Autophagic turnover of NBR1 restricts metastatic colonization during mammary tumor progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA510992 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8360420_1.fastq.gz | Fastqsanger.gz | |||
| SRR8360420_2.fastq.gz | Fastqsanger.gz | |||
| SRR8360421_1.fastq.gz | Fastqsanger.gz | |||
| SRR8360421_2.fastq.gz | Fastqsanger.gz | |||
| SRR8360422_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 22 |
Similar Datasets
Project description:Autophagy is implicated in promoting the metastatic potential of tumor cells. Utilizing a mouse model of mammary cancer to temporally delete essential autophagy regulators, ATG12 or ATG5, in tumor cells during distinct stages of carcinoma progression, we determine a stage-specific role for autophagy in suppressing metastatic colonization. In stark contrast to the tumor-promoting role of autophagy in primary mammary tumors, autophagy restricts colonization of disseminated tumor cells (DTCs) and prevents the acquisition of basal epithelial characteristics, effects that are dependent on turnover of the autophagy-specific substrate, Neighbor to BRCA1 (NBR1). Analysis of human breast cancer samples corroborates the importance of NBR1 in overall survival and metastasis, highlighting NBR1 as a potential therapeutic target in preventing DTCs from developing into overt, clinical disease.
2020-02-19 | GSE124209 | GEO
Project description:Although autophagy is being pursued as a therapeutic target in clinical oncology trials, its effects on metastasis, the principal cause of cancer mortality, remain unclear. Here, we utilize mammary cancer models to temporally delete essential autophagy regulators during carcinoma progression. Though genetic ablation of autophagy strongly attenuates primary mammary tumor growth, impaired autophagy promotes spontaneous metastasis and enables the outgrowth of disseminated tumor cells into overt macro-metastases. Transcriptomic analysis reveals that autophagy deficiency elicits a subpopulation of otherwise luminal tumor cells exhibiting basal differentiation traits, which is reversed upon preventing accumulation of the autophagy cargo receptor, Neighbor to BRCA1 (NBR1). Furthermore, pharmacological and genetic induction of autophagy suppresses pro-metastatic differentiation and metastatic outgrowth. Analysis of human breast cancer data reveal that autophagy gene expression inversely correlates with pro-metastatic differentiation signatures and predicts overall and distant metastasis-free survival. Overall, these findings highlight autophagy-dependent control of NBR1 as a key determinant of metastatic progression.
| S-EPMC7108946 | biostudies-literature
Project description:The turnover of cytoplasmic material via autophagic encapsulation and delivery to vacuoles is essential for recycling cellular constituents, especially under nutrient-limiting conditions. To determine how cells/tissues rely on autophagy, we applied in-depth multi-omic analyses to study maize (Zea mays) autophagy mutants grown under nitrogen-replete and starvation conditions. Surprisingly, broad alterations in the leaf metabolome were evident in plants missing the core autophagy component ATG12 even without stress, particularly affecting products of lipid turnover and secondary metabolites, which were underpinned by substantial changes in the transcriptome and/or proteome. Cross-comparison of mRNA and protein abundances allowed for the identification of organelles, protein complexes, and individual proteins targeted for selective autophagic clearance, and revealed several processes controlled by this catabolism. Collectively, we describe a facile proteomic strategy to survey autophagic substrates, and show that autophagy has a greater than expected influence in sculpting plant proteomes and membranes both before and during nitrogen stress.
2018-10-08 | PXD009627 | Pride
Project description:Less than 8% of patients diagnosed with pancreatic ductal adenocarcinomas (PDAC) survive more than five years in part due to late stage diagnosis. Approximately half of PDAC patients exhibit loss of SMAD4, which correlates with increased metastatic disease. Here we demonstrate that SMAD4 is a suppressor of metastatic colonization. Using isogenic human PDAC cell lines expressing or lacking SMAD4, both in vitro and in vivo, we define SMAD4-dependent gene expression changes in metastatic lesions. We performed a pooled in vivo open reading frame (ORF) screen of SMAD4 transcriptional targets and identified genes that, induce tumor seeding and growth at secondary sites. We found that expression of the transcription factor FOSL1 was sufficient to drive metastatic colonization. SMAD4 directly binds and represses the activity of the FOSL1 enhancer. These studies demonstrate a direct role for SMAD4 in regulating metastatic colonization and identify FOSL1 as a SMAD4-regulated gene involved in PDAC progression.
2021-08-02 | GSE148248 | GEO
Project description:During nutrient stress, macroautophagy is employed to degrade cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome. While the machinery responsible for initiation of macroautophagy is well characterized, our understanding of the extent to which individual proteins, protein complexes and organelles are selected for autophagic degradation, and the underlying targeting mechanisms is limited. Here, we use orthogonal proteomic strategies to provide a global molecular inventory of autophagic cargo during nutrient stress in mammalian cell lines. Through prioritization of autophagic cargo, we identify a heterodimeric pair of membrane-embedded proteins, YIPF3 and YIPF4, as receptors for Golgiphagy. During nutrient stress, YIPF4 is mobilized into ATG8-positive vesicles that traffic to lysosomes as measured via Golgiphagy flux reporters in a process that requires the VPS34 and ULK1-FIP200 arms of the autophagy system. Cells lacking YIPF3 or YIPF4 are selectively defective in elimination of Golgi membrane proteins during nutrient stress. By merging absolute protein abundance with autophagic turnover, we create a global protein census describing how autophagic degradation maps onto protein abundance and subcellular localization. Our results, available via an interactive web tool, reveal that autophagic turnover prioritizes membrane-bound organelles (principally Golgi and ER) for proteome remodeling during nutrient stress.
2023-09-06 | PXD038358 | Pride
Project description:During nutrient stress, macroautophagy is employed to degrade cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome. While the machinery responsible for initiation of macroautophagy is well characterized, our understanding of the extent to which individual proteins, protein complexes and organelles are selected for autophagic degradation, and the underlying targeting mechanisms is limited. Here, we use orthogonal proteomic strategies to provide a global molecular inventory of autophagic cargo during nutrient stress in mammalian cell lines. Through prioritization of autophagic cargo, we identify a heterodimeric pair of membrane-embedded proteins, YIPF3 and YIPF4, as receptors for Golgiphagy. During nutrient stress, YIPF4 is mobilized into ATG8-positive vesicles that traffic to lysosomes as measured via Golgiphagy flux reporters in a process that requires the VPS34 and ULK1-FIP200 arms of the autophagy system. Cells lacking YIPF3 or YIPF4 are selectively defective in elimination of Golgi membrane proteins during nutrient stress. By merging absolute protein abundance with autophagic turnover, we create a global protein census describing how autophagic degradation maps onto protein abundance and subcellular localization. Our results, available via an interactive web tool, reveal that autophagic turnover prioritizes membrane-bound organelles (principally Golgi and ER) for proteome remodeling during nutrient stress.
2023-09-13 | PXD043923 | Pride
Project description:Breast cancer (BC) remains the leading cause of cancer-related deaths among women, and the chances to develop it are duplicated by obesity. Still, the impact of obesity during BC progression remains less understood. We investigated the role of obesity in tumor progression using the murine model of 4T1 mammary carcinoma in BALB/c female mice, previously high-fat-diet (HFD) fed. HFD induced obesity, metabolic impairment, and high serum and fat leptin levels. After injection of 4T1-cells, HFD-mice accelerated tumor progression and metastasis. 4T1-cells found within HFD-mice metastatic niches presented higher clonogenic potential. 4T1-cells treated in vitro with fat-conditioned medium derived from HFD-mice, increased migration capacity through CXCL12 and CCL25 gradients. In HFD-mice, the infiltration and activation of immune cells into tumor-sentinel lymph nodes was overall reduced, except for activated CD4+ T cells expressing low CD25 levels. Within the bone marrow, the levels of haematopoiesis-related IL-6 and TNF-? decreased after 4T1-cells injection in HFD-mice whereas increased in the controls, suggesting that upregulation of both cytokines, regardless of the tumor, is disrupted by obesity. Finally, the expression of genes for leptin, CXCR4, and CCR9 (receptors of CXCL12 and CCL25, respectively) was negatively correlated with the infiltration of CD8 T cells in human triple-negative BC tumors from obese patients compared to non-obese. Together, our data present early evidence of systemic networks triggered by obesity that promote BC progression to the metastatic niches. Targeting these pathways might be useful to prevent the rapid BC progression observed among obese patients.
| S-EPMC6764084 | biostudies-literature
Project description:The turnover of cytoplasmic material via autophagic encapsulation and delivery to vacuoles is essential for recycling cellular constituents, especially under nutrient-limiting conditions. To determine how cells/tissues rely on autophagy, we applied in-depth multi-omic analyses to study maize (Zea mays) autophagy mutants grown after fixed carbon starvation. Surprisingly, broad alterations in the leaf metabolome were evident in plants missing the core autophagy component ATG12 even without stress, particularly affecting products of lipid turnover and secondary metabolites, which were underpinned by substantial changes in the transcriptome and/or proteome. Cross-comparison of mRNA and protein abundances allowed for the identification of organelles, protein complexes, and individual proteins targeted for selective autophagic clearance, and revealed several processes controlled by this catabolism. Fixed carbon starvation induced the proteins involved in alternative respiration together with the upregulation of various alternative catabolic processes. Collectively, we describe a facile proteomic strategy to survey autophagic substrates, and show that autophagy has a greater than expected influence in sculpting plant proteomes and membranes both before and during nitrogen stress.
2020-07-15 | PXD017077 | Pride
Project description:The experiment was design to address the intrinsic differences between metastatic cancer stem cells in the primary tumour and during metastatic colonization in the mouse mammary gland tumour model MMTV-pyMT.
2015-11-21 | GSE63558 | GEO
Project description:The experiment was design to address the intrinsic differences between metastatic cancer stem cells in the primary tumour and during metastatic colonization in the mouse mammary gland tumour model MMTV-pyMT. Total RNA was prepared from the indicated cancer cells freshly isolated, stained and FACS sorted either from primary tumours or from lungs upon intravenous injection of cancer cells.
2015-11-21 | E-GEOD-63558 | biostudies-arrayexpress