Behind the Indolent Facade: Uncovering the Molecular Features and Malignancy Potential in Lung Minimally Invasive Adenocarcinoma by Single‐Cell Transcriptomics

Zhang, Xin; Liang, Boxuan; Huang, Yuji; Meng, Hao; Li, Zhiming; Du, Jiaxin; Zhou, Lang; Zhong, Yizhou; Wang, Bo; Lin, Xi; Yu, Guangchuang; Chen, Xuewei; Lu, Weixiang; Chen, Zhe‐Sheng; Yang, Xingfen; Huang, Zhenlie

doi:10.1002/advs.202303753

Cited by 2 publications

(2 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IKE (30 mg/kg) and CDDP(6 mg/kg) were administered intraperitoneally every three days for six times. Tumor size was measured weekly using vernier calipers, and tumor volume was calculated as (length × width 2 )/2. Mice were euthanized 4 weeks after tumor cell inoculation.…”

Section: Methodsmentioning

confidence: 99%

“…Lung cancer represents the most prevalent malignancy and the primary cause of cancer-related mortality globally 1 . Non-small cell lung cancer (NSCLC) constitutes 82% of lung cancer cases 2 , with lung adenocarcinoma (LUAD) being the predominant subtype 3 . Despite current treatment modalities, the five-year survival rate of LUAD remains suboptimal 4 , 5 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Retinoic acid receptor alpha inhibits ferroptosis by promoting thioredoxin and protein phosphatase 1F in lung adenocarcinoma

Bian,

Shan,

Liang

et al. 2024

Commun Biol

View full text Add to dashboard Cite

Ferroptosis is a recently discovered form of cell death that plays an important role in tumor growth and holds promise as a target for antitumor therapy. However, evidence in the regulation of ferroptosis in lung adenocarcinoma (LUAD) remains elusive. Here, we show that retinoic acid receptor alpha (RARA) is upregulated with the treatment of ferroptosis inducers (FINs). Pharmacological activation of RARA increases the resistance of LUAD to ferroptosis according to cell viability and lipid peroxidation assays, while RARA inhibitor or knockdown (KD) does the opposite. Through transcriptome sequencing in RARA-KD cells and chromatin immunoprecipitation (CHIP)-Seq data, we identify thioredoxin (TXN) and protein phosphatase 1 F (PPM1F) as downstream targets of RARA, both of which inhibit ferroptosis. We confirm that RARA binds to the promotor region of TXN and PPM1F and promotes their transcription by CHIP-qPCR and dual-luciferase assays. Overexpression of TXN and PPM1F reverses the effects of RARA knockdown on ferroptosis in vitro and vivo. Clinically, RARA knockdown or inhibitor increases cells’ sensitivity to pemetrexed and cisplatin (CDDP). Immunohistochemistry (IHC) of LUAD from our cohort shows the same expression tendency of RARA and the downstream targets. Our study uncovers that RARA inhibits ferroptosis in LUAD by promoting TXN and PPM1F, and inhibiting RARA-TXN/PPM1F axis represents a promising strategy for improving the efficacy of FINs or chemotherapy in the treatment of LUAD patients.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Retinoic acid receptor alpha inhibits ferroptosis by promoting thioredoxin and protein phosphatase 1F in lung adenocarcinoma

Bian,

Shan,

Liang

et al. 2024

Commun Biol

View full text Add to dashboard Cite

show abstract

Granzyme K drives a newly-intentified pathway of complement activation

Donado,

Jonsson,

Theisen

et al. 2024

Preprint

View full text Add to dashboard Cite

Granzymes are a family of serine proteases mainly expressed by CD8+ T cells, natural killer cells, and innate-like lymphocytes. Although their major role is thought to be the induction of cell death in virally infected and tumor cells, accumulating evidence suggests some granzymes can regulate inflammation by acting on extracellular substrates. Recently, we found that the majority of tissue CD8+ T cells in rheumatoid arthritis (RA) synovium, inflammatory bowel disease and other inflamed organs express granzyme K (GZMK), a tryptase-like protease with poorly defined function. Here, we show that GZMK can activate the complement cascade by cleaving C2 and C4. The nascent C4b and C2a fragments form a C3 convertase that cleaves C3, allowing further assembly of a C5 convertase that cleaves C5. The resulting convertases trigger every major event in the complement cascade, generating the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. In RA synovium, GZMK is enriched in areas with abundant complement activation, and fibroblasts are the major producers of complement C2, C3, and C4 that serve as targets for GZMK-mediated complement activation. Our findings describe a previously unidentified pathway of complement activation that is entirely driven by lymphocyte-derived GZMK and proceeds independently of the classical, lectin, or alternative pathways. Given the widespread abundance of GZMK-expressing T cells in tissues in chronic inflammatory diseases and infection, GZMK-mediated complement activation is likely to be an important contributor to tissue inflammation in multiple disease contexts.

show abstract

Behind the Indolent Facade: Uncovering the Molecular Features and Malignancy Potential in Lung Minimally Invasive Adenocarcinoma by Single‐Cell Transcriptomics

Cited by 2 publications

References 56 publications

Retinoic acid receptor alpha inhibits ferroptosis by promoting thioredoxin and protein phosphatase 1F in lung adenocarcinoma

Retinoic acid receptor alpha inhibits ferroptosis by promoting thioredoxin and protein phosphatase 1F in lung adenocarcinoma

Granzyme K drives a newly-intentified pathway of complement activation

Contact Info

Product

Resources

About