Epigenetic repression of inflammatory cytokine production by oncogenic fusion proteins in endometrial stromal sarcoma

Primary supervisor: Richard Jenner, UCL

Secondary supervisor: Michelle Lockley, Queen Mary University of London

Project

Endometrial stromal sarcoma (ESS) is a rare uterine cancer that primarily effect premenopausal women. The two subtypes of high-grade ESS (HG-ESS) have poor prognoses with median progression-free-survival of only 7 to 11 months. Low-grade ESS (LG-ESS) has a more indolent course, but patients suffer from frequent relapses that can occur long after surgery, thus requiring long-term follow-up.

LG-ESS exhibits fusions between subunits of the repressive epigenetic regulator PRC2 and the activating epigenetic regulator NuA4 (Tip60), the most common being the JAZF1-SUZ12 fusion protein. HG-ESS is divided into two subtypes that exhibit different fusion events: those exhibiting YWHAE gene fusions and those with BCOR gene fusions. Despite the identification of these driver events, how the fusion proteins affect endometrial stromal cell state and how this leads to tumour formation are not well understood. Because of this, the standard of care for ESS, hysterectomy and bilateral salpingo-oophorectomy, is rarely curative and has not changed in decades

We have recently determined how JAZF1-SUZ12 alters epigenetic state and gene expression in the tumour cell of origin, human endometrial stromal cells (hEnSC) (Tavares et al., 2022). During the menstrual cycle, hEnSC differentiate into decidual cells that are then shed from the endometrium. We found that JAZF1-SUZ12 inhibits PRC2 activity and recruits NuA4, opening chromatin at normally repressed PRC2 target genes. These epigenetic changes result in ectopic activation of part of the stromal cell decidualisation gene expression programme while repressing expression of inflammatory cytokines, such as IL-15, CXCL1 and IL-8, that normally activate uterine natural killer (uNK) cells and other immune cells to clear hEnSC from the endometrium.

The Clinical Research Training Fellow will build upon these breakthroughs to discover how the three ESS subtypes develop and identify potential new treatments that target these mechanisms. The fellow will determine whether the inhibition of cytokine secretion by JAZF1-SUZ12 impairs immune cell-mediated killing of hEnSC and primary tumours, and whether this can be rescued by exogenous cytokine addition. They will also test whether other LG-ESS fusion proteins have similar effects to JAZF1-SUZ12, providing insight into how different gene fusions cause the same disease. The fellow will then extend this work to determine the effect of HG-ESS fusion proteins on hEnSC, increasing understanding of the basis for these more aggressive subtypes. Finally, they will test whether NuA4 inhibitors block the pathological effects of LG-ESS and HG-ESS fusion proteins.

Primary hEnSC from women without cancer will be provided by donors attending the Implantation Clinic at the University of Coventry and Warwickshire NHS Trust through our collaborator, Jan Brosens. ESS samples will be provided via the Barts Gynae Tissue Bank and the UCL/UCLH Biobank.

In summary, the research performed by the fellow will dissect the mechanisms through which fusion proteins cause ESS and, in doing so, open the door to targeted treatments for this set of understudied sarcomas.

Candidate background

This project would suit candidates with a background in gynaecological oncology or sarcoma with an interest in the immune microenvironment and/or epigenetic reprogramming in cancer.

References

1. Capozzi VA, Monfardini L, Ceni V, Cianciolo A, Butera D, Gaiano M, & Berretta R. Endometrial stromal sarcoma: A review of rare mesenchymal uterine neoplasm. J Obstet Gynaecol Res. 46:2221-2236 (2020).
2.  Y, Kim D, Sung WJ, & Hong J. High-Grade Endometrial Stromal Sarcoma: Molecular Alterations and Potential Immunotherapeutic Strategies. Front Immunol. 13:837004 (2022).
3. Tavares M, Khandelwal G, Muter J, Viiri K, Beltran M, Brosens JJ, & Jenner RG. JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation. Cell Rep. 39:110889 (2022).
4. Brighton PJ, Maruyama Y, Fishwick K, Vrljicak P, Tewary S, Fujihara R, Muter J, Lucas ES, Yamada T, Woods L, Lucciola R, Hou Lee Y, Takeda S, Ott S, Hemberger M, Quenby S, Brosens JJ. Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. Elife. 6:e31274 (2017).