Developing a differentiation-inducing therapeutic strategy for sarcomatoid renal cell carcinoma

Herein, based on the co-progenitor cell theory and the potential plasticity of sarcomatoid dedifferentiation, we developed a differentiation-inducing therapeutic strategy and identified PLOD2 as a potential intervention target by multi-omics screening.

We demonstrated that PLOD2 is significantly upregulated in the sarcomatoid component of sRCC patients compared to the adjacent normal and neighboring epithelioid counterparts, functionally driving sarcomatoid dedifferentiation through concomitant activation of cancer stemness, dedifferentiation, and EMT, and correlating with higher tumor grade, metastasis, and poorer patient survival. Depletion of PLOD2 in sRCC cells resulted in efficient epithelioid differentiation, tumor suppression and sensitization to conventional RCC therapies of doxorubicin, gemcitabine, IFN-α and VEGFR-TKI.