NEPC

Neuroendocrine Prostate Cancer (NEPC)

Neuroendocrine prostate cancer (NEPC) is a highly treatment-resistant form of prostate cancer associated with a poor prognosis.

NEPC can arise de novo, exhibiting neuroendocrine features at initial diagnosis, or develop during treatment for advanced prostate cancer, particularly following androgen deprivation therapy and other androgen receptor-targeted treatments. The latter is referred to as treatment-emergent NEPC (t-NEPC).

Our research focuses on lineage plasticity, through which prostate cancer cells acquire treatment resistance and undergo phenotypic changes, as well as the tumor microenvironment that surrounds and potentially influences this process.

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

How Does Prostate Cancer Transform into NEPC?

We are conducting high-resolution spatial transcriptomic analyses of paired tumor specimens collected from the same patients before treatment, when the tumors exhibited conventional prostate adenocarcinoma features, and after progression to NEPC.

By examining not only tumor cells but also surrounding stromal and immune cells, we aim to characterize the changes in gene expression associated with neuroendocrine differentiation and elucidate their interactions with the tumor microenvironment.

We are particularly interested in senescence-associated secretory phenotype (SASP), inflammation, TGF-β, NF-κB, and interferon (IFN) signaling pathways, and their potential roles in promoting treatment resistance and neuroendocrine differentiation.

Watanabe et al. Int J Mol Sci 2023

Understanding the Molecular Pathogenesis of NEPC Through a Nationwide Cohort

NEPC is a relatively rare disease, making it challenging for individual institutions to collect sufficient numbers of cases for comprehensive molecular analyses.

To address this limitation, we are collaborating with medical institutions across Japan to establish a nationwide NEPC cohort and conduct RNA sequencing and spatial transcriptomic analyses.

By integrating detailed spatial characterization of neuroendocrine transformation with molecular validation in a nationwide cohort, we aim to identify distinct molecular subtypes of NEPC, discover biomarkers that may predict its development, and identify novel therapeutic targets.