Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment

Sun, Xia; Jia, Lizhou; Wang, Tengqi; Zhang, Yulian; Zhao, Wei; Wang, Xiangcheng; Chen, Hao

doi:10.7150/jca.57711

Cited by 17 publications

(8 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In non-small cell lung cancer (NSCLC) cells, treatment with cisplatin induced TROP2 expression accompanied by chemoresistance due to an upregulation of the MAPK signaling pathway [ 33 ]. Moreover, EGFR-mutated NSCLC cells with high TROP2 expression developed more rapid resistance to gefitinib therapy through the interaction of TROP2 with insulin-like growth factor 2 receptor (IGF2R), the induction of AKT, and the remodeling of the tumor microenvironment [ 34 ]. The latter observation is probably related to the fact that TROP2 expression in cancer cells is a predictor of a response to treatment with AKT inhibitors [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial–Mesenchymal Transition and Invasiveness

Švec

Šťastná

Janečková

et al. 2022

Cancers

View full text Add to dashboard Cite

Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with a poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions, and its expression is maintained in most colorectal cancers (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor-suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with the transcription of genes involved in epithelial–mesenchymal transition, the regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by the Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.

show abstract

Section: Introductionmentioning

confidence: 99%

TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial–Mesenchymal Transition and Invasiveness

Švec

Šťastná

Janečková

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…The insulin-like growth factor 2 receptor (IGF2R) was found to be located in the MET nanoenvironment, and co-IP demonstrated the indirect interaction between IGF2R and MET (Figure S11). IGF2R contributes to tumor angiogenesis and drug resistance; it is an unfavorable prognostic protein marker. − The correlation between IGF2R and MET provides a new perspective for the study of IGF2R in promoting tumor mechanisms.…”

Section: Resultsmentioning

confidence: 99%

Selective and Nongenetic Peroxidase Tag of Membrane Protein: a Nucleic Acid Tool for Proximity Labeling

Yang

Huang

et al. 2021

Anal. Chem.

View full text Add to dashboard Cite

The protein nanoenvironment on the plasma membrane is intimately linked to cellular biological functions. Elucidation of the protein nanoenvironment contributes to understanding the pathological mechanism and discovery of disease biomarkers. However, methods enabling characterization of the protein nanoenvironment in the endogenous biological environment have been rarely developed. Toward this end, we created a nucleic acid tool called Apt-Gq/h for proximity labeling to decipher the endogenous protein nanoenvironment. Here, the aptamer acts as an anchor for binding the protein of interest (POI). The G-quadruplex/hemin complex induces proximity labeling of POI via catalyzing the conversion of inert small-molecule substrates into short-lived reactive species. The labeled proteins enable the subsequent affinity-based enrichment and proteomic analysis. We first characterized Apt-Gq/h-mediated POI labeling in vitro and tested its utility by interrogating the protein nanoenvironment of POI in living cells. Taking advantage of the nongenetic, multiple reaction sites, and rapid proximity labeling, Apt-Gq/h was further utilized to imaging the cell–cell connection and amplification detection of biomarkers in living cells and tissue sections. We believe that Apt-Gq/h will be a potential tool for basic science and clinical applications.

show abstract

“…Chen et al. reported that Trop2 binding to IGF2R upregulated the IGF2-IGF1R-Akt axis to enhance resistance to gefitinib and remodeling of the tumor microenvironment in NSCLC ( 21 ). In our study, a significant correlation was observed between IGF2R expression and the stromal score, indicating a potential regulatory effect of IGF2R on the tumor microenvironment and LSCC progression.…”

Section: Discussionmentioning

confidence: 99%

Proteomics analysis of cancer tissues identifies IGF2R as a potential therapeutic target in laryngeal carcinoma

Liu

Wan

et al. 2022

Front. Endocrinol.

View full text Add to dashboard Cite

BackgroundLaryngeal cancer (LC) is a prevalent head and neck malignancy; however, the essential pathophysiological mechanism underlying its tumorigenesis and progression remains elusive. Due to the perduring scarcity of effective targeted drugs for laryngeal cancer, insights into the disease’s pathophysiological mechanisms would substantially impact the treatment landscape of laryngeal cancer.MethodsTo ensure quality consistency, 10 tumor and 9 non-tumor samples underwent proteomic analysis on a single mass spectrometer using a label-free technique. Subsequently, gene expression variations between laryngeal squamous cell carcinoma and normal tissues were analyzed using The Cancer Genome Atlas (TCGA) database. Immunohistochemical expressions of insulin-like growth factor 2 receptor (IGF2R), fibronectin (FN), vimentin, and α-smooth muscle actin (SMA) in LC tissues and normal tissues were determined.ResultsIn the tumor group, significant variations were detected for 433 upregulated and 61 downregulated proteins. Moreover, the heatmap revealed that the expressions of RNA translation-related proteins and proteins involved in RNA metabolism, such as IGF2R, tenascin C (TNC), periostin (POSTN), proteasome 26S subunit ATPase 4 (PSMC4), serpin family A member 3 (SERPINA3), heat shock protein family B (small) member 6 (HSPB6), osteoglycin (OGN), chaperonin containing TCP1 subunit 6A (CCT6A), and chaperonin containing TCP1 subunit 6B (CCT6B), were prominently elevated in the tumor group. Nonsense-mediated RNA decay (NMD), RNA translation, and protein stability were significantly altered in LC tumors. IGF2R was remarkably upregulated in LC tumors. In the TCGA database, the IGF2R mRNA level was significantly upregulated in LSCC tissues. Additionally, IGF2R mRNA expression was lowest in clinical grade 1 samples, with no significant difference between grades 2 and 3. In LSCC patients, a significant positive correlation between IGF2R expression and the stromal score was detected using the ESTIMATE algorithm to estimate the immune score, stromal score, and tumor purity in the tumor microenvironment. Lastly, immunohistochemical analysis revealed that IGF2R is overexpressed in LC.ConclusionThese results demonstrate the vital role of IGF2R in LC carcinogenesis and progression and may facilitate the identification of new therapeutic targets for the prevention and treatment of LC.

show abstract

Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment

Cited by 17 publications

References 31 publications

TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial–Mesenchymal Transition and Invasiveness

TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial–Mesenchymal Transition and Invasiveness

Selective and Nongenetic Peroxidase Tag of Membrane Protein: a Nucleic Acid Tool for Proximity Labeling

Proteomics analysis of cancer tissues identifies IGF2R as a potential therapeutic target in laryngeal carcinoma

Contact Info

Product

Resources

About