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Dynamics of Tumor Heterogeneity from Primary to Metastatic Dissemination in Prostate Cancer

ABSTRACT: Identifying drivers of cancer progression to guide treatment selection is hindered by limited abilities to understand tumor heterogeneity’s impact on evolution. Here, we delineated the phenotypic variability across ~300,000 prostate tumor cells collected from multi-loci in primary and matched locoregional metastases. We found inter-patient heterogeneity to be confined to malignant populations. While malignant populations exhibit intra-locus heterogeneity, they maintain inter-loci phenotypic similarity within a patient’s prostate gland. Furthermore, the inter-loci malignant population similarity is paired with a shared clonal architecture. Lastly, we show that malignant populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity observed across primary tumor loci while showcasing cell state transition to inflammatory phenotypes. These findings provide insights into four distinct measures of tumor heterogeneity, revealing diverse evolutionary paths across patients converging to common phenotypic adaptations in early prostate cancer progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271675 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:Intra-tumor heterogeneity (ITH) has been studied at the morphologic, genomic, and transcriptomic level, but not proteomic level. Recent advances in mass spectrometric (MS) proteome quantification techniques, exemplified by SWATH-MS, a massively parallel targeting method, now also support precise quantitative proteomic comparisons across multiple samples, thus identifying molecular and implied functional differences. Here we used SWATH-MS to analyze the proteome profiles of a set of fresh-frozen prostate tissue samples derived from radical prostatectomy specimens. A high confidence set of 1,906 proteins were consistently quantified across 60 biopsy-level tissue samples from three prostatectomy patients, each consisting of 1.0 mm punch biopsies from histologically malignant (acinar and ductal adenocarcinoma) and matching benign prostatic hyperplasia tissues. The quantitative protein profiles allowed independent quantification of the degree of intra-tumor heterogeneity for each protein in benign and malignant tissues. We found that while majority of the proteins showed comparably low intra-tumor variability, 122 proteins were highly variable in malignant and/or matching benign tissues. We observed that proteins that varied between patients or tissue types also tended to be highly variable within prostate tissues, suggesting that these variability patterns will be a critical selection criterion in future protein biomarker studies. The data also permitted investigation of the heterogeneity of multiple biochemical pathways. The high variability of several of the pathways, including Glypican-1 network, alpha-linolenic acid metabolism and celecoxib pathway, explained contradictory results regarding them in the literature. In conclusion, we demonstrated a methodology for investigating proteomic intra-tumor heterogeneity from biopsy-level tissue samples, and quantified the degree of intra-tumor heterogeneity of 1,906 proteins in prostate tumors. The method and data presented here have advanced our understanding of tumor biology and offered critical insights for future biomarker development.

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Dynamics of Tumor Heterogeneity from Primary to Metastatic Dissemination in Prostate Cancer

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