Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells
NATURE COMMUNICATIONS
Authors: Latos, Paulina A.; Goncalves, Angela; Oxley, David; Mohammed, Hisham; Turro, Ernest; Hemberger, Myriam
Abstract
Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.
Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy
CANCER CELL
Authors: Gide, Tuba N.; Quek, Camelia; Menzies, Alexander M.; Tasker, Annie T.; Shang, Ping; Holst, Jeff; Madore, Jason; Lim, Su Yin; Velickovic, Rebecca; Wongchenko, Matthew; Yan, Yibing; Lo, Serigne; Carlino, Matteo S.; Guminski, Alexander; Saw, Robyn P. M.; Pang, Angel; McGuire, Helen M.; Palendira, Umaimainthan; Thompson, John F.; Rizos, Helen; da Silva, Ines Pires; Batten, Marcel; Scolyer, Richard A.; Long, Georgina V.; Wilmott, James S.
Abstract
Cancer immunotherapies provide survival benefits in responding patients, but many patients fail to respond. Identifying the biology of treatment response and resistance are a priority to optimize drug selection and improve patient outcomes. We performed transcriptomic and immune profiling on 158 tumor biopsies from melanoma patients treated with anti-PD-1 monotherapy (n = 63) or combined anti-PD-1 and anti-CTLA-4 (n = 57). These data identified activated T cell signatures and T cell populations in responders to both treatments. Further mass cytometry analysis identified an EOMES(+)CD69(+)CD45RO(+) effector memory T cell phenotype that was significantly more abundant in responders to combined immunotherapy compared with non-responders (n = 18). The gene expression profile of this population was associated with longer progression-free survival in patients treated with single agent and greater tumor shrinkage in both treatments.
COA
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