BICC1 drives pancreatic cancer stemness and chemoresistance by facilitating tryptophan metabolism

  • Sci Adv. 2024 Jun 21;10(25):eadj8650. doi: 10.1126/sciadv.adj8650.
Huizhi Sun  1 ,  Hui Li  1 ,  Yuqi Guan  1 ,  Yudong Yuan  1 ,  Chao Xu  1 ,  Danqi Fu  1 ,  Peng Xie  1 ,  Jianming Li  1 ,  Tiansuo Zhao  1 ,  Xiuchao Wang  1 ,  Yukuan Feng  1 ,  Hongwei Wang  1 ,  Song Gao  1 ,  Shengyu Yang  2 ,  Yi Shi  3 ,  Jing Liu  1  4 ,  Antao Chang  1 ,  Chongbiao Huang  1 ,  Jihui Hao  1
Affiliations
  • 1. Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China.
  • 2. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
  • 3. Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, P. R. China.
  • 4. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P. R. China.
PMID: 38896624 DOI: 10.1126/sciadv.adj8650
Abstract

Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic Cancer Stem Cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD+ synthesis and Oxidative Phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.

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