ATM- and ATR-induced primary ciliogenesis promotes cisplatin resistance in pancreatic ductal adenocarcinoma

Yu Ying Chao, Bu Miin Huang, I. Chen Peng, Pei Rong Lee, Yi Shyun Lai, Wen Tai Chiu, Yi Syuan Lin, Shih Chieh Lin, Jung Hsuan Chang, Pai Sheng Chen, Shaw Jenq Tsai, Chia Yih Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. Here, we showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. Collectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR-mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.

Original languageEnglish
Pages (from-to)4487-4503
Number of pages17
JournalJournal of Cellular Physiology
Volume237
Issue number12
DOIs
Publication statusPublished - 2022 Dec

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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