Biology subjects

Kiviaho, A.

Publications and source records attributed to Kiviaho, A..

4 recordsLinked to original sources

bioRxiv2026

AR suppression rewires a SOX4 regulatory program to promote enzalutamide resistance in prostate cancer

Treatment resistance in prostate cancer remains a major clinical challenge. While single-cell transcriptomics enables mapping of cellular composition and resistance-associated states, the gene regulatory programs driving these state transitions remain poorly defined. Here, we integrate single-cell chromatin accessibility and transcriptome sequencing data from an in vitro model to resolve the regulatory program architecture underlying anti-androgen resistance. We identify coordinated remodeling of androgen signaling- and stress response-associated regulatory programs, together with a pronounced gain of a SOX4-driven regulatory program in resistant cells. Analysis of clinical datasets reveals that SOX4 activity is both context-dependent and lineage-specific. In primary tumors, SOX4 cis-regulatory activity is elevated in PTEN-loss tumors, consistent with a PTEN-PI3K/AKT/mTOR-SOX4 axis that primes AR-independent epithelial lineages for subsequent activation of a more extensive SOX4 trans-regulatory program. This program is further amplified following AR-targeted therapy, indicating therapy-induced reinforcement of SOX4-linked regulatory adaptation. TF footprinting additionally implicates Nuclear Factor I family transcription factors as upstream regulators of SOX4, supporting a role in promoting SOX4 activation following AR inhibition. Together, these findings demonstrate that AR inhibition reshapes the gene regulatory landscape to promote engagement of the SOX4 program, facilitating prostate cancer progression under anti-androgen therapy.

cancer biology↗

bioRxiv2024

Deep phenotyping of the prostate tumor microenvironment reveals molecular stratifiers of relapse and links inflammatory chemokine expression to aberrant metabolism

Understanding the molecular characteristics and changes of the tumor microenvironment (TME) associated with aggressive prostate cancer (PCa) is essential for precise diagnosis and treatment. We interrogated spatially resolved integrated transcriptomics and metabolomics data to build molecular strafiers discriminating patients with aggressive, potentially relapsing, and metastasizing PCa. We report a relapse associated (RA) gene expression signature characterized by upregulated immune response related gene expression scoring high in cancer, stroma, and glandular tissue of relapsing patients. Further, we identified a signature specific to a distinct sub-group of morphologically non-cancerous glands in prostate tissue from patients with relapsing cancer. This signature, named chemokine-enriched-gland (CEG) signature, was characterized by upregulated gene expression of pro-inflammatory chemokines. Glands with a high CEG score were enriched for club-like cells and surrounding stroma was infiltrated by immune cells. Tissue regions scoring high for both CEG and RA signatures were associated with reduced levels of citrate and zinc and loss of normal prostate secretory gland functions via reduced expression of genes necessary for citrate secretion. In summary we report that aggressive PCa is associated with an increased inflammatory status linked to chemokine production and club-like cell enrichment in potentially pre-cancerous prostate glands displaying an aberrant metabolism.

cancer biology↗

bioRxiv2024

Androgen deprivation therapy-resistant club cells are linked to myeloid cell-driven immunosuppression in the prostate tumor microenvironment

Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 110 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells partake in inducing myeloid inflammation previously associated with androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.

cancer biology↗

bioRxiv2021

Single-cell ATAC and RNA sequencing reveal pre-existing and persistent subpopulations of cells associated with relapse of prostate cancer

Prostate cancer is profoundly heterogeneous and patients would benefit from methods that stratify clinically indolent from more aggressive forms of the disease. We employed single-cell assay for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identified pre-existing and treatment-persistent cell subpopulations that possess transcriptional stem-like features and regenerative potential when subjected to treatment. We found distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent stem-like cells were able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal hitherto unrecognized molecular predictors of treatment response. This suggests that high analytical resolution of pre-clinical models may powerfully inform clinical decision-making.

cancer biology↗