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 |
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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.
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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.
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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.
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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.
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