PXD035100-1

PXD035100 is an original dataset announced via ProteomeXchange.

Title	ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression
Description	Anaplastic lymphoma kinase (ALK) fusion variants in non-small-cell-lung cancer (NSCLC) consist of numerous dimerising fusion partners, with the most common being EML4. Clinical data suggests that the degree of treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs among the variant present in the patient tumor. Therefore, a better understanding the oncogenic signaling networks driven by different ALK-fusion variants is important. Here, we developed highly controlled doxycycline-inducible cell models bearing four different ALK fusion proteins, namely EML4-ALK-V1, EML4-ALK-V3, KIF5B-ALK, and TFG-ALK, in the context of non-tumorigenic NL20 human bronchial epithelial cells. These were complimented by patient-derived NSCLC cell lines harboring either EML4-ALK-V1 or EML4-ALK-V3 fusions. RNAseq and phosphoproteomics analysis were employed to identify dysregulated genes and hyper/hypo-phosphorylated proteins associated with ALK fusion expression. Among ALK fusion induced responses, we noted a robust inflammatory signature that included up-regulation of the Serpin B4 serine protease inhibitor in both NL20-inducible cell models and ALK-positive NSCLC patient-derived cell lines. We show that STAT3 is a major transcriptional regulator of SERPINB4 downstream of ALK fusions, along with NF-B and AP1. The upregulation of SERPINB4 promotes survival of ALK fusion expressing cells and inhibits natural killer (NK) cell-mediated cytotoxicity. In conclusion, our study reveals a novel ALK downstream survival axis that regulates Serpin B4 expression and identifies a molecular target that has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.
HostingRepository	PRIDE
AnnounceDate	2023-02-16
AnnouncementXML	Submission_2023-02-16_01:30:36.392.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	JonatanGabre
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-06 02:36:04	ID requested
⏵ 1	2023-02-16 01:30:36	announced
2	2023-11-14 08:57:37	announced	2023-11-14: Updated project metadata.

submitter keyword: Human, NSCLCL, Orbitrap Fusion Lumos

BengtHallberg
contact affiliation	Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Sweden.
contact email	bengt.hallberg@gu.se
lab head
JonatanGabre
contact affiliation	University of Gothenburg, Gothenburg, Sweden University of Ghent, Ghent, Belgium
contact email	jonatan.gabre@gu.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035100
     1. Label: PRIDE project
     2. Name: ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression