Biology subjects

Wisniewska, K.

Publications and source records attributed to Wisniewska, K..

3 recordsLinked to original sources

bioRxiv2023

Tamoxifen Response at Single Cell Resolution in Estrogen Receptor-Positive Primary Human Breast Tumors

In ER+/HER2- breast cancer, multiple measures of intra-tumor heterogeneity are associated with worse response to endocrine therapy. To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live human tumors and normal breast specimens immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within the malignant cell compartment of human tumors. Tamoxifen resistance signatures from 3 distinct resistant subpopulations are prognostic in large cohorts of ER+ breast cancer patients and enriched in endocrine therapy resistant tumors. This novel ex vivo model system now provides a foundation to define responsive and resistant sub-populations within heterogeneous tumors, to develop precise single cell-based predictors of response to therapy, and to identify genes and pathways driving resistance to therapy.

cancer biology↗

bioRxiv2022

Single-Cell Transcriptional and Epigenetic Profiles of Male Breast Cancer Nominate Salient Cancer-Specific Enhancers

Male breast cancer represents about 1% of all breast cancer diagnoses and, although there are some similarities between male and female breast cancer, the paucity of data available on male breast cancer makes it difficult to establish targeted therapies. To date, most male breast cancers (MBC) are treated according to protocols established for female breast cancer (FBC). Thus, defining the transcriptional and epigenetic landscape of MBC with improved resolution is critical for developing better avenues for therapeutic intervention. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) profiles at single-cell resolution of two treatment naive MBC tumors processed immediately after surgical resection. These data enable the detection of differentially expressed genes between male and female breast tumors across immune, stromal, and malignant cell types, to highlight several genes that may have therapeutic implications. Notably, MYC target genes and mTORC1 signaling genes were significantly upregulated in the malignant cells of MBC compared to the female counterparts. To understand how the regulatory landscape of MBC give rise to these male-specific gene expression patterns, we leveraged the scATAC-seq data to systematically link changes in chromatin accessibility to changes in gene expression within each cell type. We observed cancer-specific rewiring of several salient enhancers and posit that these enhancers have a higher regulatory load than lineage specific enhancers. We highlight two examples of previously unannotated cancer-cell specific enhancers of ANXA2 and PRDX4 gene expression and show evidence for super-enhancer regulation of LAMB3 and CD47 in male breast cancer cells. Overall, this dataset annotates clinically relevant regulatory networks in male breast tumors, providing a useful resource that expands our current understanding of the gene expression programs that underlie the biology of MBC.

genomics↗

bioRxiv2022

A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer

The human genome contains regulatory elements, such as enhancers, that are often rewired by cancer cells for the activation of genes that promote tumorigenesis and resistance to therapy. This is especially true for cancers that have little or no known driver mutations within protein coding genes, such as ovarian cancer. Herein, we have utilized an integrated set of genomic and epigenomic datasets to identify clinically relevant super-enhancers that are preferentially amplified in ovarian cancer patients. We have systematically probed the top 86 super-enhancers, using CRISPR-interference and CRISPR-deletion assays coupled to RNA-sequencing, to nominate two salient super-enhancers that drive proliferation and migration of cancer cells. Utilizing Hi-C, we constructed chromatin interaction maps that enabled the annotation of direct target genes for these super-enhancers and later confirmed their activity specifically within the cancer cell compartment of human tumors using single-cell genomics data. Together, our multi-omic approach has examined a number of fundamental questions about how regulatory information encoded into super-enhancers drives gene expression networks that underlie the biology of ovarian cancer.

cancer biology↗