Biology subjects

Brown, G. T.

Publications and source records attributed to Brown, G. T..

2 recordsLinked to original sources

bioRxiv2026

Hepatobiliary Progenitor-like Reprogramming in Liver Metastases

Metastatic progression requires cancer cells to adapt to the unique constraints of distant organ microenvironments, yet the mechanisms that drive organ-specific adaptations remain poorly understood. Here, we show that the liver actively rewrites metastatic cancer cell identity, driving tumor cells toward a hepatobiliary progenitor-like state. Through integrated transcriptomic, proteomic, metabolomic, and epigenomic analyses of patient-derived rapid-autopsy samples and experimental models, we identify this state as selectively enriched in liver metastases. It is characterized by co-activation of hepatic and biliary/progenitor regulators HNF4A and SOX9 and is observed across multiple epithelial cancers, indicating a conserved response to the hepatic niche. Mechanistically, hepatocyte-derived TGF-{beta} and hypoxia converge to activate a HIF-1-ACLY axis, increasing nuclear acetyl-coenzyme A availability and histone acetylation at hepatic lineage regulatory elements to drive hepatobiliary reprogramming. This coordinated niche-response program can be captured transcriptionally and is associated with inferior overall survival. Disruption of this pathway suppresses hepatic reprogramming and impairs liver metastatic fitness. These findings identify the liver as an active determinant of metastatic cell fate, linking microenvironmental signaling to metabolic and chromatin remodeling programs that enable lineage plasticity. More broadly, they reveal organ-specific reprogramming as a fundamental principle of metastasis and a therapeutic vulnerability in liver metastases.

cancer biology↗

bioRxiv2023

Large Scale Comparative Deconvolution Analysis of the Canine and Human Osteosarcoma Tumor Microenvironment Uncovers Conserved Clinically Relevant Subtypes

Osteosarcoma is a relatively rare but aggressive cancer of the bones with a shortage of effective biomarkers. Although less common in humans, Osteosarcomas are fairly common in adult pet dogs and have been shown to share many similarities with their human analogs. In this work, we analyze bulk transcriptomic data of 213 primary and 100 metastatic Osteosarcoma samples from 210 pet dogs enrolled in nation-wide clinical trials to uncover three Tumor Microenvironment (TME)-based subtypes: Immune Enriched (IE), Immune Enriched Dense Extra-Cellular Matrix-like (IE-ECM) and Immune Desert (ID) with distinct cell type compositions, oncogenic pathway activity and chromosomal instability. Furthermore, leveraging bulk transcriptomic data of canine primary tumors and their matched metastases from different sites, we characterize how the Osteosarcoma TME evolves from primary to metastatic disease in a standard of care clinical setting and assess its overall impact on clinical outcomes of canines. Most importantly, we find that TME-based subtypes of canine Osteosarcomas are conserved in humans and predictive of progression free survival outcomes of human patients, independently of known prognostic biomarkers such as presence of metastatic disease at diagnosis and percent necrosis following chemotherapy. In summary, these results demonstrate the power of using canines to model the human Osteosarcoma TME and discover novel biomarkers for clinical translation.

cancer biology↗