Spatial whole transcriptome profiling of primary tumor from patients with metastatic prostate cancer

TY - JOUR

T1 - Spatial whole transcriptome profiling of primary tumor from patients with metastatic prostate cancer

AU - Salachan, Paul Vinu

AU - Rasmussen, Martin

AU - Ulhøi, Benedicte Parm

AU - Jensen, Jørgen Bjerggaard

AU - Borre, Michael

AU - Sørensen, Karina Dalsgaard

PY - 2023/12

Y1 - 2023/12

N2 - Prostate cancer (PCa) is a highly heterogeneous disease in terms of its molecular makeup and clinical prognosis. The prostate tumor microenvironment (TME) is hypothesized to play an important role in driving disease aggressiveness, but precise mechanisms remain elusive. In our study, we used spatial transcriptomics to explore for the first time the spatial gene expression heterogeneity within primary prostate tumors from patients with metastatic disease. In total, we analyzed 5459 tissue spots from three PCa patients comprising castration-resistant (CRPC) and neuroendocrine (NEPC) disease stages. Within CRPC, we identified a T cell cluster whose activity might be impaired by nearby regulatory T cells, potentially mediating the aggressive disease phenotype. Moreover, we identified Hallmark signatures of epithelial-mesenchymal transition in a cancer-associated fibroblast (CAF) cluster, indicating the aggressive characteristic of the primary TME leading to metastatic dissemination. Within NEPC, we identified active immune-stroma cross-talk exemplified by significant ligand-receptor interactions between CAFs and M2 macrophages. Further, we identified a malignant cell population that was associated with the down-regulation of an immune-related gene signature. Lower expression of this signature was associated with higher levels of genomic instability in advanced PCa patients (SU2C cohort, n = 99) and poor recurrence free survival in early-stage PCa patients (TCGA cohort, n = 395), suggesting prognostic biomarker potential. Taken together, our study reveals the importance of whole transcriptome profiling at spatial resolution for biomarker discovery and for advancing our understanding of tumor biology.

AB - Prostate cancer (PCa) is a highly heterogeneous disease in terms of its molecular makeup and clinical prognosis. The prostate tumor microenvironment (TME) is hypothesized to play an important role in driving disease aggressiveness, but precise mechanisms remain elusive. In our study, we used spatial transcriptomics to explore for the first time the spatial gene expression heterogeneity within primary prostate tumors from patients with metastatic disease. In total, we analyzed 5459 tissue spots from three PCa patients comprising castration-resistant (CRPC) and neuroendocrine (NEPC) disease stages. Within CRPC, we identified a T cell cluster whose activity might be impaired by nearby regulatory T cells, potentially mediating the aggressive disease phenotype. Moreover, we identified Hallmark signatures of epithelial-mesenchymal transition in a cancer-associated fibroblast (CAF) cluster, indicating the aggressive characteristic of the primary TME leading to metastatic dissemination. Within NEPC, we identified active immune-stroma cross-talk exemplified by significant ligand-receptor interactions between CAFs and M2 macrophages. Further, we identified a malignant cell population that was associated with the down-regulation of an immune-related gene signature. Lower expression of this signature was associated with higher levels of genomic instability in advanced PCa patients (SU2C cohort, n = 99) and poor recurrence free survival in early-stage PCa patients (TCGA cohort, n = 395), suggesting prognostic biomarker potential. Taken together, our study reveals the importance of whole transcriptome profiling at spatial resolution for biomarker discovery and for advancing our understanding of tumor biology.

KW - cancer-associated fibroblasts

KW - immune checkpoint targets

KW - metastatic prostate cancer

KW - spatial gene expression

KW - tumor microenvironment

KW - Prognosis

KW - Humans

KW - Transcriptome

KW - Male

KW - Gene Expression Profiling

KW - Prostatic Neoplasms, Castration-Resistant/pathology

KW - Prostate/pathology

KW - Prostatic Neoplasms/pathology

KW - Biomarkers

KW - Tumor Microenvironment/genetics

UR - http://www.scopus.com/inward/record.url?scp=85169541156&partnerID=8YFLogxK

U2 - 10.1002/ijc.34708

DO - 10.1002/ijc.34708

M3 - Journal article

C2 - 37655984

SN - 0020-7136

VL - 153

SP - 2055

EP - 2067

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 12

ER -