Biology subjects

Roussos-Torres, E. T.

Publications and source records attributed to Roussos-Torres, E. T..

3 recordsLinked to original sources

bioRxiv2023

Organoid generation from mouse mammary tumors captures the genetic heterogeneity of clinically relevant copy number alterations

Breast cancer metastases exhibit many different genetic alterations, including copy number amplifications. Using publicly available datasets, we identify copy number amplifications in metastatic breast tumor samples and using our organoid-based metastasis assays, and we validate FGFR1 is amplified in collectively migrating organoids. Because the heterogeneity of breast tumors is increasingly becoming relevant to clinical practice, we demonstrate our organoid method captures genetic heterogeneity of individual tumors.

cancer biology↗

bioRxiv2022

A comprehensive single-cell breast tumor atlas defines cancer epithelial and immune cell heterogeneity and interactions predicting anti-PD-1 therapy response

We present an integrated single-cell RNA-seq resource of the breast tumor microenvironment consisting of 236,363 cells from 119 biopsy samples across 8 publicly available datasets. In this computational study, we first leverage this novel resource to define cancer epithelial cell heterogeneity based on two clinically relevant markers and identify six new and distinct subsets of natural killer cells. We then illustrate how cancer epithelial cell heterogeneity impacts immune cell interactions. We develop T cell InteractPrint, which considers how cancer epithelial cell heterogeneity shifts the predicted strength of T cell interactions. We use InteractPrint to predict response to immune checkpoint inhibition (ICI) in two clinical trials testing immunotherapy in patients with breast cancer. T cell InteractPrint was predictive in both trials (AUC = 0.81 and 0.84), versus PD-L1 expression (AUC = 0.54 and 0.72). This result provides an alternative predictive biomarker to PD-L1 to select patients who should receive ICI. STATEMENT OF SIGNIFICANCEWe developed a novel integrated single-cell atlas of the breast tumor microenvironment to interrogate breast tumor cell heterogeneity and define how heterogenous cancer epithelial cell and immune cell interactions predict response to anti-PD-1 therapy.

cancer biology↗

bioRxiv2021

Phenotypic shifts of tumor associated macrophages and STAT3 mediated suppression of myeloid derived suppressor cells drive sensitization of HER2+ tumor immunity.

Understanding how novel therapeutic combinations alter solid tumor microenvironments (TME) in immunosuppressive tumors such as breast cancer is essential to improve their responses to immune checkpoint inhibitors (ICIs). Entinostat, an oral histone deacetylase inhibitor (HDACi), has been shown to improve responses to ICIs in various tumor models with immunosuppressive TMEs, but the precise alterations induced by entinostat and mechanisms of synergy with ICIs remain unknown. Here, we employ single-cell RNA-sequencing on HER2 overexpressing breast tumors from mice treated with entinostat + ICIs to characterize these changes across cell types in the TME. This analysis demonstrates that treatment with entinostat induces a shift from a pro-tumor to an anti-tumor TME signature characterized predominantly by changes in the myeloid cells. Notably, myeloid-derived suppressor cells (MDSCs) are shifted toward the less suppressive granulocytic phenotype in association with reduced signaling through the STAT3 pathway. In addition, tumor-associated macrophages are shifted toward an anti-tumor M1 phenotype by epigenetic reprogramming. Overall, these entinostat-induced TME changes reduce immunosuppression and increase mechanisms of tumor cell killing to improve ICI responses and broaden the population of patients who could potentially benefit from immunotherapy.

immunology↗