogene PTC cases with 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric PTC patients. FUNDING. The Ministry of Science, ICT & Future Planning (grant number NRF-2016R1A2B4012417 91 and 2019R1A2C2084332), the Ministry of Health & Welfare, Republic of Korea (grant number 92 H14C1277), the Ministry of Education (grant number 2020R1A6A1A03047972), and the Seoul 93 National University Hospital Research Fund (grant number 04-2015-0830).
Young Ah Lee, Hyunjung Lee, Sun-Wha Im, Young Shin Song, Do-Youn Oh, Hyoung Jin Kang, Jae-Kyung Won, Kyeong Cheon Jung, Dohee Kwon, Eun-Jae Chung, J. Hun Hah, Jin Chul Paeng, Ji-hoon Kim, Jaeyong Choi, Ok-Hee Kim, Ji Min Oh, Byeong-Cheol Ahn, Lori J. Wirth, Choong Ho Shin, Jong-Il Kim, Young Joo Park
Glioblastoma is a highly malignant and incurable brain tumor characterized by intrinsic and adaptive resistance to immunotherapies. However, how glioma cells induce tumor immunosuppression and escape immunosurveillance remains poorly understood. Here, we find upregulation of cancer-intrinsic Chitinase-3-like-1 (CHI3L1) signaling modulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Mechanistically, CHI3L1 binding with Galectin-3 (Gal3) selectively promotes TAM migration and infiltration with a protumor M2-like but not an antitumor M1-like phenotype in vitro and in vivo, governed by a transcriptional program of NFκB/CEBPβ in the CHI3L1/Gal3-PI3K/AKT/mTOR axis. Conversely, Galectin-3-binding protein (Gal3BP) negatively regulates this process by competing with Gal3 to bind CHI3L1. Administration of a Gal3BP mimetic peptide in syngeneic glioblastoma mouse models reverses immune suppression and attenuates tumor progression. These results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.
Apeng Chen, Yinan Jiang, Zhengwei Li, Lingxiang Wu, Ulises Santiago, Han Zou, Chunhui Cai, Vaibhav Sharma, Yongchang Guan, Lauren H. McCarl, Jie Ma, Yijen L. Wu, Joshua Michel, Yi Shi, Liza Konnikova, Nduka M. Amankulor, Pascal O. Zinn, Gary Kohanbash, Sameer Agnihotri, Songjian Lu, Xinghua Lu, Dandan Sun, George K. Gittes, Qianghu Wang, Xiangwei Xiao, Dean Yimlamai, Ian F. Pollack, Carlos J. Camacho, Baoli Hu
MHC-E, a non-classical MHC molecule, restricted CD8 T-cell responses have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E restricted CD8 T-cell responses in HIV infection however remains unknown. In this study, CD8 T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in-vitro assays, we observed HLA-E restricted T-cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immuno-dominant Gag-KF11 epitope in T-cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8 T-cell responses. KF11 presented via HLA-E in HIV infected cells was recognized by antigen specific CD8 T cells. Importantly, bulk CD8 T cells obtained from HIV infected individuals recognized infected cells via HLA-E presentation. Ex-vivo analyses at the epitope level showed a higher responder frequency of HLA-E restricted responses to KF11 compared to KL9. Taken together, our findings of HLA-E restricted HIV specific immune responses offer intriguing and possibly paradigm shifting insights into factors that contribute to the immuno-dominance of CD8 T-cell responses in HIV infection.
Anju Bansal, Mika N. Gehre, Kai Qin, Sarah Sterrett, Ayub Ali, Ying Dang, Sojan Abraham, Margaret C. Costanzo, Leon A. Venegas, Jianming Tang, N. Manjunath, Mark A. Brockman, Otto O. Yang, June Kan-Mitchell, Paul A. Goepfert
Unlike the better-studied aberrant epigenome in the tumor, the clinicopathologic impact of DNA methylation in the tumor microenvironment (TME), especially the contribution from cancer-associated fibroblast (CAF), remains elusive. CAFs exhibit profound patient-to-patient tumorigenic heterogeneity. We ask whether such heterogeneity may be exploited to quantify the level of TME malignancy or not. We developed a robust and efficient methylome/transcriptome co-analysis system for CAFs and paired normal fibroblasts (NFs) from non-small-cell lung cancer patients. We found 14,781 CpG sites of CAF/NF differential methylation, of which 3,707 sites showed higher methylation changes in ever-smokers than in non-smokers. Concomitant CAF/NF differential gene expression analysis pinpointed to a subset of 54 smoking-associated CpG sites with strong methylation-regulated gene expression. A methylation index that summarizes the beta-values of these CpGs was built for NF/CAF discrimination (MIND) with high sensitivity and specificity. The potential of MIND in detecting pre-malignancy across individual patients was shown. MIND succeeded in predicting tumor recurrence in multiple lung cancer cohorts without reliance on patient survival data, suggesting that the malignancy level of TME may be effectively graded by this index. Precision TME grading may provide additional pathological information to guide cancer prognosis and open up more options in personalized medicine.
Sheng-Fang Su, Hao Ho, Jia-Hua Li, Ming-Fang Wu, Hsu-Chieh Wang, Hsiang-Yuan Yeh, Shuenn-Wen Kuo, Huei-Wen Chen, Chao-Chi Ho, Ker-Chau Li
Depression is a neuropsychiatric disease associated with neuronal anomalies within specific brain regions. In the present study, we screened microRNA (miRNA) expression profiles in the dentate gyrus (DG) of hippocampus and found miR-26a-3p was markedly down-regulated in the rat model of depression, whereas up-regulation of miR-26a-3p within DG regions rescued the neuronal deterioration and depression-like phenotypes resulting from stress exposure, effects which appear to be mediated by the PTEN pathway. The knock-down of miR-26a-3p in DG regions of normal control rats induced depression-like behaviors, effects which were accompanied with an activation of PTEN-PI3K/Akt signaling pathway and neuronal deterioration via suppression of autophagy, impairments in synaptic plasticity and the promotion of neuronal apoptosis. In conclusion, these results suggested that a miR-26a-3p deficits within the hippocampal DG mediated the neuronal anomalies contributing to the display of depression-like behaviors. This miRNA may serve as a potential therapeutic target for the treatment of depression.
Ye Li, Cuiqin Fan, Liyan Wang, Tian Lan, Rui Gao, Wenjing Wang, Shu Yan Yu
Perineuronal nets (PNNs), a specialized form of extracellular matrix, are abnormal in the human brain of Rett syndrome (RTT). We previously reported that PNNs function to restrict synaptic plasticity in hippocampal area CA2, which is unusually resistant to long-term potentiation (LTP) and has been linked to social learning in mice. Here we reported that PNNs appear elevated in area CA2 of a human RTT hippocampus and that PNNs develop precociously and remain elevated in area CA2 of a mouse model of RTT (Mecp2-null). Further, we provided evidence that LTP could be induced at CA2 synapses prior to PNN maturation (postnatal day 8-11) in wildtype mice and that this window of plasticity was prematurely restricted at CA2 synapses in Mecp2-null mice. Degrading PNNs in Mecp2-null hippocampus was sufficient to rescue the premature disruption of CA2 plasticity. We identified several molecular targets that were altered in the developing Mecp2-null hippocampus that may explain aberrant PNNs and CA2 plasticity, and we discovered that CA2 PNNs are negatively regulated by neuronal activity. Collectively, our findings demonstrated that CA2 PNN development is regulated by Mecp2 and identified a novel window of hippocampal plasticity that is disrupted in a mouse model of RTT.
Kelly E. Carstens, Daniel J. Lustberg, Emma Shaughnessy, Katharine E. McCann, Georgia M. Alexander, Serena M. Dudek
Myeloid-derived suppressor cells (MDSC) are major negative regulators of immune responses in cancer and chronic infections. It remains unclear if regulation of MDSC activity at different conditions is controlled by similar mechanisms. We compared MDSC in mice with cancer and lymphocytic choriomeningitis virus (LCMV) infection. Chronic LCMV infection caused the development of monocytic - M-MDSC but did not induce polymorphonuclear - PMN-MDSC. In contrast, both MDSC populations were present in cancer models. An acquisition of immune suppressive activity by PMN-MDSC in cancer was controlled by IRE1α and ATF6 pathways of the endoplasmic reticulum (ER) stress response. Abrogation of PMN-MDSC activity by blockade of the ER stress response resulted in increase in tumor-specific immune response and reduced tumor progression. In contrast, the ER stress response was dispensable for suppressive activity of M-MDSC in cancer and LCMV infection. Acquisition of immune suppressive activity by M-MDSC in spleens was mediated by IFN-γ signaling. However, it was dispensable for suppressive activity of M-MDSC in tumor tissues. Suppressive activity of M-MDSC in tumors was retained due to the effect of IL-6 present at high concentrations in tumor site. These results demonstrate disease and population-specific mechanisms of MDSC accumulation and need for targeting of different pathways to achieve inactivation of these cells.
Evgenii N. Tcyganov, Shino Hanabuchi, Ayumi Hashimoto, David Campbell, Gozde Kar, Timothy W.F. Slidel, Corinne Cayatte, Aimee Landry, Fernanda Pilataxi, Susana Hayes, Brian Dougherty, Kristin C. Hicks, Kathy Mulgrew, Chih-Hang A. Tang, Chih-Chi A. Hu, Wei Guo, Sergei Grivennikov, Mohammed-Alkhatim A. Ali, Jean-Christophe Beltra, E. John Wherry, Yulia Nefedova, Dmitry I. Gabrilovich
The western pattern diet is rich not only in fat and calorie but also in phosphate. Negative impacts of excessive fat and calorie intake on health are widely accepted, whereas potential harms of excessive phosphate intake are poorly recognized. Here we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the functioning nephron number, circulating fibroblast growth factor-23 (FGF23), a hormone that increases phosphate excretion per nephron, was increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubular fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubular lumen, which damaged tubular cells through binding to Toll-like receptor-4 expressed on them. Persistent tubular damage induced interstitial fibrosis, reduced the nephron number, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, progression of chronic kidney disease (CKD) ensued when the serum FGF23 level exceeded 53 pg/mL. The present study identified the calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.
Kazuhiro Shiizaki, Asako Tsubouchi, Yutaka Miura, Kinya Seo, Takahiro Kuchimaru, Hirosaka Hayashi, Yoshitaka Iwazu, Marina Miura, Batpurev Battulga, Nobuhiko Ohno, Toru Hara, Rina Kunishige, Mamiko Masutani, Keita Negishi, Kazuomi Kario, Kazuhiko Kotani, Toshiyuki Yamada, Daisuke Nagata, Issei Komuro, Hiroshi Itoh, Hiroshi Kurosu, Masayuki Murata, Makoto Kuro-o
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