Biology subjects

Houck-Loomis, B.

Publications and source records attributed to Houck-Loomis, B..

5 recordsLinked to original sources

bioRxiv2021

ERα-LBD, a novel isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance

Estrogen receptor alpha (ER) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of a novel ER isoform, ER-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ER-LBD is found to promote breast cancer growth and resistance to the ER antagonist fulvestrant. ER-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ER-LBD expression and function does not appear to be restricted to cancers that express full length ER but also promotes growth of triple negative breast cancers and ER-LBD transcript (ESR1-LBD) is also present in BC samples from both ER(+) and ER(-) human tumors. These findings point to ER-LBD as a potential mediator of breast cancer progression and therapy resistance. SIGNIFICANCE STATEMENTEndocrine resistant and metastatic breast cancer (BC) is a clinically significant problem. Our study of fulvestrant resistant cancer cells led to the discovery of a novel ER isoform which we call ER-LBD. Encoded by a truncated transcript variant (ESR1-LBD) and lacking the N-terminal domains (activation of transcription and DNA binding), ER-LBD displays a unique role in BC tumorigenesis and progression by mechanisms that may involve metabolic and cell growth advantages, stemness and therapy resistance. Importantly, ESR1-LBD is preferentially expressed in human breast tumor tissues and may be used as prognostic marker in BC.

cancer biology↗

bioRxiv2021

Regional and clonal T cell dynamics at single cell resolution in immune checkpoint blockade

Paired T cell receptor and RNA single cell sequencing (scTCR/RNA-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scTCR/RNA-seq dataset of 162,062 single T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients who underwent resections for progressing lung cancers after immune checkpoint blockade (ICB). We found marked regional heterogeneity in tumor persistence that was associated with heterogeneity in CD4 and CD8 T cell phenotypes; regions with persistent cancer cells were enriched for follicular helper CD4 T cells (TFH), regulatory T cells (Treg), and exhausted CD8 T cells. Clonal analysis demonstrated that highly-expanded T cell clones were predominantly of the CD8 subtype, were ubiquitously present across all sampled regions, found in the peripheral circulation, and expressed gene signatures of large and dual-expanded clones that have been predictive of response to ICB. Longitudinal tracking of CD8 T cell clones in the peripheral blood revealed that the persistence of ubiquitous CD8 T cell clones, as well as phenotypically distinct clones with tumor-reactive features, correlated with systemic tumor control. Finally, tracking CD8 T cell clones across tissues revealed the presence of TCF-1+ precursor exhausted CD8 T cells in tumor draining LNs that were clonally linked to expanded exhausted CD8 T cells in tumors. Altogether, this comprehensive scTCR/RNA-seq dataset with regional, longitudinal, and clonal resolution provides fundamental insights into the tissue distribution, persistence, and differentiation trajectories of ICB-responsive T cells that underlie clinical responses to ICB.

immunology↗

bioRxiv2020

Multi-omic analysis of lung tumors defines pathways activated in neuroendocrine transformation

Lineage plasticity, a capacity to reprogram cell phenotypic identity under evolutionary pressure, is implicated in treatment resistance and metastasis in multiple cancers. In lung adenocarcinomas (LUADs) amenable to treatment with targeted inhibitors, transformation to an aggressive neuroendocrine (NE) carcinoma resembling small cell lung cancer (SCLC) is a recognized mechanism of acquired resistance. Defining molecular mechanisms of NE transformation in lung cancer has been limited by a paucity of well annotated pre- and post-transformation clinical samples. We hypothesized that mixed histology LUAD/SCLC tumors may capture cancer cells proximal to, and on either side of, histologic transformation. We performed detailed genomic, epigenomic, transcriptomic and proteomic characterization of combined LUAD/SCLC tumors as well as pre- and post-transformation clinical samples. Our data support that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm in pre-transformation LUADs. Consistent shifts in gene expression programs in NE transformation include induction of several stem/progenitor cell regulatory pathways, including upregulation of PRC2 and WNT signaling, and suppression of Notch pathway activity. We observe induction of PI3K/AKT and an immunosuppressive phenotype in NE transformation. Taken together our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer.

cancer biology↗

bioRxiv2017

Cell "hashing" with barcoded antibodies enables multiplexing and doublet detection for single cell genomics

Despite rapid developments in single cell sequencing technology, sample-specific batch effects, detection of cell doublets, and the cost of generating massive datasets remain outstanding challenges. Here, we introduce cell \"hashing\", where oligo-tagged antibodies against ubiquitously expressed surface proteins are used to uniquely label cells from distinct samples, which can be subsequently pooled. By sequencing these tags alongside the cellular transcriptome, we can assign each cell to its sample of origin, and robustly identify doublets originating from multiple samples. We demonstrate our approach by pooling eight human PBMC samples on a single run of the 10x Chromium system, substantially reducing our per-cell costs for library generation. Cell \"hashing\" is inspired by, and complementary to, elegant multiplexing strategies based on genetic variation, which we also leverage to validate our results. We therefore envision that our approach will help to generalize the benefits of single cell multiplexing to diverse samples and experimental designs.

genomics↗

bioRxiv2017

Large-scale simultaneous measurement of epitopes and transcriptomes in single cells.

Recent high-throughput single-cell sequencing approaches have been transformative for understanding complex cell populations, but are unable to provide additional phenotypic information, such as protein levels of cell-surface markers. Using oligonucleotide-labeled antibodies, we integrate measurements of cellular proteins and transcriptomes into an efficient, sequencing-based readout of single cells. This method is compatible with existing single-cell sequencing approaches and will readily scale as the throughput of these methods increase.

genomics↗