Abstract:This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
“…Consistent with our previous findings ( 39 ), DKO mice developed pronounced liver metastasis at 7 months of age; IHC staining clearly showed the absence of pan-CK, highly expressed SYP, and Ki67 in the liver metastatic foci of DKO mice ( Figure 7E ), suggesting that they were NEPC cells derived from the prostate. Notably, TKO mice exhibited reduced liver metastasis compared with DKO mice ( Figure 7F ).…”
Section: Resultssupporting
confidence: 92%
“…Pbsn-Cre4 ; Rb1 fl/fl ; Trp53 fl/fl (DKO) mice and Adora2a fl/fl mice were crossed to obtain the Pbsn-Cre4 ; Rb1 fl/fl ; Trp53 fl/fl ; Adora2a fl/fl (TKO) line. The generation of the murine PCa organoids from these GEMMs were conducted as we previously reported ( 39 ). The male mice of C57BL/6J (6-to-8-week-old, male), BALB/c athymic nude mice (6-to-8-week-old, male), and FVB (6-to-8-week-old, male) mice were purchased from Shanghai SLAC Laboratory Animal Company.…”
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of
Adora2a
in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.
“…Consistent with our previous findings ( 39 ), DKO mice developed pronounced liver metastasis at 7 months of age; IHC staining clearly showed the absence of pan-CK, highly expressed SYP, and Ki67 in the liver metastatic foci of DKO mice ( Figure 7E ), suggesting that they were NEPC cells derived from the prostate. Notably, TKO mice exhibited reduced liver metastasis compared with DKO mice ( Figure 7F ).…”
Section: Resultssupporting
confidence: 92%
“…Pbsn-Cre4 ; Rb1 fl/fl ; Trp53 fl/fl (DKO) mice and Adora2a fl/fl mice were crossed to obtain the Pbsn-Cre4 ; Rb1 fl/fl ; Trp53 fl/fl ; Adora2a fl/fl (TKO) line. The generation of the murine PCa organoids from these GEMMs were conducted as we previously reported ( 39 ). The male mice of C57BL/6J (6-to-8-week-old, male), BALB/c athymic nude mice (6-to-8-week-old, male), and FVB (6-to-8-week-old, male) mice were purchased from Shanghai SLAC Laboratory Animal Company.…”
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of
Adora2a
in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.
“…Similar expression levels of CD4 on CD4+ T lymphocytes from different immune statuses were observed, consistent with previous reports. 2 , 41 , 42 Thus, the microwell MFI can indicate concentration variations in CD4+ T lymphocytes. Fig.…”
Systemic immune monitoring is a crucial clinical tool for disease early diagnosis, prognosis and treatment planning by quantitative analysis of immune cells. However, conventional immune monitoring using flow cytometry faces huge challenges in large-scale sample testing, especially in mass health screenings, because of time-consuming, technical-sensitive and high-cost features. However, the lack of high-performance detection platforms hinders the development of high-throughput immune monitoring technology. To address this bottleneck, we constructed a generally applicable DNA framework signal amplification platform (DSAP) based on post-systematic evolution of ligands by exponential enrichment and DNA tetrahedral framework-structured probe design to achieve high-sensitive detection for diverse immune cells, including CD4+, CD8+ T-lymphocytes, and monocytes (down to 1/100 μl). Based on this advanced detection platform, we present a novel high-throughput immune-cell phenotyping system, DSAP, achieving 30-min one-step immune-cell phenotyping without cell washing and subset analysis and showing comparable accuracy with flow cytometry while significantly reducing detection time and cost. As a proof-of-concept, DSAP demonstrates excellent diagnostic accuracy in immunodeficiency staging for 107 HIV patients (AUC > 0.97) within 30 min, which can be applied in HIV infection monitoring and screening. Therefore, we initially introduced promising DSAP to achieve high-throughput immune monitoring and open robust routes for point-of-care device development.
“…Organoids: The generation of tumor organoids derived from Pbsn-Cre4; Pten fl/fl ; Trp53 fl/fl and Pbsn-Cre4; Pten fl/fl ; Hi-Myc genetically engineered mice has been described previously. [40] Briefly, prostate tumors were harvested, minced, and digested in DMEM containing 0.2 mg mL −1 collagenase I (Sangon Biotech, A004194), 0.2 mg mL −1 collagenase IV (Sangon Biotech, A004186), 0.01 mg mL −1 Dnase I (STEMCELL Technologies, 0 7900), 0.1 mg mL −1 dispase (Sangon Biotech, A002100-0050) and 2% fetal bovine serum at 37 °C for 1.5 h. Then, cells were digested in 0.25% trypsin/EDTA (Sigma, T4049) for 5 min at 37 °C. Single cell suspension was obtained through a 40 μm cell strainer.…”
Section: Methodsmentioning
confidence: 99%
“…Pbsn‐Cre4 , Pten fl/fl , and Trp53 fl/fl mouse strains were obtained from JAX lab and crossed as previously reported. [ 40 ] Pbsn‐Cre4 ; Pten fl/fl ; Hi‐Myc mouse strains were crossed by Pbsn‐Cre4 , Pten fl/fl mice and Hi‐Myc mice which were provided by the NCI mouse repository. C57BL/6J mice were purchased from Shanghai Lingchang Biotechnology Co., Ltd. For the PCa organoid xenograft experiment, 300 organoids were orthotopically transplanted into prostates of 8‐week‐old C57BL/6J mice.…”
Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1𝜷 in TAMs. IL-1𝜷 induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1𝜷 antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1𝜷 is an important androgen-responsive immunotherapeutic target for advanced PCa.
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