Context-dependent roles for autophagy in myeloid cells in tumor progression [Atg5_Pymt]
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ABSTRACT:
PROVIDER: PRJNA1129012 | ENA |
REPOSITORIES: ENA
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Project description:Autophagy is known to suppress tumor initiation by removing genotoxic stresses in normal cells. Conversely, autophagy is also known to support tumor progression by alleviating metabolic stresses in neoplastic cells. Centered on this pro-tumor role of autophagy, there have been many clinical trials to treat cancers through systemic blocking of autophagy. Such systemic inhibition affects both tumor cells and non-tumor cells, and the consequence of blocked autophagy in non-tumor cells in the context of tumor microenvironment is relatively understudied. Here, we examined the effect of autophagy-deficient myeloid cells on the progression of autophagy-competent tumors. We found that blocking autophagy only in myeloid cells modulated tumor progression markedly but such effects were context dependent. In a tumor implantation model, the growth of implanted tumor cells was substantially reduced in mice with autophagy-deficient myeloid cells; T cells infiltrated deeper into the tumors and were responsible for the reduced growth of the implanted tumor cells. In an oncogene-driven tumor induction model, however, tumors grew faster and metastasized more in mice with autophagy-deficient myeloid cells. These data demonstrate that the autophagy status of myeloid cells plays a critical role in tumor progression, promoting or suppressing tumor growth depending on the context of tumor-myeloid cell interactions. This study indicates that systemic use of autophagy inhibitors in cancer therapy may have differential effects on rates of tumor progression in patients due to effects on myeloid cells and that this warrants more targeted use of selective autophagy inhibitors in a cancer therapy in a clinical setting.
2024-07-02 | GSE270912 | GEO
Project description:Autophagy is known to suppress tumor initiation by removing genotoxic stresses in normal cells. Conversely, autophagy is also known to support tumor progression by alleviating metabolic stresses in neoplastic cells. Centered on this pro-tumor role of autophagy, there have been many clinical trials to treat cancers through systemic blocking of autophagy. Such systemic inhibition affects both tumor cells and non-tumor cells, and the consequence of blocked autophagy in non-tumor cells in the context of tumor microenvironment is relatively understudied. Here, we examined the effect of autophagy-deficient myeloid cells on the progression of autophagy-competent tumors. We found that blocking autophagy only in myeloid cells modulated tumor progression markedly but such effects were context dependent. In a tumor implantation model, the growth of implanted tumor cells was substantially reduced in mice with autophagy-deficient myeloid cells; T cells infiltrated deeper into the tumors and were responsible for the reduced growth of the implanted tumor cells. In an oncogene-driven tumor induction model, however, tumors grew faster and metastasized more in mice with autophagy-deficient myeloid cells. These data demonstrate that the autophagy status of myeloid cells plays a critical role in tumor progression, promoting or suppressing tumor growth depending on the context of tumor-myeloid cell interactions. This study indicates that systemic use of autophagy inhibitors in cancer therapy may have differential effects on rates of tumor progression in patients due to effects on myeloid cells and that this warrants more targeted use of selective autophagy inhibitors in a cancer therapy in a clinical setting.
2024-07-02 | GSE270910 | GEO
Project description:Context-dependent roles for autophagy in myeloid cells in tumor progression [Atg5_MC38]
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Project description:The clear role of autophagy in human inflammatory diseases such as Crohn’s disease was first identified by genome-wide association studies and subsequently dissected in multiple mechanistic studies. ATG16L1 has been particularly well studied in knockout and hypomorph settings as well as models recapitulating the Crohn’s disease-associated T300A polymorphism. Interestingly, ATG16L1 has a single homolog, ATG16L2, which is independently implicated in diseases including Crohn’s disease and systemic lupus erythematosus. However, the contribution of ATG16L2 to canonical autophagy pathways and other cellular functions is poorly understood.To better understand its role, we generate and analyze the first, to our knowledge, ATG16L2 knockout mouse. Our results show that ATG16L1 and ATG16L2 contribute very distinctly to autophagy and cellular ontogeny in myeloid, lymphoid and epithelial lineages. Dysregulation of any of these lineages could contribute to complex diseases like Crohn’s disease and systemic lupus erythematosus, highlighting the value of examining cell-specific effects. We also identify a novel genetic interaction between ATG16L2 and epithelial ATG16L1. These findings are discussed in the context of how these genes may contribute distinctly to human disease.
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Project description:To Study the role of mutant Braf V600E and ERK dependent phosphorylation of TFEB in regulation of autophagy and lysosome biogenesis in the context of melanoma growth and metastasis, we used whole geneome RNA-seq to study role TFEB mediated BRAFV600E autophagy regulation.
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Project description:Autophagy is associated with both survival and cell death in myeloid malignancies. Therefore, deciphering its role in different genetically defined subtypes of acute myeloid leukemia (AML) is critical. Activating mutations of the KIT receptor tyrosine kinase are frequently detected in core-binding factor AML and are associated with a greater risk of relapse. Herein, we report that basal autophagy was significantly increased by the KITD816V mutation in AML cells and contributed to support their cell proliferation and survival. Invalidation of the key autophagy protein Atg12 strongly reduced tumor burden and improved survival of immunocompromised NSG mice engrafted with KITD816V TF-1 cells. Downstream of KITD816V, STAT3, but not AKT or ERK pathways, was identified as a major regulator of autophagy. Accordingly, STAT3 pharmacological inhibition or downregulation inhibited autophagy and reduced tumor growth both in vitro and in vivo. Taken together, our results support the notion that targeting autophagy or STAT3 opens up an exploratory pathway for finding new therapeutic opportunities for patients with CBF-AML or others malignancies with KITD816V mutations.
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Project description:Macrophages are very plastic and play key roles in maintenance of tissue homeostasis. In cancer progression, macrophages also take parts through all the processes, from the initiation, progression, to the final tumor metastasis. Although energy deprivation and autophagy are widely used for cancer therapy, most of these strategies are not meant to target macrophages resulting in undesired effects and unsatisfactory outcomes for cancer immunotherapy. Herein, we developed a lanthanum nickel oxide (LNO) nanozyme that possesses phosphatase-like activity for ATP hydrolysis. Meanwhile, the autophagy of macrophages induced by LNO promotes the polarization of macrophages from M2-like macrophage (M2) to M1-like macrophage (M1) and reduces tumor-associated macrophages in tumor-bearing mice, exhibiting capability of killing tumor-associated macrophage and anti-tumor effect in vivo. Furthermore, pre-coating by myeloid cell membrane on the surface of LNO significantly enhanced antitumor immunity. Our findings demonstrate that phosphatase-like nanozyme, LNO can specifically induce macrophage autophagy that improves therapeutic efficacy and offers valuable strategies for cancer immunotherapy.
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Project description:N6-methyladenosine (m6A) serves as the most abundant mRNA modification within eukaryotes that is involved in autophagy and progression of non-small cell lung cancer (NSCLC). The role of the m6A demethylase FTO in NSCLC progression has recently received widespread attention. However, the mechanism of FTO-mediated autophagy regulation in NSCLC progression is unclear. In this study, we found that FTO was significantly up-regulated in NSCLC, and down-regulation of FTO blocked the growth, invasion and migration of NSCLC cells via autophagy induction. Importantly, SESN2 was involved in m6A regulation during autophagy in NSCLC cells. FTO deficiency prompted IGF2BP1 to interact with SESN2 mRNA, which led to an increase in SESN2 mRNA stability as well as enhanced SESN2 protein levels. However, FTO inhibited autophagic flux via down-regulation of SESN2, thereby promoting the growth, invasion and migration of NSCLC cells. Our findings uncovered that FTO-mediated autophagy inhibition promotes malignant progression of NSCLC via reduction of SESN2 mRNA stability, thus providing novel notions for the prevention and treatment of NSCLC.
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