Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene.

Single-cell transcriptomics studies have begun to identify breast epithelial cell and stromal cell specific transcriptome differences between BRCA1/2 mutation carriers and non-carriers. We generated a single-cell transcriptome atlas of breast tissues from BRCA1, BRCA2 mutation carriers and compared this single-cell atlas of mutation carriers with our previously described single-cell breast atlas of healthy non-carriers. We observed that BRCA1 but not BRCA2 mutations altered the ratio between basal (basal-myoepithelial), luminal progenitor (luminal adaptive secretory precursor, LASP), and mature luminal (luminal hormone sensing) cells in breast tissues. A unique subcluster of cells within LASP cells is underrepresented in case of BRCA1 and BRCA2 mutation carriers compared with non-carriers. Both BRCA1 and BRCA2 mutations specifically altered transcriptomes in epithelial cells which are an integral part of NFκB, LARP1, and MYC signaling. Signaling pathway alterations in epithelial cells unique to BRCA1 mutations included STAT3, BRD4, SMARCA4, HIF2A/EPAS1, and Inhibin A signaling. BRCA2 mutations were associated with upregulation of IL6, PDK1, FOXO3, and TNFSF11 signaling. These signaling pathway alterations are sufficient to alter sensitivity of BRCA1/BRCA2-mutant breast epithelial cells to transformation as epithelial cells from BRCA1 mutation carriers overexpressing hTERT + PIK3CAH1047R generated adenocarcinomas, whereas similarly modified mutant BRCA2 cells generated basal carcinomas in NSG mice. Thus, our studies provide a high-resolution transcriptome atlas of breast epithelial cells of BRCA1 and BRCA2 mutation carriers and reveal their susceptibility to PIK3CA mutation-driven transformation. SIGNIFICANCE: This study provides a single-cell atlas of breast tissues of BRCA1/2 mutation carriers and demonstrates that aberrant signaling due to BRCA1/2 mutations is sufficient to initiate breast cancer by mutant PIK3CA.

Diagnosing destabilization risk in global land carbon sinks.

Global net land carbon uptake or net biome production (NBP) has increased during recent decades1. Whether its temporal variability and autocorrelation have changed during this period, however, remains elusive, even though an increase in both could indicate an increased potential for a destabilized carbon sink2,3. Here, we investigate the trends and controls of net terrestrial carbon uptake and its temporal variability and autocorrelation from 1981 to 2018 using two atmospheric-inversion models, the amplitude of the seasonal cycle of atmospheric CO2 concentration derived from nine monitoring stations distributed across the Pacific Ocean and dynamic global vegetation models. We find that annual NBP and its interdecadal variability increased globally whereas temporal autocorrelation decreased. We observe a separation of regions characterized by increasingly variable NBP, associated with warm regions and increasingly variable temperatures, lower and weaker positive trends in NBP and regions where NBP became stronger and less variable. Plant species richness presented a concave-down parabolic spatial relationship with NBP and its variability at the global scale whereas nitrogen deposition generally increased NBP. Increasing temperature and its increasing variability appear as the most important drivers of declining and increasingly variable NBP. Our results show increasing variability of NBP regionally that can be mostly attributed to climate change and that may point to destabilization of the coupled carbon-climate system.

Nocturnal plant respiration is under strong non-temperature control.

Most biological rates depend on the rate of respiration. Temperature variation is typically considered the main driver of daily plant respiration rates, assuming a constant daily respiration rate at a set temperature. Here, we show empirical data from 31 species from temperate and tropical biomes to demonstrate that the rate of plant respiration at a constant temperature decreases monotonically with time through the night, on average by 25% after 8 h of darkness. Temperature controls less than half of the total nocturnal variation in respiration. A new universal formulation is developed to model and understand nocturnal plant respiration, combining the nocturnal decrease in the rate of plant respiration at constant temperature with the decrease in plant respiration according to the temperature sensitivity. Application of the new formulation shows a global reduction of 4.5 -6 % in plant respiration and an increase of 7-10% in net primary production for the present-day.

Process-oriented analysis of dominant sources of uncertainty in the land carbon sink.

The observed global net land carbon sink is captured by current land models. All models agree that atmospheric CO2 and nitrogen deposition driven gains in carbon stocks are partially offset by climate and land-use and land-cover change (LULCC) losses. However, there is a lack of consensus in the partitioning of the sink between vegetation and soil, where models do not even agree on the direction of change in carbon stocks over the past 60 years. This uncertainty is driven by plant productivity, allocation, and turnover response to atmospheric CO2 (and to a smaller extent to LULCC), and the response of soil to LULCC (and to a lesser extent climate). Overall, differences in turnover explain ~70% of model spread in both vegetation and soil carbon changes. Further analysis of internal plant and soil (individual pools) cycling is needed to reduce uncertainty in the controlling processes behind the global land carbon sink.

A single-cell atlas of the healthy breast tissues reveals clinically relevant clusters of breast epithelial cells.

Single-cell RNA sequencing (scRNA-seq) is an evolving technology used to elucidate the cellular architecture of adult organs. Previous scRNA-seq on breast tissue utilized reduction mammoplasty samples, which are often histologically abnormal. We report a rapid tissue collection/processing protocol to perform scRNA-seq of breast biopsies of healthy women and identify 23 breast epithelial cell clusters. Putative cell-of-origin signatures derived from these clusters are applied to analyze transcriptomes of ~3,000 breast cancers. Gene signatures derived from mature luminal cell clusters are enriched in ~68% of breast cancers, whereas a signature from a luminal progenitor cluster is enriched in ~20% of breast cancers. Overexpression of luminal progenitor cluster-derived signatures in HER2+, but not in other subtypes, is associated with unfavorable outcome. We identify TBX3 and PDK4 as genes co-expressed with estrogen receptor (ER) in the normal breasts, and their expression analyses in >550 breast cancers enable prognostically relevant subclassification of ER+ breast cancers.

Threshold disorder as a source of diverse and complex behavior in random nets.

We study the diversity of complex spatio-temporal patterns in the behavior of random synchronous asymmetric neural networks (RSANNs). Special attention is given to the impact of disordered threshold values on limit-cycle diversity and limit-cycle complexity in RSANNs which have 'normal' thresholds by default. Surprisingly, RSANNs exhibit only a small repertoire of rather complex limit-cycle patterns when all parameters are fixed. This repertoire of complex patterns is also rather stable with respect to small parameter changes. These two unexpected results may generalize to the study of other complex systems. In order to reach beyond this seemingly disabling 'stable and small' aspect of the limit-cycle repertoire of RSANNs, we have found that if an RSANN has threshold disorder above a critical level, then there is a rapid increase of the size of the repertoire of patterns. The repertoire size initially follows a power-law function of the magnitude of the threshold disorder. As the disorder increases further, the limit-cycle patterns themselves become simpler until at a second critical level most of the limit cycles become simple fixed points. Nonetheless, for moderate changes in the threshold parameters, RSANNs are found to display specific features of behavior desired for rapidly responding processing systems: accessibility to a large set of complex patterns.