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

Abstract

Intratumor molecular heterogeneity of hepatocellular carcinoma (HCC) is partly attributed to the presence of cancer stem/progenitor cells (CSCs), which represents a root of tumor recurrence and chemoresistance. Tumor lineage plasticity is an emerging hallmark of cancer where tumor cells hijack developmental signaling pathways to gain cellular plasticity and evade therapeutic targeting. However, the underlying molecular events remain largely elusive.

Our recent study identified CD133/Prom1 in HCC tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. We also demonstrated CD133 to enrich following chemotherapy, while CD133/Prom1-depletion enhanced HCC tumors’ chemosensitivity. Unfortunately, CD133 is not specific to HCC, but is also expressed in normal regenerating liver. Identifying critical factors expressed specifically in liver CD133+ CSCs, but not in liver normal CD133+ stem/progenitor cells thus may offer new therapeutic opportunities overcoming chemoresistance in HCC.

Herein, we found Serine Protease Inhibitor Kazal-Type 1 (SPINK1) to be distinctly expressed in HCC CD133+ subpopulation but not in normal regenerating liver CD133+ cells. Expression of SPINK1 increased during early liver progenitor development, peaked during the premature hepatocyte stage, decreased during hepatocyte maturation and increased progressively from well-differentiated to poorly differentiated HCCs. Enhanced transcriptional activity of SPINK1 was mediated by promoter binding of the epithelial cell-specific transcription factor ELF3, which like CD133, were both increased following chemotherapy treatment. Consistently, targeted depletion of CD133 would reduce both ELF3 and SPINK1. Functionally, SPINK1 inhibition mitigated tumor initiation, self-renewal and chemoresistance. Mechanistically, secretory SPINK1 bound to EGFR activating ERK/Cyclin D1/E2F2 signaling to induce dedifferentiation of HCC cells into their ancestral lineages.

In sum, oncofetal protein SPINK1 drives CD133+ HCC towards a dedifferentiated progenitor lineage. Targeting SPINK1 may represent a novel therapeutic option for the treatment of HCC, aiming at the CD133+ CSC tumor roots and overcoming chemoresistance.