FER kinase governs invasive tumor growth through dynamic control of oncogenic growth factor receptor activity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1076893 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27983662_1.fastq.gz | Fastqsanger.gz | |||
| SRR27983662_2.fastq.gz | Fastqsanger.gz | |||
| SRR27983663_1.fastq.gz | Fastqsanger.gz | |||
| SRR27983663_2.fastq.gz | Fastqsanger.gz | |||
| SRR27983664_1.fastq.gz | Fastqsanger.gz |
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Project description:EGFR antagonism using monoclonal antibodies remains the only approved and targeted first line treatment option for non-resectable head and neck squamous cell carcinoma (HNSCC), yielding a modest 13% response rate. While it is clear that alternative growth factor receptor (GFR) signals govern refractory behavior towards EGFR antagonism, it remains unknown which upstream mechanisms control subcellular GFR activation. Here, we show that FER, a non-receptor tyrosine kinase, controls invasive tumor growth through dynamic GFR activation and recycling. Using patient derived organoid (PDO) models HNSCC we demonstrate that FER is essential for invasive growth in collagen extracellular matrix (ECM) networks. We show that inactivation of FER impairs growth factor dependent phosphorylation of EGFR-Y1068 and MET-Y1234/5. Additionally, FER controls ligand dependent endocytic recycling, and endocytic velocity, implying multifactorial functional regulation of proximal receptors during HNSCC invasion. Loss of function experiments using either genetic intervention or a FER PROteolysis-TArgeting Chimera (PROTAC) strategy in PDO-based xenograft mouse models, demonstrate that FER is essential for invasive growth and metastasis of HNSCC. Finally, we demonstrate direct clinical relevance by showing that FER expression levels correlate with poor survival in HNSCC patients. In sum, we conclude that FER is a master regulator of HNSCC invasive growth and metastasis, and nominate FER as a prominent candidate for targeted clinical intervention in HNSCC patients.
2024-03-31 | GSE255878 | GEO
Project description:Triple-Negative Breast Cancer (TNBC) is a poorly targetable cancer subtype that exhibits a high metastatic potential. To develop new intervention strategies, it is crucial to understand the mechanisms governing migratory and invasive features of TNBC cells. Previously it was shown that high expression of the non-receptor tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in high grade and basal breast cancer. Here, we show that FER controls proliferation and invasion of TNBC cells through the direct substrates MAPK1 and Dynactin 2 (DCTN2; Dynamitin). Our data demonstrate that FER regulates tumor cell proliferation through phosphorylation of MAPK1 on tyrosine 187, and recycling endosome function and subsequent invasion of breast cancer cells through tyrosine 6 residue (Y6) of DCTN2. We show that DCTN2-Y6 is essential for Dynein complex formation and the development of tubular recycling domains at the early endosome. By controlling this crucial step in endosomal recycling, FER drives and sustains adhesion and invasion of (triple negative) breast cancer cells. Our data provide clinical ramification by demonstrating that high grade and basal breast cancers expressing elevated FER levels are more susceptible to taxane-based chemotherapy interventions. In conclusion, our study links FER to kinase-dependent control of intracellular vesicular transport and tumor progression in breast cancer. Importantly, our results indicate that FER represents a predictive and functional biomarker in high grade basal breast cancers.
2022-04-15 | PXD021307 | Pride
Project description:To identify changes in gene expression in daf-16 mutants, we compared expression in fer-15 young adults to expression in fer-15(b26); daf-16(m26) young adults grown at 25?C. At Stanford University, four samples of fer-15 and five samples of fer-15; daf-16 animals were prepared. At the University of Colorado, seven samples of fer-15 and six samples of fer-15; daf-16 was prepared. Set of arrays that are part of repeated experiments Place of growth: At Stanford vs Colorado Genotype: mutant strains vs wt (N2) mixed stage; some expts are reverse dye (wt in channel 2) Biological Replicate Computed
2008-07-29 | E-GEOD-12167 | biostudies-arrayexpress
Project description:To identify changes in gene expression in daf-16 mutants, we compared expression in fer-15 young adults to expression in fer-15(b26); daf-16(m26) young adults grown at 25?C. At Stanford University, four samples of fer-15 and five samples of fer-15; daf-16 animals were prepared. At the University of Colorado, seven samples of fer-15 and six samples of fer-15; daf-16 was prepared. Set of arrays that are part of repeated experiments Place of growth: At Stanford vs Colorado Genotype: mutant strains vs wt (N2) mixed stage; some expts are reverse dye (wt in channel 2)
2008-07-29 | GSE12167 | GEO
Project description:To identify changes in gene expression in age-1 mutants, we compared expression in fer-15(b26) animals to expression in fer-15(b26); age-1(hx542) mutants. We prepared RNA from young adult fer-15(b26) mutants grown at 25?C (five samples prepared at Stanford University and six samples prepared at the University of Colorado) and young adult fer-15(b26); age-1(hx542) mutants (four samples at Stanford University and six samples at the University of Colorado). Set of arrays that are part of repeated experiments Place of growth: Stanford vs Colorado Genotype: mutant strains vs wt (N2) mixed stage; some expts are reverse dye Biological Replicate Computed
2008-07-29 | E-GEOD-12166 | biostudies-arrayexpress
Project description:To identify changes in gene expression in age-1 mutants, we compared expression in fer-15(b26) animals to expression in fer-15(b26); age-1(hx542) mutants. We prepared RNA from young adult fer-15(b26) mutants grown at 25?C (five samples prepared at Stanford University and six samples prepared at the University of Colorado) and young adult fer-15(b26); age-1(hx542) mutants (four samples at Stanford University and six samples at the University of Colorado). Set of arrays that are part of repeated experiments Place of growth: Stanford vs Colorado Genotype: mutant strains vs wt (N2) mixed stage; some expts are reverse dye
2008-07-29 | GSE12166 | GEO
Project description:Plants have evolved cell wall integrity signaling pathways to maintain cell wall homeostasis during rapid growth and in response to environmental stress. The cell wall leucine-rich repeat extensins LRX3/4/5, the RAPID ALKALINIZATION FACTOR (RALF) peptides RALF22/23, and FERONIA (FER) function as a module to regulate plant growth and salt stress responses via the sense of cell wall integrity. However, the intracellular signaling pathways that mediate the effects of the LRX3/4/5-RALF22/23-FER module are still largely unknown. Here, we report that jasmonic acid (JA), salicylic acid (SA), and abscisic acid (ABA) accumulate constitutively in lrx345 and fer mutants. Blocking JA pathway rescues the retarded growth phenotype of the lrx345 and fer-4 mutants, while disruption of ABA biosynthesis suppresses the salt-hypersensitivity of these mutants. Many salt stress-responsive genes display abnormal expression patterns in the lrx345 and fer-4 mutants, as well as in wild type plants treated with epigallocatechin gallate (EGCG), an inhibitor of pectin methylesterases, suggesting that the cell wall integrity is a critical factor that determines the expression of stress-responsive genes. Production of reactive oxygen species (ROS) is constitutively increased in the lrx345 and fer-4 mutants, and inhibition of ROS accumulation suppresses the salt-hypersensitivity of these mutants. Together, our results suggest that the LRX3/4/5-RALF22/23-FER module controls plant growth and salt stress responses by regulating hormonal homeostasis and ROS accumulation.
2021-07-15 | GSE136268 | GEO
Project description:The cotyledons of etiolated seedlings from terrestrial flowering plants must emerge from the soil surface, while roots must penetrate the soil to ensure plant survival. We show here that the soil emergence related transcription factor PHYTOCHROME-INTERACTING FACTOR 3 (PIF3) regulates root penetration via transducing external signals perceived by the receptor kinase FERONIA (FER) in Arabidopsis thaliana. The loss of FER function in the fer-4 mutant resulted in a severe defect in root penetration into hard soil or medium. Single-cell RNA-seq profiling of roots revealed a distinct cell clustering pattern, especially for root cap cells, and revealed PIF3 as a putative FER-regulated transcription factor. Biochemical, imaging, and genetic experiments confirmed that PIF3 is required for root soil penetration. Moreover, FER interacted with and stabilized PIF3, which then modulated the expression of mechanosensitive ion channels and the sloughing of outer cells in the root cap. We propose a novel mechanism of soil penetration by plant roots.
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Project description:Catharanthus roseus Receptor-Like Kinase 1-like (CrRLK1L) family proteins are considered as potential cell wall sensors in plants. CrRLK1L subfamily proteins harbor two extracellular malectin-like domains that may bind to cell wall polymers, and an intracellular kinase domain that transmits signals via the phosphorylation of intracellular substrates. In Arabidopsis, there are 17 CrRLK1L family members, among which FER is the most widely studied. A growing body of evidence support that FER not only regulates plant growth and development, such as root hair development, pavement cell morphogenesis, flowering, and fertilization, but also controls plant responses to biotic and abiotic stresses. To decipher molecular mechanisms underlying the FER-mediated regulation of plant growth and development, we performed an immunoprecipitation-mass spectrometry (IP-MS) assay using FER-GFP transgenic plants to search for FER-interacting proteins.
2024-08-30 | PXD047595 | Pride
Project description:In vertebrate muscle, loss of Dysferlin results in the activation of compensatory muscle gene expression, even at pre-pathological stages. We hypothesized that if C. elegans fer-1 is also expressed in muscle, then fer-1 mutant worms might also exhibit compensatory muscle gene expression. To test this hypothesis, we used Affymetrix microarrays to profile gene expression from synchronized wild type and fer-1 mutant adults. To improve the specificity of this approach, we profiled two well characterized loss-of-function fer-1 mutants (hc1ts and hc24ts) and considered genes that changed similarly in both mutants as fer-1-regulated transcripts.
2009-06-25 | GSE16753 | GEO