In-silico analysis of TMEM2 as a pancreatic adenocarcinoma and cancer-associated fibroblast biomarker, and functional characterization of NSC777201, for targeted drug development

Prateeti Srivastava ^1,2, Vijesh Kumar Yadav ^3,4, Tzu-Hao Chang ^2,5

¹The Program for Translational Medicine, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.
²Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.
³Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital New Taipei 23561, Taiwan.
⁴Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University Taipei 110, Taiwan.
⁵Clinical Big Data Research Center, Taipei Medical University Hospital Taipei 110, Taiwan.
⁶UPMC Hillman Cancer Center, University of Pittsburgh Pittsburgh, PA 15232, USA.
⁷Department of Pathology, University of Pittsburgh Pittsburgh, PA 15213, USA.
⁸Graduate Institute of Medical Sciences, National Defense Medical Center Taipei 114, Taiwan.
⁹The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.
¹⁰TMU Research Center of Cancer Translational Medicine, Taipei Medical University Taipei 110, Taiwan.
¹¹Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University Taipei 11031, Taiwan.
¹²Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.
¹³PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Academia Sinica Taipei 11031, Taiwan.
¹⁴School of Pharmacy, National Defense Medical Center Taipei 11490, Taiwan.
¹⁵PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University Taipei 11031, Taiwan.

⁰The Program for Translational Medicine, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.

American Journal of Cancer Research +

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July 15, 2024

View abstract on PubMed

Summary

This study identifies TMEM2 as a theragnostic biomarker in pancreatic cancer, influenced by cancer-associated fibroblasts and hyaluronic acid. The compound NSC777201 shows promise in targeting TMEM2 and reversing key pancreatic adenocarcinoma progression processes.

Area Of Science

Oncology
Cancer Biology
Molecular Therapeutics

Background

Pancreatic adenocarcinoma (PAAD) is a deadly cancer with a complex tumor microenvironment dominated by cancer-associated fibroblasts (CAFs).
CAFs alter the extracellular matrix through interactions with hyaluronic acid (HA) and hyaluronidase, processes critical for PAAD progression but not fully understood.
The therapeutic potential of targeting hyaluronidase in PAAD remains largely unexplored.

Purpose Of The Study

To investigate the interaction between CAFs, hyaluronidase, and hyaluronic acid in PAAD development.
To assess the efficacy of NSC777201, a novel anti-cancer compound targeting hyaluronidase, in PAAD.
To identify potential theragnostic biomarkers associated with CAF activity in PAAD.

Main Methods

Computational analysis of Gene Expression Omnibus (GEO) dataset GSE172096 comparing CAFs and normal fibroblasts.
In-house sequencing of PAAD cells treated with NSC777201 to identify differentially expressed genes (DEGs).
Validation of DEGs using TCGA-PAAD and Human Protein Atlas (HPA) databases, Ingenuity Pathway Analysis (IPA), molecular docking, and in vitro/in vivo studies.

Main Results

Identified 416 DEGs associated with CAFs and 570 DEGs with NSC777201 treatment, with nine overlapping DEGs.
Discovered transmembrane protein TMEM2 as a key DEG strongly correlated with FAP (CAF marker) and associated with higher-risk PAAD.
Demonstrated NSC777201 inhibits TMEM2 expression, regulates CAF cell senescence, and shows therapeutic potential in vitro and in vivo.

Conclusions

TMEM2 is identified as a theragnostic biomarker in PAAD, influenced by CAF activity and HA accumulation.
NSC777201 effectively targets TMEM2 and demonstrates significant potential in reversing critical PAAD progression processes.
NSC777201 represents a promising therapeutic agent for pancreatic adenocarcinoma.

Keywords:

CAFs NSC777201 Pancreatic adenocarcinoma transmembrane protein 2 (TMEM2) tumor microenvironment