During the progression of pancreatic ductal adenocarcinoma (PDAC), heterogeneous subclonal populations emerge that drive primary tumor growth, regional spread, distant metastasis, and patient death. ...However, the genetics of metastases largely reflects that of the primary tumor in untreated patients, and PDAC driver mutations are shared by all subclones. This raises the possibility that an epigenetic process might operate during metastasis. Here we report large-scale reprogramming of chromatin modifications during the natural evolution of distant metastasis. Changes were targeted to thousands of large chromatin domains across the genome that collectively specified malignant traits, including euchromatin and large organized chromatin histone H3 lysine 9 (H3K9)-modified (LOCK) heterochromatin. Remarkably, distant metastases co-evolved a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP), and oxPPP inhibition selectively reversed reprogrammed chromatin, malignant gene expression programs, and tumorigenesis. These findings suggest a model whereby linked metabolic-epigenetic programs are selected for enhanced tumorigenic fitness during the evolution of distant metastasis.
amplification occurs in approximately 15% of estrogen receptor-positive (ER
) human breast cancers. We investigated mechanisms by which
amplification confers antiestrogen resistance to ER
breast ...cancer.
ER
tumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER
/
-amplified breast cancer cells, and patient-derived xenografts (PDX) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by coimmunoprecipitation and proximity ligation, ER genomic activity by ChIP sequencing, and gene expression by RT-PCR.
ER
/
-amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER
/
amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER
/
-amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from
-amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER
/
amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone.
s
These data suggest the ERα pathway remains active in estrogen-deprived ER
/
-amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists.
.
Background
Cancer resequencing studies have revealed epigenetic enzymes as common targets for recurrent mutations. The monomethyltransferase MLL3 is among the most recurrently mutated enzymes in ER+ ...breast cancer. The H3K4me1 marks created by MLL3 can define enhancers. In ER+ breast cancer, ERα genome‐binding sites are primarily distal enhancers. Thus, we hypothesize that mutation of MLL3 will alter the genomic binding and transcriptional regulatory activity of ERα.
Methods
We investigated the genomic consequences of knocking down MLL3 in an MLL3/PIK3CA WT ER+ breast cancer cell line.
Results
Loss of MLL3 led to a large loss of H3K4me1 across the genome, and a shift in genomic location of ERα‐binding sites, which was accompanied by a re‐organization of the breast cancer transcriptome. Gene set enrichment analyses of ERα‐binding sites in MLL3 KD identified endocrine therapy resistance terms, and we showed that MLL3 KD cells are resistant to tamoxifen and fulvestrant. Many differentially expressed genes are controlled by the small collection of new locations of H3K4me1 deposition and ERα binding, suggesting that loss of functional MLL3 leads to new transcriptional regulation of essential genes. Motif analysis of RNA‐seq and ChIP‐seq data highlighted SP1 as a critical transcription factor in the MLL3 KD cells. Differentially expressed genes that display a loss of ERα binding upon MLL3 KD also harbor increased SP1 binding.
Conclusions
Our data show that a decrease in functional MLL3 leads to endocrine therapy resistance. This highlights the importance of genotyping patient tumor samples for MLL3 mutation upon initial resection, prior to deciding upon treatment plans.
MLL3 is the 6th most commonly mutated gene in ER+ breast cancer patients, however its role in regulating the transcriptional activity of ERα in breast cancer is still unclear. Our data imply that mutations in MLL3 lend to endocrine therapy resistance through an altered genomic enhancer and ERα binding landscape resulting in an altered transcriptome, and therefore genotyping should be done prior to deciding upon course of treatment.
In response to estrogens, estrogen receptor alpha (ERα), a critical regulator of homeostasis, is degraded through the 26S proteasome. However, despite the continued presence of estrogen before ...menopause, ERα protein levels are maintained. We discovered that ERK1/2-RSK2 activity oscillates during the estrous cycle. In response to high estrogen levels, ERK1/2 is activated and phosphorylates ERα to drive ERα degradation and estrogen-responsive gene expression. Reduction of estrogen levels results in ERK1/2 deactivation. RSK2 maintains redox homeostasis, which prevents sustained ERK1/2 activation. In juveniles, ERK1/2-RSK2 activity is not required. Mammary gland regeneration demonstrates that ERK1/2-RSK2 regulation of ERα is intrinsic to the epithelium. Reduced RSK2 and enrichment in an estrogen-regulated gene signature occur in individuals taking oral contraceptives. RSK2 loss enhances DNA damage, which may account for the elevated breast cancer risk with the use of exogenous estrogens. These findings implicate RSK2 as a critical component for the preservation of estrogen homeostasis.
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•ERK1/2-RSK2 signaling maintains estrogen homeostasis in the adult mouse•ERK1/2 drives ERα degradation and estrogen-mediated transcription•RSK2 prevents sustained ERK1/2 activity by inhibiting ROS production•Oral contraceptives correlate with lowered RSK2 and an enhanced estrogen response
Ludwik et al. find that ERK1/2-RSK2 activity oscillates with each reproductive cycle. The estrogen surge activates ERK1/2, which phosphorylates estrogen receptor alpha to drive estrogen responsiveness. Active RSK2 acts as a brake on the estrogen response by maintaining redox homeostasis. Oral contraceptive use correlates with disruption of ERK1/2-RSK2 regulation.
Avian diet selection is hypothesized to be sensitive to seasonal changes in breeding status, but few tests exist for frugivorous tropical birds. Frugivorous birds provide an interesting test case ...because fruits are relatively deficient in minerals critical for reproduction. Here, we quantify annual patterns of fruit availability and diet for two frugivorous hornbill (Bucerotidae) species over a 5.5-y period to test for patterns of diet selection. Data from the lowland tropical rain forest of the Dja Reserve, Cameroon, are used to generate two nutritional indices. One index estimates the nutrient concentration of the diet chosen by Ceratogymna atrata and Bycanistes albotibialis on a monthly basis using 3165 feeding observations combined with fruit pulp sample data. The second index is an estimate of nutrient concentration of a non-selective or neutral diet across the study area based on tree fruiting phenology, vegetation survey and fruit-pulp sample data. Fifty-nine fruit pulp samples representing 40 species were analysed for 16 nutrient categories to contribute to both indices. Pulp samples accounted for approximately 75% of the observed diets. The results support expected patterns of nutrient selection. The two hornbill species selected a diet rich in calcium during the early breeding season (significantly so for B. albotibialis in July and August). Through the brooding and fledging periods, they switched from a calcium-rich diet to one rich in iron and caloric content as well as supplemental protein in the form of invertebrates. Calcium, the calcium to phosphorus ratio and fat concentration were the strongest predictors of breeding success (significant for calcium and Ca:P for B. albotibialis in June). We conclude that hornbills actively select fruit based on nutritional concentration and mineral concentration and that the indices developed here are useful for assessing frugivore diet over time.
Seed dispersal is a process critical to the maintenance of tropical forests, yet little is known about the interactions of most dispersers with their communities. In the Dja Reserve, Cameroon, seed ...dispersal by the hornbills Certaogymna atrata, C. cylindricus and C. fistulator (Aves: Bucerotidae) was evaluated with respect to the taxonomic breadth of plants dispersed, location of seed deposition and effects on seed germination. Collectively, the three hornbill species consumed fruits from 59 tree and liana species, and likely provided dispersal for 56 of them. Hornbill-dispersed tree species composed 22% of the known tree flora of the site. Hornbill visit lengths, visit frequencies, and seed passage times indicated that few seeds were deposited beneath parent trees; in five hornbill/tree species pairings studied, 69–100% of the seeds ingested were deposited away from the parent trees. Germination trials showed that hornbill gut passage is gentle on seeds. Of 24 tree species tested, 23 germinated after passage by hornbills; of 17 planted with controls taken directly from trees, only four species showed evidence of inhibition of germination rate, while seven experienced unchanged germinated rates and six experienced enhanced germination rates. Results suggested that Certaogymna hornbill rank among the most important seed dispersers found in Afrotropical forests, and they deserve increased conservation attention. Ceratogymna hornbills are likely to become increasingly important in forest regeneration as populations of larger mammalian seed dispersers (such as forest elephants and primates) diminish.
Abstract Intraspecific biodiversity is vital for species persistence in an increasingly volatile world. By embracing methods that integrate information at different spatiotemporal scales, we can ...directly monitor and reconstruct changes in intraspecific biodiversity. Here we combined genetics and otolith biochronologies to describe the genotypic and phenotypic diversity of Chinook salmon ( Oncorhynchus tshawytscha ) in the Yuba River, California, comparing cohorts that experienced a range of hydroclimatic conditions. Yuba River salmon have been heavily impacted by habitat loss and degradation, and large influxes of unmarked hatchery fish each year have led to concern about introgression and uncertainty around the viability of its wild populations, particularly the rarer spring‐run salmon. Otolith strontium isotopes showed that Yuba River origin fish represented, on average, 42% (range 7%–73%) of spawners across six return years (2009–2011, 2018–2020), with large interannual variability. The remainder of adult Chinook salmon in the river were primarily strays from the nearby Feather River hatchery, and since 2018 from the Mokelumne River hatchery. Among the Yuba‐origin spawners, on average, 30% (range 14%–50%) exhibited the spring‐run genotype. The Yuba‐origin fish also displayed a variety of outmigration phenotypes that differed in the timing and size at which they left the Yuba river. Early‐migrating fry dominated the returns (mean 59%, range 33%–89%), and their contribution rates were negatively correlated with freshwater flows. It is unlikely that fry survival rates are elevated during droughts, suggesting that this trend reflects disproportionately low survival of larger later migrating parr, smolts, and yearlings along the migratory corridor in drier years. Otolith daily increments indicated generally faster growth rates in non‐natal habitats, emphasizing the importance of continuing upstream restoration efforts to improve in‐river growing conditions. Together, these findings show that, despite a long history of habitat degradation and hatchery introgression, the Yuba River maintains intraspecific biodiversity that should be taken into account in future management, restoration, and reintroduction plans. The finding that genotypic spring‐run are reproducing, surviving, and returning to the Yuba River every year suggests that re‐establishment of an independent population is possible, although hatchery‐wild interactions would need to be carefully considered. Integrating methods is critical to monitor changes in key genetic, physiological, and behavioral traits to assess population viability and resilience.
To compare group and individual psychedelic-assisted therapy in terms of clinician time, costs and patient access.
Using 2023 data from two group therapy trial sites, one using ...3,4-Methylenedioxymethamphetamine (MDMA) to treat posttraumatic stress disorder (PTSD), and one using psilocybin to treat major depressive disorder (MDD), we compared overall variable costs, clinician costs and clinician time required by therapy protocols utilizing groups versus individual patient therapy. Using published literature, we estimated the prevalence of adults with PTSD and MDD eligible for treatment with psychedelic therapy and projected the savings in time and cost required to treat these prevalent cases.
Group therapy saved 50.9% of clinician costs for MDMA-PTSD and 34.7% for psilocybin-MDD, or $3,467 and $981 per patient, respectively. To treat all eligible PTSD and MDD patients in the U.S. in 10 years with group therapy, 6,711 fewer full-time equivalent (FTE) clinicians for MDMA-PTSD and 1,159 fewer for FTE clinicians for psilocybin-MDD would be needed, saving up to $10.3 billion and $2.0 billion respectively, discounted at 3% annually.
Adopting group therapy protocols where feasible would significantly reduce the cost of psychedelic-assisted therapies. By enhancing the number of patients served per clinician, group therapy could also ameliorate the anticipated shortage of appropriately trained clinicians, thereby accelerating access to these promising new therapies.
Throughout spring and summer 2020, ozone stations in the northern extratropics recorded unusually low ozone in the free troposphere. From April to August, and from 1 to 8 kilometers altitude, ozone ...was on average 7% (≈4 nmol/mol) below the 2000–2020 climatological mean. Such low ozone, over several months, and at so many stations, has not been observed in any previous year since at least 2000. Atmospheric composition analyses from the Copernicus Atmosphere Monitoring Service and simulations from the NASA GMI model indicate that the large 2020 springtime ozone depletion in the Arctic stratosphere contributed less than one-quarter of the observed tropospheric anomaly. The observed anomaly is consistent with recent chemistry-climate model simulations, which assume emissions reductions similar to those caused by the COVID-19 crisis. COVID-19 related emissions reductions appear to be the major cause for the observed reduced free tropospheric ozone in 2020.
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