Biology subjects

Laughney, A. M.

Publications and source records attributed to Laughney, A. M..

3 recordsLinked to original sources

bioRxiv2023

Lineage-specific intolerance to oncogenic drivers restricts histological transformation

Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC following treatment with targeted therapies. Here we designed models to follow the conversion of LUAD to SCLC and found the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells, transcriptionally resembling the pulmonary basal lineage. These findings suggest histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs. One-Sentence SummaryBy modeling histological transformation of lung cancer, we uncover neuroendocrine-specific tolerance to Myc as an oncogenic driver.

cancer biology↗

bioRxiv2022

Obesity promotes breast epithelium DNA damage in BRCA mutation carriers

Obesity is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated bodyweight is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear due to inconsistent findings from epidemiological studies and lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelium of BRCA mutation carriers is positively correlated with body mass index and with biomarkers of metabolic dysfunction. Additionally, RNA-sequencing reveals significant obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which impacts neighboring breast epithelial cells. We found that blockade of estrogen biosynthesis or estrogen receptor activity decreases DNA damage, whereas treatment with leptin or insulin increases DNA damage in BRCA heterozygous epithelial cells. Furthermore, we show that increased adiposity is associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between bodyweight and breast cancer development in BRCA mutation carriers and suggests that maintaining a healthy bodyweight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population. One Sentence SummaryElevated bodyweight is positively associated with DNA damage in breast epithelium of BRCA mutation carriers

cancer biology↗

bioRxiv2020

High resolution mouse subventricular zone stem cell niche transcriptomereveals features of lineage, anatomy, and aging

Adult neural stem cells (NSC) serve as a reservoir for brain plasticity and origin for certain gliomas. Lineage tracing and genomic approaches have portrayed complex underlying heterogeneity within the major anatomical location for NSC, the subventricular zone (SVZ). To gain a comprehensive profile of NSC heterogeneity, we utilized a well validated stem/progenitor specific reporter transgene in concert with single cell RNA sequencing to achieve unbiased analysis of SVZ cells from infancy to advanced age. The magnitude and high specificity of the resulting transcriptional data sets allow precise identification of the varied cell types embedded in the SVZ including specialized parenchymal cells (neurons, glia, microglia), and non-central nervous system cells (endothelial, immune). Initial mining of the data delineates four quiescent NSC and three progenitor cell subpopulations formed in a linear progression. Further evidence indicates that distinct stem and progenitor populations reside in different regions of the SVZ. As stem/progenitor populations progress from neonatal to advanced age, they acquire a deficiency in transition from quiescence to proliferation. Further data mining identifies stage specific biological processes, transcription factor networks, and cell surface markers for investigation of cellular identities, lineage relationships, and key regulatory pathways in adult NSC maintenance and neurogenesis. Significance StatementAdult neural stem cells (NSC) are closely related to multiple neurological disorders and brain tumors. Comprehensive investigation of their composition, lineage, and aging will provide new insights that may lead to enhanced patient treatment. This study applies a novel transgene to label and manipulate neural stem/progenitor cells, and monitor their evolution during aging. Together with high-throughput single cell RNA sequencing, we are able to analyze the subventricular zone (SVZ) cells from infancy to advanced age with unprecedented granularity. Diverse new cell states are identified in the stem cell niche, and an aging related NSC deficiency in transition from quiescence to proliferation is identified. The related biological features provide rich resources to inspect adult NSC maintenance and neurogenesis.

neuroscience↗