Biology subjects

Valle, L. D.

Publications and source records attributed to Valle, L. D..

3 recordsLinked to original sources

bioRxiv2026

Spatial context of cellular heterogeneity in triple-negative breast cancer reveals actionable subtypes

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous disease with limited targeted treatment options. Leveraging bulk and spatial transcriptomics and cellular mapping of breast tissue from a large patient cohort, we identified three reproducible TNBC ecosystem subtypes that encode distinct spatial tumor-microenvironment architectures and clinically relevant treatment-response phenotype. Our analyses define: (1) an immune-exhausted subtype associated with immune checkpoint therapy (ICT); (2) a highly fibrotic/hypoxic subtype; and (3) a metabolically reprogrammed subtype characterized by nuclear-receptor and fatty-acid signaling. Spatial profiling further revealed subtype-specific organization of epithelial, immune, and stromal programs across tumor centers and invasive edges. Multiplexed imaging independently supported the contrasting immune-infiltrated and stromal-excluded architectures of the immune-engaged and fibrotic subtypes. The unique markers associated with the subtypes also provide the basis for subtyping and candidate therapeutic vulnerabilities. Our study provides a robust framework for personalized medicine, highlighting that targeting specific spatio-cellular architectures is critical to improving clinical outcomes.

cancer biology↗

bioRxiv2025

A novel subtyping method for TNBC with implications for prognosis and therapy

The biological heterogeneity of triple-negative breast cancer (TNBC) poses significant challenges for diagnosis, prognosis, and treatment. While prior TNBC subtype classifications exist, they are not widely used clinically. Here, we aimed to subtype TNBC based on transcriptomic profiles using cell type and state heterogeneity in tumor tissue from 250 pre-treatment women (127 African-American and 123 European-American). We identified three major subtypes and three distinct groups exhibiting unique cell-type composition and mechanisms: Subtype-1 immune signaling/T-cell response; Subtype-2 pro-fibrotic and immune desert; Subtype-3 fatty acid and nuclear receptor signaling. Subtype-1 showed potential responsiveness to immunotherapy, while Subtypes-2 and 3 suggested alternative therapeutic targets. In Subtype-3, which contained a patient group with high ESR1, (but not high ER protein expression) we identified putative mutations in the gene that are unique to these patients. This framework provides a path toward personalized TNBC treatment and is accessible through a user-friendly RShiny application for clinical use.

bioinformatics↗

bioRxiv2019

Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor

Metaplastic breast carcinoma (MBC) is a clinically aggressive and rare subtype of breast cancer, with similar features to basal-like breast cancers. Due rapid growth rates and characteristic heterogeneity, MBC is often unresponsive to standard chemotherapies; and novel targeted therapeutic discovery is urgently needed. Histone deacetylase inhibitors (DACi) suppress tumor growth and metastasis through regulation of the epithelial-to-mesenchymal transition axis in various cancers, including basal-like breast cancers. We utilized a new MBC patient-derived xenograft (PDX) to examine the effect of DACi therapy on MBC. Cell morphology, cell cycle-associated gene expressions, transwell migration, and metastasis were evaluated in patient-derived cells and tumors after treatment with romidepsin and panobinostat. Derivations of our PDX model, including cells, spheres, organoids, explants, and in vivo implanted tumors were treated. Finally, we tested the effects of combining DACi with approved chemotherapeutics on relative cell biomass. DACi significantly suppressed the total number of lung metastasis in vivo using our PDX model, suggesting a role for DACi in preventing circulating tumor cells from seeding distal tissue sites. These data were supported by our findings that DACi reduced cell migration, populations, and expression of mesenchymal-associated genes. While DACi treatment did affect cell cycle-regulating genes in vitro, tumor growth was not affected compared to controls. Importantly, gene expression results varied depending on the cellular or tumor system used, emphasizing the importance of using multiple derivations of cancer models in preclinical therapeutic discovery research. Furthermore, DACi sensitized and produced a synergistic effect with approved oncology therapeutics on inherently resistant MBC. This study introduced a role for DACi in suppressing the migratory and mesenchymal phenotype of MBC cells through regulation of the epithelial-mesenchymal transition axis and suppression of the CTC population. Preliminary evidence that DACi treatment in combination with MEK1/2 inhibitors exerts a synergistic effect on MBC cells was also demonstrated.

cancer biology↗