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REVIEW ARTICLE

Lineage plasticity and histological transformation: tumor histology as a spectrum

Xiaoling Li^1,2 , Eric E. Gardner³ , Sonia Molina-Pinelo⁴ , Clare Wilhelm⁵ , Ping Mu^1,2 , Álvaro Quintanal-Villalonga^5,*

¹Department of Urology, Yale School of Medicine, Yale University, New Haven, CT, USA
²Yale Cancer Center, Yale University, New Haven, CT, USA
³Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
⁴Institute of Biomedicine of Seville (IBiS), HUVR, CSIC, Universidad de Sevilla, Seville, Spain
⁵Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
* Correspondence: Álvaro Quintanal-Villalonga(quintaa1@mskcc.org)

Lineage plasticity, the ability of cells to transition to an alternative phenotype as a means for adaptation, is an increasingly recognized mechanism of tumor evolution and a driver of resistance to anticancer therapies. The most extensively described clinical settings impacted by such molecular phenomena include neuroendocrine transformation in androgen receptor-dependent prostate adenocarcinoma, and adenocarcinoma-to-neuroendocrine and adenocarcinoma-to-squamous transdifferentiation in epidermal growth factor receptor-driven lung adenocarcinoma, affecting 10%–20% of patients treated with targeted therapy. Recent analyses of human tumor samples and in vivo models of histological transformation have led to insights into the biology of lineage plasticity, including biomarkers predictive of high risk of transformation. However, no clinically available therapies aimed to prevent or revert plasticity are currently available. In the present review, we will provide a biological and therapeutic overview of the current understanding of common and divergent molecular drivers of neuroendocrine and squamous transdifferentiation in tumors from different origins, including descriptive analysis of previously known and recently described molecular events associated with histological transformation, and propose evidence-based alternative models of transdifferentiation. A clear definition of the commonalities and differences of transforming tumors in different organs and to different histological fates will be important to translate molecular findings to the clinical setting.

https://doi.org/10.1038/s41422-025-01180-x

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