scholarly journals Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marco Bolis ◽  
Daniela Bossi ◽  
Arianna Vallerga ◽  
Valentina Ceserani ◽  
Manuela Cavalli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Single Cell ◽  
Disease Progression ◽  
Macrophage Polarization ◽  
Driver Mutations ◽  
M2 Macrophage ◽  
Web Resource ◽  
Cancer Transcriptome ◽  
Genomic Studies

AbstractComprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in a qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory – reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided enabling the investigation of dynamic transcriptional perturbations linked to disease progression.

scholarly journals Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression.

2021 ◽  
Author(s):  
Marco Bolis ◽  
Daniela Bossi ◽  
Arianna Vallerga ◽  
Valentina Ceserani ◽  
Manuela Cavalli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Single Cell ◽  
Disease Progression ◽  
Macrophage Polarization ◽  
Driver Mutations ◽  
M2 Macrophage ◽  
Web Resource ◽  
Cancer Transcriptome ◽  
Genomic Studies

Abstract Comprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in an unprecedented qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory – reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided that enables the investigation of dynamic transcriptional perturbations linked to disease progression.

scholarly journals Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages

2020 ◽  
Vol 8 (1) ◽  
pp. e000489 ◽  
Author(s):  
Marta Di Martile ◽  
Valentina Farini ◽  
Francesca Maria Consonni ◽  
Daniela Trisciuoglio ◽  
Marianna Desideri ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Macrophage Polarization ◽  
Melanoma Cells ◽  
Response To Therapy ◽  
Major Constituent ◽  
M2 Macrophage ◽  
Tumor Associated Macrophages

BackgroundA bidirectional crosstalk between tumor cells and the surrounding microenvironment contributes to tumor progression and response to therapy. Our previous studies have demonstrated that bcl-2 affects melanoma progression and regulates the tumor microenvironment. The aim of this study was to evaluate whether bcl-2 expression in melanoma cells could influence tumor-promoting functions of tumor-associated macrophages, a major constituent of the tumor microenvironment that affects anticancer immunity favoring tumor progression.MethodsTHP-1 monocytic cells, monocyte-derived macrophages and melanoma cells expressing different levels of bcl-2 protein were used. ELISA, qRT-PCR and Western blot analyses were used to evaluate macrophage polarization markers and protein expression levels. Chromatin immunoprecipitation assay was performed to evaluate transcription factor recruitment at specific promoters. Boyden chamber was used for migration experiments. Cytofluorimetric and immunohistochemical analyses were carried out to evaluate infiltrating macrophages and T cells in melanoma specimens from patients or mice.ResultsHigher production of tumor-promoting and chemotactic factors, and M2-polarized activation was observed when macrophages were exposed to culture media from melanoma cells overexpressing bcl-2, while bcl-2 silencing in melanoma cells inhibited the M2 macrophage polarization. In agreement, the number of melanoma-infiltrating macrophages in vivo was increased, in parallel with a greater expression of bcl-2 in tumor cells. Tumor-derived interleukin-1β has been identified as the effector cytokine of bcl-2-dependent macrophage reprogramming, according to reduced tumor growth, decreased number of M2-polarized tumor-associated macrophages and increased number of infiltrating CD4+IFNγ+and CD8+IFNγ+effector T lymphocytes, which we observed in response to in vivo treatment with the IL-1 receptor antagonist kineret. Finally, in tumor specimens from patients with melanoma, high bcl-2 expression correlated with increased infiltration of M2-polarized CD163+macrophages, hence supporting the clinical relevance of the crosstalk between tumor cells and microenvironment.ConclusionsTaken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies.

scholarly journals BMP4 Induces M2 Macrophage Polarization and Favors Tumor Progression in Bladder Cancer

2017 ◽  
Vol 23 (23) ◽  
pp. 7388-7399 ◽  
Author(s):  
Víctor G. Martínez ◽  
Carolina Rubio ◽  
Mónica Martínez-Fernández ◽  
Cristina Segovia ◽  
Fernando López-Calderón ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Progression ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization

scholarly journals Human Prostate Cancer-Associated Macrophage Subtypes with Prognostic Potential Revealed by Single-cell Transcriptomics

2020 ◽  
Author(s):  
Joseph C Siefert ◽  
Bianca Cioni ◽  
Mauro J Muraro ◽  
Mohammed Alshalalfa ◽  
Judith Vivié ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Cell ◽  
Cancer Progression ◽  
Human Tumor ◽  
Tumour Microenvironment ◽  
Gene Signature ◽  
Human Prostate ◽  
M2 Macrophage ◽  
Human Prostate Cancer ◽  
Macrophage Subtypes

ABSTRACTMacrophages in the tumor microenvironment are causally linked with prostate cancer development and progression, yet little is known about their composition in neoplastic human tissue. By performing single cell transcriptomic analysis of human prostate cancer resident macrophages, three distinct populations were identified in the diseased prostate. Unexpectedly, macrophages isolated from the tumor-adjacent site of the prostatectomy specimen were identical to those from the tumorous site. Markers associated with canonical M1 and M2 macrophage phenotypes were identifiable, however these were not the main factors defining unique subtypes. The genes selectively associated with each macrophage cluster were used to develop a gene signature which was highly associated with both recurrence-free and metastasis-free survival. These results highlight the relevance of tissue-specific macrophage subtypes in the tumour microenvironment for prostate cancer progression and demonstrates the utility of profiling single-cell transcriptomics in human tumor samples as a strategy to design gene classifiers for patient prognostication.

Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer

2018 ◽  
Vol 399 (11) ◽  
pp. 1285-1295 ◽  
Author(s):  
Ling-li Zhang ◽  
Lian-feng Zhang ◽  
Yun-bo Shi
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Tumor Progression ◽  
Macrophage Polarization ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
Akt Inhibitor ◽  
Endogenous Expression ◽  
M2 Macrophage Polarization ◽  
Proliferation And Invasion

Abstract The paxillin and M2 macrophage are all involved in cell proliferation and tumor progression, and this study aims to explore the interaction between them in colon cancer and the role of paxillin in cancer progression. Expression of mRNAs and proteins was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, separately. Endogenous expression of genes was modulated by recombinant plasmids and cell transfection. The levels of cytokines were determined by enzyme-linked immunosorbent assay (ELISA). The cell viability, invasion and migration were detected using the MTT assay, the transwell assay and the wound-healing cell migration assay, respectively. A nude mouse model for human colon cancer was constructed for tumor orthotopic expression. Paxillin was up-regulated in tumor-associated macrophages (TAMs). Paxillin was up-regulated in process of M2 macrophage polarization. M2 macrophage polarization was inhibited with paxillin suppressed. Down-regulated paxillin inhibited cell proliferation and invasion in colon cancer through suppressing M2 macrophage polarization. PI3k/Akt inhibitor repressed M2 macrophage polarization through down-regulating paxillin. PI3k/Akt inhibitor inhibited the function of the macrophage in promoting cell proliferation and invasion of colon cancer through down-regulating paxillin. Down-regulated paxillin in macrophages inhibited tumor growth of colon cancer. With the PI3K/AKT pathway inhibited, down-regulated paxillin suppressed colon cancer cell proliferation and invasion by inhibiting the M2 macrophage polarization, thereby restraining the tumor progression.

scholarly journals Single-Cell Analysis Reveals Macrophage-Driven T Cell Dysfunction in Severe COVID-19 Patients

2020 ◽  
Author(s):  
Xiaoqing Liu ◽  
Airu Zhu ◽  
Jiangping He ◽  
Zhao Chen ◽  
Longqi Liu ◽  
...  
Keyword(s):  
T Cell ◽  
Pleural Effusion ◽  
Single Cell ◽  
Peripheral Blood ◽  
Macrophage Polarization ◽  
Immune Dysregulation ◽  
M2 Macrophage ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Mechanistic Investigation

The vastly spreading COVID-19 pneumonia is caused by SARS-CoV-2. Lymphopenia and cytokine levels are tightly associated with disease severity. However, virus-induced immune dysregulation at cellular and molecular levels remains largely undefined. Here, the leukocytes in the pleural effusion, sputum, and peripheral blood biopsies from severe and mild patients were analyzed at single-cell resolution. Drastic T cell hyperactivation accompanying elevated T cell exhaustion was observed, predominantly in pleural effusion. The mechanistic investigation identified a group of CD14+ monocytes and macrophages highly expressing CD163 and MRC1 in the biopsies from severe patients, suggesting M2 macrophage polarization. These M2-like cells exhibited up-regulated IL10, CCL18, APOE, CSF1 (M-CSF), and CCL2 signaling pathways. Further, SARS-CoV-2-specific T cells were observed in pleural effusion earlier than in peripheral blood. Together, our results suggest that severe SARS-CoV-2 infection causes immune dysregulation by inducing M2 polarization and subsequent T cell exhaustion. This study improves our understanding of COVID-19 pathogenesis.

Characteristics of Chinese patients with advanced prostate cancer: A muliticentre, non-interventional, observational, prospective, registry study of docetaxel.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 328-328
Author(s):  
Dalin He ◽  
Zhongquan Sun ◽  
Jianming Guo ◽  
Zhigen Zhang ◽  
Yuxi Shan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Disease Progression ◽  
Remission Rate ◽  
Eastern Cooperative Oncology Group ◽  
Specific Antigen ◽  
Chinese Patients ◽  
Second Line ◽  
Registry Study ◽  
First Line

328 Background: Prostate cancer (PC) is the second most frequently diagnosed malignancy in males worldwide, and stands in 7th place among malignancies in Chinese males. This study investigated the real-world treatment patterns of docetaxel as chemotherapy in patients with advanced PC in China. Methods: This was a multi-center, prospective, observational, non-interventional, product registry study. All patients with advanced PC who failed with previous endocrine therapies, were receiving docetaxel containing chemotherapy, and consented to participate in the study were eligible to be enrolled. Patients were followed-up 2 years, for the collection and analysis of data on docetaxel treatment mode, prostate specific antigen (PSA) remission rate, survival time, etc. Results: A total of 407 patients were enrolled from Aug 2011 through Jun 2014, with a mean Gleason score of 8.0 (SD: 1.11), and median PSA of 61.0 (range: 0.0 to 5000.0) ng/ml. 302 (74.2%) patients were classified as clinical stage IV. For Eastern Cooperative Oncology Group (ECOG) score, 145 (35.6%), 205 (50.4%), 48 (11.8%), patients had scores of 0, 1, 2, respectively. Metastasis to bone was present in 340 (83.5%) patients; metastasis to other organs (liver, lungs, adrenal glands, brain, etc.) was present in 57 (14.0%) patients. Last disease progression prior to enrolment was evidenced by tumor progression in 132 (32.4%) patients and by PSA elevation in 379 (93.1%) patients. 173 (43.0%) and 120 (29.9%) patients started docetaxel therapy after failure of the first line and second line endocrine therapies, respectively; 51 (12.7%) patients after failure of the third line or more endocrine therapies. Conclusions: This abstract presented characteristics of Chinese patients with advanced PC revealed by a Chinese PC study, which indicated Chinese patients were in later stage and higher risk compared with their western counterparts. The majority of patients started docetaxel therapy after failure of first line and second line endocrine therapies. PSA elevation and tumor progression were the 2 main causes that Urologists determined for disease progression. Clinical trial information: no registration number.

scholarly journals A balancing act: PHLPP2 fine tunes AKT activity and MYC stability in prostate cancer

2019 ◽  
Vol 218 (6) ◽  
pp. 1771-1772 ◽  
Author(s):  
Roxanne Toivanen ◽  
Luc Furic
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Disease Progression ◽  
Prostate Tumor ◽  
Pten Loss ◽  
Akt Activation ◽  
Cell Biol

PTEN loss stimulates prostate tumor progression by sustaining AKT activation. Nowak et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201902048) surprisingly show that the AKT-suppressing phosphatase PHLPP2 promotes disease progression in the context of dual PTEN and p53 loss by increasing MYC stability.

scholarly journals Musashi-1 Regulates MIF1-Mediated M2 Macrophage Polarization in Promoting Glioblastoma Progression

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1799
Author(s):  
Yi-Ping Yang ◽  
Chian-Shiu Chien ◽  
Aliaksandr A. Yarmishyn ◽  
Man-Sheung Chan ◽  
Andy Chi-Lung Lee ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Rna Binding ◽  
Macrophage Polarization ◽  
Tumor Model ◽  
M2 Macrophage ◽  
Current Standard ◽  
Biological Targets ◽  
Migration Capacity

Glioblastoma (GBM) is the most malignant brain tumor which is characterized by high proliferation and migration capacity. The poor survival rate has been attributed to limitations of the current standard therapies. The search for novel biological targets that can effectively hamper tumor progression remains extremely challenging. Previous studies indicated that tumor-associated macrophages (TAMs) are the abundant elements in the tumor microenvironment that are closely implicated in glioma progression and tumor pathogenesis. M2 type TAMs are immunosuppressive and promote GBM proliferation. RNA-binding protein Musashi-1 (MSI1) has recently been identified as a marker of neural stem/progenitor cells, and its high expression has been shown to correlate with the growth of GBM. Nevertheless, the relationship between MSI1 and TAMs in GBM is still unknown. Thus, in our present study, we aimed to investigate the molecular interplay between MSI1 and TAMs in contributing to GBM tumorigenesis. Our data revealed that the secretion of macrophage inhibitory factor 1 (MIF1) is significantly upregulated by MSI1 overexpression in vitro. Importantly, M2 surface markers of THP-1-derived macrophages were induced by recombinant MIF1 and reduced by using MIF1 inhibitor (S,R)-3-(4-hHydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1). Furthermore, GBM tumor model data suggested that the tumor growth, MIF1 expression and M2 macrophage population were significantly downregulated when MSI1 expression was silenced in vivo. Collectively, our findings identified a novel role of MSI1 in the secretion of MIF1 and the consequent polarization of macrophages into the M2 phenotype in promoting GBM tumor progression.

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