NEPC

Neuroendocrine Prostate Cancer (NEPC)

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer associated with treatment resistance and poor clinical outcomes.

In addition to tumors that exhibit neuroendocrine features at initial diagnosis, treatment-emergent NEPC (t-NEPC) can develop during the course of treatment for advanced prostate cancer, particularly following androgen receptor (AR)-targeted therapies.

Our research focuses on lineage plasticity, through which prostate cancer cells alter their cellular identity during the acquisition of treatment resistance, as well as on the tumor microenvironment that may promote and sustain this transition.

Watanabe R, Haffner M, Nelson P et al. Urol. Oncol. 2026

How does prostate cancer evolve into NEPC?

We compare prostate adenocarcinoma before treatment with NEPC that emerges after therapy in the same patients and perform high-resolution spatial transcriptomic analyses.

By analyzing not only tumor cells but also surrounding stromal and immune cells, we aim to characterize changes in gene expression and tumor–microenvironment interactions associated with the transition to NEPC.

In particular, we investigate SASP, inflammation, TGF-β, NF-κB, and interferon signaling to understand the microenvironmental factors that may contribute to treatment resistance and neuroendocrine differentiation.

Watanabe et al. Int J Mol Sci 2023

Molecular Characterization of NEPC through a Nationwide Cohort

NEPC is a rare disease, making it difficult for any single institution to collect and analyze a sufficiently large number of cases.

To address this challenge, we have established a nationwide multicenter cohort of NEPC in collaboration with institutions across Japan and are conducting RNA sequencing and spatial transcriptomic analyses.

By characterizing the transition to NEPC at spatial resolution and validating these findings in the nationwide cohort, we aim to establish a molecular classification of NEPC, identify predictors of NEPC development, and discover novel therapeutic targets.