SPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma

Ki Fong Man, Lei Zhou, Huajian Yu, Ka Hei Lam, Wei Cheng, Jun Yu, Terence K. Lee, Jing Ping Yun, Xin Yuan Guan, Ming Liu, Stephanie Ma

Research output: Journal article publicationJournal articleAcademic researchpeer-review

3 Citations (Scopus)


Tumor lineage plasticity, considered a hallmark of cancer, denotes the phenomenon in which tumor cells co-opt developmental pathways to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the underlying molecular events remain largely elusive. Our recent study identified CD133/Prom1 in hepatocellular carcinoma (HCC) tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. Here we show SPINK1 to strongly associate with CD133 + HCC, and tumor dedifferentiation. Enhanced transcriptional activity of SPINK1 is mediated by promoter binding of ELF3, which like CD133, is found to increase following 5-FU and cisplatin treatment; while targeted depletion of CD133 will reduce both ELF3 and SPINK1. Functionally, SPINK1 overexpression promotes tumor initiation, self-renewal, and chemoresistance by driving a deregulated EGFR-ERK-CDK4/6-E2F2 signaling axis to induce dedifferentiation of HCC cells into their ancestral lineages. Depleting SPINK1 function by neutralizing antibody treatment or in vivo lentivirus-mediated Spink1 knockdown dampens HCC cancer growth and their ability to resist chemotherapy. Targeting oncofetal SPINK1 may represent a promising therapeutic option for HCC treatment.

Original languageEnglish
Article number7863
JournalNature Communications
Publication statusPublished - 29 Nov 2023

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy


Dive into the research topics of 'SPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma'. Together they form a unique fingerprint.

Cite this