Biology subjects

Kyprianou, N.

Publications and source records attributed to Kyprianou, N..

3 recordsLinked to original sources

bioRxiv2026

Neuroendocrine prostate cancer converges on a fetal pulmonary neuroendocrine-like program

Advanced prostate cancer can relapse as neuroendocrine prostate cancer (NEPC), a treatment-resistant, androgen receptor (AR)-independent state whose developmental identity remains unclear. We integrated single-cell, bulk, cistrome and spatial datasets from multiple cohorts and mapped malignant states to human fetal atlases. In the discovery cohort (35,696 tumor cells, 20 patients), NEPC cells were malignant and shared copy-number architecture with adenocarcinoma (chromosome-level r = 0.64). NEPC most closely matched a fetal, lineage-restricted neuroendocrine program, best supported as pulmonary neuroendocrine-like among alternatives tested (islet, chromaffin, sympathoblast), with consistent direction across three cohorts; the pulmonary-versus-islet distinction was method-sensitive and remains provisional. Stage and pseudotime analyses supported an ordered luminal-to-neuroendocrine sequence, with FOXA2/SOX2 early and ASCL1/NEUROD1/MYCN late across five datasets. A regulatory screen nominated a circuit centered on ASCL1 whose convergent enhancers overlapped fetal pulmonary neuroendocrine chromatin and showed FOXA1 binding in cell-line and xenograft models (87.0% versus 33.8%; P = 0.016). In one NEPC Visium section, the program localized to malignant territory defined by copy number (AUROC 0.85). Based on three NEPC patients with cross-cohort replication, these data support NEPC as an adenocarcinoma-related malignant state converging on a fetal pulmonary neuroendocrine-like program and nominate ASCL1-linked regulatory and surface targets.

cancer biology↗

bioRxiv2021

Extracellular Vesicles Carry Distinct Proteo-Transcriptomic Signatures That are Different from Their Cancer Cell of Origin

Circulating extracellular vesicles (EVs) contain molecular footprints from their cell of origin and may provide potential non-invasive access for detection, characterization, and monitoring of numerous diseases. Despite their growing promise, the integrated proteo-transcriptomic landscape of EVs and their donor cells remain poorly understood. To assess their cargo, we conducted small RNA sequencing and mass spectrometry (LC-MS/MS) of EVs isolated from in vitro cancer cell culture and prostate cancer patients serum. Here, we report that EVs enrich for distinct molecular cargo, and their proteo-transcriptome is predominantly different from their cancer cell of origin, implicating a coordinated disposal and delivery mechanism. We have discovered that EVs package their cargo in a non-random fusion, as their most enriched RNAs and proteins are not the most abundant cargo from their donor cells. We show that EVs enrich for 4 times more cytoskeletal and 2 times extracellular proteins than their donor cells. While the donor cells carry 10 times more mitochondrial and 3 times nuclear proteins than their EVs. EVs predominantly (40-60%) enrich for small RNA (~15-200 nucleotides) molecules that implicate cell differentiation, development, and signaling signatures. Finally, our integrated proteo-transcriptomic analyses reveal that EVs are enriched of RNAs (RNY3, vtRNA, and MIRLET-7) and their complementary proteins (YBX1, IGF2BP2, SRSF1/2), implicating an interrelated mechanism that may protect and regulate transcripts until a biological function is achieved. Based on these results, we envision that the next-generation clinical assays will take an integrative multi-omic (proteomic and transcriptomic) approach for liquid biopsy in numerous diseases.

bioinformatics↗

bioRxiv2020

RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis

Despite advances in diagnosis and treatment, metastatic prostate cancer remains incurable and is associated with high mortality rates. Thus, novel actionable drug targets are urgently needed for therapeutic interventions in advanced prostate cancer. Here we report receptor-interacting protein kinase 2 (RIPK2) as an actionable drug target for suppressing prostate cancer metastasis. RIPK2 is frequently amplified in lethal prostate cancers and its overexpression is associated with disease progression and aggressiveness. Genetic and pharmacological inhibition of RIPK2 significantly suppressed prostate cancer progression in vitro and metastasis in vivo. Multi-level proteomic analysis revealed that RIPK2 strongly regulates c-Myc protein stability and activity, largely by activating the MKK7/JNK/c-Myc phosphorylation pathway--a novel, non-canonical RIPK2 signaling pathway. Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc--a potent oncoprotein for which no drugs have been approved for clinical use yet. These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival.

cancer biology↗