2. Academic Validation
  3. mRNA-Lipid Nanoparticle-Mediated Restoration of PTPN14 Exhibits Antitumor Effects by Overcoming Anoikis Resistance in Triple-Negative Breast Cancer

mRNA-Lipid Nanoparticle-Mediated Restoration of PTPN14 Exhibits Antitumor Effects by Overcoming Anoikis Resistance in Triple-Negative Breast Cancer

  • Adv Sci (Weinh). 2024 Aug;11(32):e2309988. doi: 10.1002/advs.202309988.
Wei Li 1 2,  Masha Huang 3,  Zhaoping Wu 4,  Yu Zhang 3,  Ying Cai 3,  Juncheng Su 5,  Jia Xia 6,  Fan Yang 7,  Desheng Xiao 8,  Wen Yang 3,  Yingjie Xu 3 9,  Zhaoqian Liu 1 2
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China.
  • 2 Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078, P. R. China.
  • 3 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
  • 4 Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China.
  • 5 Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China.
  • 6 Department of Nephrology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China.
  • 7 Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, 250011, P. R. China.
  • 8 Department of Pathology, School of Basic Medicine, Xiangya Hospital, Central South University, Changsha, 410013, P. R. China.
  • 9 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
PMID: 39189475 DOI: 10.1002/advs.202309988
Abstract

Triple-negative breast Cancer (TNBC) poses a challenging prognosis due to early metastasis driven by anoikis resistance. Identifying crucial regulators to overcome this resistance is vital for improving patient outcomes. In this study, a genome-wide CRISPR/Cas9 knockout screen in TNBC cells has identified tyrosine-protein Phosphatase nonreceptor type 14 (PTPN14) as a key regulator of anoikis resistance. PTPN14 expression has shown a progressive decrease from normal breast tissue to metastatic tumors. Overexpressing PTPN14 has induced anoikis and inhibited cell proliferation in TNBC cells, while normal human breast cells are unaffected. Mechanistically, PTPN14 is identified as a key factor in dephosphorylating breast Cancer antiestrogen resistance 3, a novel substrate, leading to the subsequent inhibition of PI3K/Akt and ERK signaling pathways. Local delivery of in vitro transcribed PTPN14 mRNA encapsulated by lipid nanoparticles in a TNBC mouse model has effectively inhibited tumor growth and metastasis, prolonging survival. The study underscores PTPN14 as a potential therapeutic target for metastatic TNBC, with the therapeutic strategy based on mRNA expression of PTPN14 demonstrating clinical application prospects in alleviating the burden of both primary tumors and metastatic disease.

Keywords

PTPN14; anoikis resistance; cancer therapy; mRNA therapeutics; triple‐negative breast cancer.

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