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Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages.

ABSTRACT: Glutamine synthetase (GS) generates glutamine from glutamate and controls the release of inflammatory mediators. In macrophages, GS activity, driven by IL10, associates to the acquisition of M2-like functions. Conditional deletion of GS in macrophages inhibits metastasis by boosting the formation of anti-tumor, M1-like, tumor-associated macrophages (TAMs). From this basis, we evaluated the pharmacological potential of GS inhibitors in targeting metastasis, identifying glufosinate as a specific human GS inhibitor. Glufosinate was tested in both cultured macrophages and on mice bearing metastatic lung, skin and breast cancer. We found that glufosinate rewires macrophages toward an M1-like phenotype both at the primary tumor and metastatic site, countering immunosuppression and promoting vessel sprouting. This was also accompanied to a reduction in cancer cell intravasation and extravasation, leading to synchronous and metachronous metastasis growth inhibition, but no effects on primary tumor growth. Glufosinate treatment was well-tolerated, without liver and brain toxicity, nor hematopoietic defects. These results identify GS as a druggable enzyme to rewire macrophage functions and highlight the potential of targeting metabolic checkpoints in macrophages to treat cancer metastasis.

SUBMITTER: Menga A

PROVIDER: S-EPMC7539200 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages.

Menga Alessio A Serra Marina M Todisco Simona S Riera-Domingo Carla C Ammarah Ummi U Ehling Manuel M Palmieri Erika M EM Di Noia Maria Antonietta MA Gissi Rosanna R Favia Maria M Pierri Ciro L CL Porporato Paolo E PE Castegna Alessandra A Mazzone Massimiliano M

EMBO molecular medicine 20200904 10

Glutamine synthetase (GS) generates glutamine from glutamate and controls the release of inflammatory mediators. In macrophages, GS activity, driven by IL10, associates to the acquisition of M2-like functions. Conditional deletion of GS in macrophages inhibits metastasis by boosting the formation of anti-tumor, M1-like, tumor-associated macrophages (TAMs). From this basis, we evaluated the pharmacological potential of GS inhibitors in targeting metastasis, identifying glufosinate as a specific h ...[more]

PMID: 32885605

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Project description:Background Contrast-enhanced ultrasound (CEUS) has proven valuable in diagnosing benign and malignant pancreatic diseases, but its value in evaluating hepatic metastasis remains to be further explored. This study investigated the relationship between CEUS features of pancreatic ductal adenocarcinoma (PDAC) and concomitant or recurrent liver metastases after treatment. Methods This retrospective study included 133 participants with PDAC who were diagnosed with pancreatic lesions with CEUS at Peking Union Medical College Hospital from January 2017 to November 2020. According to the CEUS classification methods in our center, all the pancreatic lesions were classified as either with rich or poor blood supply. Additionally, quantitative ultrasonographic parameters were measured in the center and periphery of all pancreatic lesions. CEUS modes and parameters of the different hepatic metastasis groups were compared. The diagnostic performance of CEUS was calculated for diagnosing synchronous and metachronous hepatic metastasis. Results The proportions of rich blood supply and poor blood supply were 46% (32/69) and 54% (37/69), respectively, in the no hepatic metastasis group; 42% (14/33) and 58% (19/33), respectively, in the metachronous hepatic metastasis (MHM) group; and 19% (6/31) and 81% (25/31), respectively, in the synchronous hepatic metastasis (SHM) group. The wash-in slope ratio (WIS ratio) between the center of the lesion and around the lesion and peak intensity ratio (PI ratio) between the center of the lesion and around the lesion had higher values in the negative hepatic metastasis group (P<0.05). In predicting synchronous and metachronous hepatic metastasis, the WIS ratio had the best diagnostic performance. The sensitivity (SEN), specificity (SPE), accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) were 81.8%, 95.7%, 91.2%, 90.0%, and 91.7%, respectively, for MHM; and 87.1%, 95.7%, 93.0%, 90.0%, and 94.3%, respectively, for SHM. Conclusions CEUS would be helpful in image surveillance for synchronous or metachronous hepatic metastasis of PDAC.

Project description:Purpose: Based on the one of the largest hepatocellular carcinoma (HCC) population with bone metastasis (BM) from the single center in Tianjin, China, the present study aimed to investigate the risk and survival of synchronous bone metastasis (sBM) and metachronous bone metastasis (mBM) in HCC, and to reveal characteristics and related factors of HCC patients with bone metastasis. Methods: HCC patients with bone metastasis between 2009 and 2017 from Tianjin Medical University Cancer Institute & Hospital, Tianjin, China, were involved. Chi-square test/ Fisher's exact test and Logistic regression were used to estimate the risk factors of bone metastasis in HCC. Kaplan-Meier method was used to estimate the survival of HCC patients, and the Log-rank test was used to analyze the survival of HCC patients. The prognostic factors of HCC patients with BM were identified via Kaplan-Meier method and multivariable COX regression model. Results: Among 4421 HCC patients, 128 patients with BM were identified. Of the 128 patients with BM, 77 patients (60.16%) were with sBM and 51 patients (39.84%) were with mBM. The incidence of sBM in HCC was 1.74% at initial diagnosis. The most common metastatic site of sBM was rib, followed by lumbar, thoracic, and sacral. The median latency time from HCC diagnosis to mBM was six months. The most common site of mBM was thoracic, followed by lumbar, sacral and rib. Alcohol-drinking history (P=0.027), numbers (P=0.023) and size (P=0.008) of intrahepatic tumor, lymph node metastasis (P<0.001), serum ALP (P=0.004) and HGB (P=0.004) level were found to be correlated with the occurrence of BM. The overall survival between non-BM and BM were statistically different (P=0.028). Conclusion: The incidence of sBM in HCC was 1.74% at initial diagnosis. The median latency time from HCC diagnosis to mBM was 6 months. The characteristics between occurrence and prognosis showed significant difference between sBM and mBM. Early identification of high-risk BM population was essential for the improvement of both quality of life and prognosis. The revealed related factors can potentially guide sBM and mBM identification and early diagnosis in HCC.

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Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages.

Publications

Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages.

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