Ontology highlight
ABSTRACT:
PROVIDER: PRJEB65356 | ENA |
REPOSITORIES: ENA
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Project description:Oncogene inactivation induced senescence facilitates tumor relapse
| PRJEB78692 | ENA
Project description:Phenotypically, there is a heterogeneous response of cancer cells to chemotherapy or targeted therapy. While therapeutically much attention is focused on cell death, there is growing evidence suggesting that a subpopulation of cancer cells undergo therapy-induced senescence. Depending on the therapy, dose and timing, senescence may be a dominant phenotype over cell death. An integrated FACS approach identified two types of therapy-induced senescence in human melanoma cells, irreversible senescence induced by Aurora kinase inhibition vs. transient senescence induced by B-RAF kinase inhibition. Autophagy and ER stress response precede and are required for therapy-induced senescence in cancer cells, mirroring their functions in normal cells undergoing oncogene-induced senescence. Importantly, autophagy serves a survival pathway for senescent cancer cells. Antagonizing autophagy converts therapy-induced senescence into cell death but paradoxically promotes cell proliferation or quiescence. Our work calls for a rationale-based design of combination therapy for cancer treatment that should lead to a greater synergy. There are three or four replicates per treatment per time point.
2015-06-05 | E-GEOD-38466 | biostudies-arrayexpress
Project description:Phenotypically, there is a heterogeneous response of cancer cells to chemotherapy or targeted therapy. While therapeutically much attention is focused on cell death, there is growing evidence suggesting that a subpopulation of cancer cells undergo therapy-induced senescence. Depending on the therapy, dose and timing, senescence may be a dominant phenotype over cell death. An integrated FACS approach identified two types of therapy-induced senescence in human melanoma cells, irreversible senescence induced by Aurora kinase inhibition vs. transient senescence induced by B-RAF kinase inhibition. Autophagy and ER stress response precede and are required for therapy-induced senescence in cancer cells, mirroring their functions in normal cells undergoing oncogene-induced senescence. Importantly, autophagy serves a survival pathway for senescent cancer cells. Antagonizing autophagy converts therapy-induced senescence into cell death but paradoxically promotes cell proliferation or quiescence. Our work calls for a rationale-based design of combination therapy for cancer treatment that should lead to a greater synergy. There are three or four replicates per treatment per time point.
2016-09-01 | E-GEOD-50474 | biostudies-arrayexpress
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: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:Hypoxia is negatively associated with glioblastoma patient survival and contributes strongly to tumor resistance. Unfortunately novel anti-angiogenic therapy increases hypoxia and activates survival pathways in tumor cells leading to inevitable tumor relapse. Here we demonstrate that primary glioma cultures and cell lines depend on autophagy to survive severe hypoxia but also at normal oxygen levels. Positive regulators of autophagy are expressed at higher levels in tumor cells and induction in severe hypoxia is more prominent compared to normal brain cells. We demonstrate that autophagy is an essential/critical target for novel treatment in glioblastoma. We show ATG9A is induced by severe hypoxia and could be a novel player of the autophagic response in glioma cells. ATG9A targeting inhibited tumor growth, suggesting an essential role in glioma cell survival in vivo. While autophagy induction was also observed in normal astrocytes, glioma cells displayed a higher sensitivity towards autophagy inhibitors. Importantly, patient-derived cultures exhibited varying sensitivity towards anti-autophagy treatment, where certain cultures were dependent on autophagy already in normoxic conditions. The treatment of tumor bearing mice with the autophagy inhibitor chloroquine significantly increased mice survival, but combination treatment of the agent with bevacizumab did not reveal additive or synergistic effect. The present study demonstrates that inhibition of autophagy using chloroquine as a single agent provides a novel treatment strategy against glioblastoma. It remains to be seen whether autophagy inhibition will improve current standard of care treatment of newly diagnosed glioblastoma patients and whether more specific inhibitors will lead to stronger therapeutic outcome. (Provisional)
2015-11-10 | E-MTAB-3085 | biostudies-arrayexpress
Project description:Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I) bound peptides, but this selection pressure favors outgrowth of MHC-I deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell-mediated killing of MHC-I deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-I deficient tumor cells to apoptosis by T cell-derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified pro-apoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFNg and TNFa-producing T cells. Tumors with a substantial population of MHC-I deficient cancer cells could be controlled by T cells when both pathways were targeted using genetic or pharmacological approaches.
2022-09-13 | GSE213078 | GEO
Project description:Gain-of-function mutation of PIK3CA represents one of the most common oncogenic events in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing PIK3CA-H1047R. Surprisingly, the majority of mammary tumors induced by PIK3CA-H1047R expression recurred following PIK3CA-H1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including spontaneous focal amplification of c-Met or c-Myc. While amplification of c-Met allowed tumor survival dependent on activation of endogenous PI3K, tumors with amplification of c-Myc become independent of the PI3K pathway. Functional analyses further demonstrated that c-Myc contributed to tumors’ independence of oncogene and resistance to PI3K inhibition. Together, our data suggest that MYC elevation in tumors may be a potential mechanism conferring resistance to current PI3K-targeted therapies. Affymetrix SNP array analysis was performed with Mouse Diversity Genotyping Arrays (Affymetrix) on genomic DNA extracted from frozen biopsies of 6 recurrent mouse mammary tumor samples. Copy number analysis was performed for the mouse mammary tumors using genomic DNA from normal mammary tissue as the reference for copy number inference.
2011-08-01 | E-GEOD-27691 | biostudies-arrayexpress
Project description:Gain-of-function mutation of PIK3CA represents one of the most common oncogenic events in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing PIK3CA-H1047R. Surprisingly, the majority of mammary tumors induced by PIK3CA-H1047R expression recurred following PIK3CA-H1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including spontaneous focal amplification of c-Met or c-Myc. While amplification of c-Met allowed tumor survival dependent on activation of endogenous PI3K, tumors with amplification of c-Myc become independent of the PI3K pathway. Functional analyses further demonstrated that c-Myc contributed to tumors’ independence of oncogene and resistance to PI3K inhibition. Together, our data suggest that MYC elevation in tumors may be a potential mechanism conferring resistance to current PI3K-targeted therapies.
2011-08-02 | GSE27691 | GEO
Project description:Accumulating evidence supports the role of the DNA damage response (DDR) in the negative regulation of tumorigenesis. Previous data show that inactivation of WIP1 phosphatase, as a means of activating DDR signaling, delays tumor onset in multiple mouse models. Unexpectedly, we found that targeting WIP1 also accelerates tumor relapse. Through chromatin remodeling, DDR signaling poises the reactivation of early pluripotency genes, including OCT4A, contributing to tumor relapse. Redistribution of DNMT3B to heterochromatic sequences appears to be a key initiating event in DDR-dependent OCT4 locus reactivation. However, full reactivation requires the presence of a driving oncogene such as Myc and macroH2A downregulation, both of which are commonly present in advanced human cancers. Using genetic lineage tracing experiments, we further showed that Oct4a-expressing cells contributed to tumor relapse. Furthermore, conditional deletion of Oct4a was sufficient to significantly delay the relapse of myc-driven B-cell lymphomas. Here, we have uncovered an unexpected tumor-promoting role of DDR signaling in enforcing oncogene-induced tumor relapse by poising cancer cell reprogramming into a stemness-like state. Our data support a model in which clonal evolution serves as an alternative organizational structure of certain tumors, such that nearly any cancer cell may acquire novel epigenetic traits to facilitate tumor relapse without necessarily committing to a Cancer Stem Cell model.
2019-06-13 | GSE99796 | GEO