Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo

Alyssa D. Merting, Dakota B. Poschel, Chunwan Lu, John D. Klement, Dafeng Yang, Honglin Li, Huidong Shi, Eric Chapdelaine, Mitzi Montgomery, Michael T. Redman, Natasha M. Savage, Asha Nayak-Kapoor, Kebin Liu

Research output: Contribution to journalArticlepeer-review

Abstract

A hallmark of human colorectal cancer is lost expression of FAS, the death receptor for FASL of cytotoxic T lymphocytes (CTLs). However, it is unknown whether restoring FAS expression alone is sufficient to suppress csolorectal-cancer development. The FAS promoter is hypermethylated and inversely correlated with FAS mRNA level in human colorectal carcinomas. Analysis of single-cell RNA-Seq datasets revealed that FAS is highly expressed in epithelial cells and immune cells but down-regulated in colon-tumor cells in human colorectal-cancer patients. Codon usage-optimized mouse and human FAS cDNA was designed, synthesized, and encapsulated into cationic lipid to formulate nanoparticle DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Overexpression of codon usage-optimized FAS in metastatic mouse colon-tumor cells enabled FASLinduced elimination of FAS+ tumor cells in vitro, suppressed colon tumor growth, and increased the survival of tumor-bearing mice in vivo. Overexpression of codon-optimized FAS-induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. DOTAP-Chol-mFAS therapy exhibited no significant liver toxicity. Our data determined that tumor-selective delivery of FAS DNA nanoparticles is sufficient for suppression of human colon tumor growth in vivo.

Original languageEnglish (US)
Article number361
JournalCancers
Volume14
Issue number2
DOIs
StatePublished - Jan 1 2022

Keywords

  • Cationic lipid nanopar
  • Colon cancer
  • Cytotoxic T lymphocyte
  • FAS
  • Metastasis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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