NCI Division of Cancer Biology Junior Investigators Meeting (Abstract): Submission #6

Presenter Information
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First Name: Florencia 
Middle Initial: {Empty}
Last Name: Picech
Degree(s): Ph.D.
Position/Title/Career Status: Associate Research Scientist
Organization: Columbia University
Organization Address:
New York

Email: fp2447@cumc.columbia.edu

Abstract Information
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Abstract Category: Use my abstract for team formation only (do not consider it for a presentation)
Abstract Keywords: {Empty}
Abstract Title: A single-cell atlas identifies distinct programs of metastatic progression across prostate cancer subtypes
Abstract:
Metastasis is the major cause of mortality in patients with advanced prostate cancer, yet the mechanisms underlying metastatic progression and treatment response remain poorly understood. Androgen receptor (AR) signaling is central to prostate tumorigenesis being the main therapeutic target. However, metastatic prostate cancer encompasses distinct biological subtypes that retain AR dependence or evolve toward AR independence, raising questions about how these divergent states influence metastatic progression and adaptation.
To investigate this heterogeneity, we generated genetically engineered mouse models (GEMMs) recapitulating alterations in key genes and pathways frequently dysregulated in human metastatic disease, including Pten, p53, Rb1, DNA damage response, and MAPK/RAS signaling. These models display diverse metastatic phenotypes, including bone metastasis, and both AR-high and AR-low disease in an immunocompetent background. Single-cell RNA sequencing across 181 samples from normal prostate, prostate tumors, and metastases from multiple anatomical sites generated an atlas of tumor, stromal, and immune cell populations.
The atlas revealed distinct tumor-intrinsic programs associated with AR status. AR-high tumors were enriched for epithelial-to-mesenchymal transition and osteogenic programs, consistent with osteomimicry, and exhibited a hypoxic, glycolytic profile. In contrast, AR-low tumors showed enrichment of neurodifferentiation and neurotransmitter signaling, consistent with neuromimicry, together with increased oxidative phosphorylation. These features were maintained in metastases, suggesting distinct mechanisms of adaptation. Furthermore, the tumor microenvironment was characterized by myeloid dominance across all metastatic tumors, with distinct neutrophil populations identified across subtypes.
Together, these findings demonstrate coordinated tumor-intrinsic and microenvironmental adaptations during prostate cancer metastasis establishing a platform to identify therapeutic vulnerabilities across disease subtypes.