Targeting PLOD2 induces epithelioid differentiation and improves therapeutic response in sarcomatoid renal cell carcinoma

Introduction: Sarcomatoid renal cell carcinoma (sRCC), a lethal variant arising through sarcomatoid dedifferentiation of epithelioid RCC (eRCC), poses significant clinical challenges due to the lack of molecular biomarkers and limited therapeutic options, with a median survival time for patients of less than 12 months.

Objectives: To dissect the molecular basis of sarcomatoid dedifferentiation and develop novel therapeutic strategies for sRCC.

Methods: Guided by the coprogenitor theory and tumor plasticity principles, we developed a differentiation-induction strategy targeting sarcomatoid dedifferentiation. Integrated transcriptomic and proteomic profiling revealed PLOD2 as a candidate therapeutic target. Spatial profiling of clinical sRCC specimens revealed selective PLOD2 overexpression in sarcomatoid components. Functional assays, including genetic ablation and pharmacological inhibition, were performed in sRCC cell lines and xenograft models to validate the role of PLOD2 in conferring sarcomatoid dedifferentiation plasticity and sarcomatoid morphology. Therapeutic significance was evaluated by PLOD2 intervention alone or in combination with conventional therapies (doxorubicin, gemcitabine, IFN-α, and axitinib).

Results: Compared with neighboring epithelioid RCC and adjacent normal components, PLOD2 expression was markedly upregulated in sarcomatoid regions. PLOD2 fuelled sarcomatoid dedifferentiation plasticity by activating Cancer stemness, dedifferentiation, and EMT, partially via downstream activation of DCLK1, a Cancer stem cell marker. PLOD2 ablation reversed sarcomatoid phenotypes, restored epithelioid differentiation, and sensitized tumors to conventional RCC therapies. Notably, minoxidil, an FDA-approved PLOD2 inhibitor, effectively suppressed sarcomatoid features and synergized with standard treatments in preclinical models.

Conclusion: Targeting PLOD2-mediated tumor plasticity represents a novel differentiation-inducing strategy to reprogram sRCC into therapy-responsive epithelioid states. The repurposing potential of minoxidil provides an immediate translatable strategy to improve clinical outcomes in this treatment-resistant malignancy.

Differentiation induction; PLOD2; Sarcomatoid dedifferentiation; Sarcomatoid renal cell carcinoma; Therapeutic strategy; Tumor plasticity.