Pancreatic Tumor Microenvironment Maintains Tumor Growth through Nucleosides Secretion
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PROVIDER: PRJNA770663 | ENA |
REPOSITORIES: ENA
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Project description:MoS2 has found application in various biomedical fields, such as bioimaging and drug delivery. Nonetheless, utilizing MoS2 for anti-tumor therapy remains challenging, especially tumor immunotherapy. Macrophages, pivotal constituents of the tumor microenvironment, play a crucial role in driving tumor progression and chemoresistance. Modulating macrophages to reshape this microenvironment stands as a promising avenue for effective tumor treatment. In this study, we unveil a mechanism by which MoS2 induces the metamorphosis of macrophages from an M0 to an M1 phenotype, thus altering the tumor microenvironment. This transformation triggers pathways associated with inflammation within M1-type macrophages, leading to an upsurge in the expression of inflammatory molecules like IL1β. Macrophages activated by MoS2 exhibit a propensity to impede tumor cell proliferation. Through comprehensive RNA-sequencing analysis, we noted that MoS2 induces a greater enrichment of differentially expressed genes in the cytokine release pathway within macrophages. The excessive secretion of IL1β by MoS2-activated macrophages emerges as a pivotal catalyst, heightening ROS levels and decreasing GSH levels within tumor cells, ultimately culminating in ferroptosis. Therefore, we suggest MoS2 effectively reshapes the tumor microenvironment by steering macrophages toward releasing inflammatory molecules. The MoS2-triggered activation of macrophages, inducing the secretion of IL1β, emerges as a potent trigger for ferroptosis within tumor cells. Consequently, MoS2 holds substantial promise as an efficacious strategy for anti-tumor immunotherapy, achieved through the polarization of macrophages.
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Project description:Pancreatic tumor microenvironment confers highly malignant properties on pancreatic cancer cells
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is extraordinarily chemoresistant and the abundant stromal content of these tumors contributes to the ineffective treatment of this disease. While the genetic alterations of PDAC have been well characterized, the epigenetic pathways regulating PDAC remain, for the most part, elusive. Employing an in vivo shRNA screen targeting epigenetic regulators, we identified members of the BET family of chromatin adaptors as key regulators of PDAC cell growth and maintenance of the tumor stroma. BET family members contribute to PDAC cell growth by modulating the activity of two key transcriptional programs, MYC and GLI. Within the cancer cells, BET inhibition also results in down-regulation of a key mediator of the tumor microenvironment, SHH, corresponding to a decrease in the stromal content of tumors. Taken together, these results suggest that therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Total RNA was isolated from 4 untreated PDAC cell lines or those exposedto the BET bromodomain inhibibitor CPI203 (1.6 uM) or control DMSO for 5 and 10 hours
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Project description:Tumor associated macrophages (TAMs) are known to play a role in a multitude of processes that facilitate lung cancer growth, including the suppression of tumoricidal immune activation and the absorption of chemotherapeutics. Therefore, deciphering new therapies to reprogram TAMs towards an anti-tumor phenotype is at the cutting-edge of therapy development. The presence of iron-loaded macrophages has been associated with a better prognosis in lung cancer patients. Iron accumulation in macrophages stimulates pro-tumoricidal macrophage activity that triggers cytotoxic T-cell responses in the tumor microenvironment. In this study, we propose super-paramagnetic iron oxide nanoparticles (SPIONs) as a promising anti-lung cancer adjuvant therapy to reduce tumor cell growth. We used SPIONs to target iron to macrophages and observed that SPION-loaded macrophages reduced tumor cell growth due to the oxidative stress. Additionally, we found that SPIONs completely rewire the tumor microenvironment in mice towards an anti-tumor state and that in combination with crizotinib, a lung cancer targeted therapy, SPIONs show an additive effect in decelerating tumor growth
2024-04-18 | PXD040145 | Pride
Project description:Tumor-associated macrophages (TAMs) have emerged as prominent cells within the tumor microenvironment playing critical roles in extracellular matrix remodeling, tumor cell proliferation and invasion, angiogenesis, and metastasis. Cathepsin proteases, produced by tumor cells and TAMs, have been demonstrated to mediate these processes, but it still remains unclear how these typically lysosomal enzymes are capable of executing their functions in the extracellular space. Here we identify a novel interaction between STAT6 and STAT3 that potently upregulates cathepsin secretion in macrophages in response to TH2 cytokine stimulation. Systematic gene expression analyses reveal that the TH2 cytokine IL-4 synergizes with IL-6 or IL-10 to activate the IRE1α/ XBP1 axis of the unfolded protein response. Pharmacological inhibition of the IRE1α axis blunts cathepsin secretion in macrophages and blocks macrophage-mediated tumor cell invasion. Finally, we show that genetic ablation of either STAT6 or STAT3 signaling impairs tumor development and invasion. Thus, these findings demonstrate that TH2 cytokine-mediated STAT6 and STAT3 activation in macrophages promotes a professional secretory phenotype capable of enhancing tumor cell invasion in a cathepsin-dependent manner.
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