A number of intrinsic and extrinsic regulators have now been demonstrated to play important roles in driving HCC tumor lineage plasticity, including PGC740, CLDN641, and the interplay of TGF-β and GDF-124, etc. Here, we report on the role of endogenous/secretory SPINK1 in inducing HCC to a more stem/progenitor state and making HCC cells resistant to chemotherapy. Here, SPINK1 is linked to hepatocellular carcinoma.