• Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors

      Neo, Wen Hao; orcid: 0000-0002-6827-3027; email: wenhao.neo@cruk.manchester.ac.uk; Meng, Yiran; orcid: 0000-0002-9333-2383; Rodriguez-Meira, Alba; Fadlullah, Muhammad Z. H.; Booth, Christopher A. G.; orcid: 0000-0003-3841-6637; Azzoni, Emanuele; orcid: 0000-0002-4572-5692; Thongjuea, Supat; orcid: 0000-0002-9129-4694; de Bruijn, Marella F. T. R.; orcid: 0000-0002-4934-4125; Jacobsen, Sten Eirik W.; Mead, Adam J.; orcid: 0000-0001-8522-1002; email: adam.mead@imm.ox.ac.uk; et al. (Nature Publishing Group UK, 2021-12-02)
      Abstract: Yolk sac (YS) hematopoiesis is critical for the survival of the embryo and a major source of tissue-resident macrophages that persist into adulthood. Yet, the transcriptional and epigenetic regulation of YS hematopoiesis remains poorly characterized. Here we report that the epigenetic regulator Ezh2 is essential for YS hematopoiesis but dispensable for subsequent aorta–gonad–mesonephros (AGM) blood development. Loss of EZH2 activity in hemogenic endothelium (HE) leads to the generation of phenotypically intact but functionally deficient erythro-myeloid progenitors (EMPs), while the generation of primitive erythroid cells is not affected. EZH2 activity is critical for the generation of functional EMPs at the onset of the endothelial-to-hematopoietic transition but subsequently dispensable. We identify a lack of Wnt signaling downregulation as the primary reason for the production of non-functional EMPs. Together, our findings demonstrate a critical and stage-specific role of Ezh2 in modulating Wnt signaling during the generation of EMPs from YS HE.
    • Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

      Simões, Bruno M.; orcid: 0000-0003-1253-6657; email: bruno.simoes@manchester.ac.uk; Santiago-Gómez, Angélica; Chiodo, Chiara; Moreira, Tiago; Conole, Daniel; orcid: 0000-0002-3389-8377; Lovell, Scott; Alferez, Denis; Eyre, Rachel; Spence, Katherine; Sarmiento-Castro, Aida; et al. (Nature Publishing Group UK, 2020-05-30)
      Abstract: Estrogen receptor (ER) positive breast cancer is frequently sensitive to endocrine therapy. Multiple mechanisms of endocrine therapy resistance have been identified, including cancer stem-like cell (CSC) activity. Here we investigate SFX-01, a stabilised formulation of sulforaphane (SFN), for its effects on breast CSC activity in ER+ preclinical models. SFX‐01 reduced mammosphere formation efficiency (MFE) of ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and aldehyde dehydrogenase (ALDH) activity of patient-derived xenograft (PDX) tumors, which was reversed by combination with SFX‐01. SFX-01 significantly reduced tumor-initiating cell frequency in secondary transplants and reduced the formation of spontaneous lung micrometastases by PDX tumors in mice. Mechanistically, we establish that both tamoxifen and fulvestrant induce STAT3 phosphorylation. SFX-01 suppressed phospho‐STAT3 and SFN directly bound STAT3 in patient and PDX samples. Analysis of ALDH+ cells from endocrine-resistant patient samples revealed activation of STAT3 target genes MUC1 and OSMR, which were inhibited by SFX-01 in patient samples. Increased expression of these genes after 3 months’ endocrine treatment of ER+ patients (n = 68) predicted poor prognosis. Our data establish the importance of STAT3 signaling in CSC-mediated resistance to endocrine therapy and the potential of SFX-01 for improving clinical outcomes in ER+ breast cancer.