Periodic Reporting for period 2 - MOMENDO (Molecular Mechanisms of Endometriosis)
Reporting period: 2018-01-01 to 2019-12-31
Endometriosis (the presence of endometrial-like tissue in sites outside the uterus) is a common condition, affecting 6-10% of women of reproductive age. Endometriosis is a chronic inflammatory disease that is associated with pelvic pain, painful periods, pain with sexual intercourse, and subfertility. It has a significant impact on health-related quality of life, as recent studies reported that endometriosis had affected work in 51% of the women and affected relationships in 50% of the women at some time during their life with a negative impact on quality of life, and it has been estimated that the health burden and public health costs associated with endometriosis are high with over 9000€ per woman per year in the EU. Current treatment strategies for endometriosis are restricted to surgical excision of the lesions or suppression of ovarian function to mimic a premature menopause. In up to 75% of cases, symptoms recur after surgery, and long-term ovarian suppression is often ineffective, suppresses fertility and has unwelcome side effects. Therefore, there is an unmet clinical need for new treatments for endometriosis. Identification of relevant molecular mechanisms which are functionally linked to the patient symptoms is therefore a major priority. The MOMENDO consortium was comprised of an internationally competitive and recognized interdisciplinary team dedicated to identifying novel pathogenetic mechanisms of endometriosis by utlilizing innovative techniques and etiological concepts, and by incorporating state-of-the-art topics in biomedical research. To reach this goal, we focussed on aspects of the disease which are of particular relevance to patient symptoms which have a major negative impact on quality of life, namely (i) molecular mechanisms of endometriosis-associated pain, (ii) new mechanisms linked to chronic inflammation in endometriosis, and (iii) novel, state-of-the-art etiological concepts (iron overload, microRNA involvement, endometrial stem cells). The knowledge generated by these studies was ultilized and combined with novel therapeutic concepts, including (iv) novel endocrine approaches, (v) a targeting of metabolic mechanisms in the inflammatory microenvironment, (vi) the use of herbal medicines with antioxidant activity and (vii) the induced differentiation of endometriotic and cancer stem cells as a tool of overcoming unlimited growth of endometriotic lesions and (viii) the use of iron-chelating reagents as an antiinflammatory measure in peritoneal endometriosis. Overall, MOMENDO made a major contribution to the molecular understanding of disease mechanisms which will help to develop new therapies for the disease.
We have demonstrated that endometriotic lesions contain a higher amount of nociceptive neurons than surrounding control tissue, and that this imbalance is due to an altered steroidal milieu. The role of the extracellular matrix in the pathogenesis of endometriosis was explored, demonstrating a role for the matrix receptor Syndecan-1 and the carbohydrate hyaluronan in the disease. Both factors were also found to be linked to a stem cell function as a possible prerequisite for unlimited proliferation and persistence of endometriotic lesions. The new concept of iron overload was extended to the field of microRNAs and extracellular matrix research demonstrating a novel role for the proteoglycan syndecan-1 in the activation of the inflammatory factor NF-kB. Furthermore, we made important contributions to the characterization of endometriotic and endometriosis-associated cancer stem cells, defining their marker signature. Extending the analysis to the individual patient level through global transcriptomic analyses of patient derived spheroids, new insights towards individualized therapies were gained in this study towards the link between endometriosis and malignancies. Further highlights are the demonstration of preclinical anti-endometriotic efficacy of natural antioxidant drugs against endometriotic invasiveness and a stem cell phenotype, and the application of novel endocrine approaches in the treatment of endometriosis-associated pain, based on novel clinicopathological findings of our consortium. Considering the socioeconomic burden of endometriosis, these outputs of MOMENDO have considerable societal and IP-related implications. For example, analytical AFM developed by Serend-IP, detecting cell structures a million times smaller than a millimeter, allows to distinguish aggressive endometriotic from less aggressive cells. We published the project results in 13 scientific publications so far, and presented them to the scientific community at several international conferences. Moreover, we successfully trained 26 young researchers in the multidisciplinary field of endometriosis research.
Endometriosis research is an under-investigated area particularly from a mechanistic point of view, and the contributions we made to understand how pain symptoms are generated in endometriosis, and how they can be approached therapeutically is an important addition to the field. Several innovative techniques and subtopics with high commercialization potential for analytics, diagnostics and therapeutics are part of the work performed. The application of quantitative AFM, stem cell analysis, novel modes of endocrine regulation and microRNAs are highly novel aspects. MOMENDO has resulted in a broad panel of preclinical therapeutic applications of the aforementioned innovative analytical techniques in several cell models, in proprietary in vivo models, and in patient-derived samples. We have explored epigenetic regulation in mechanistic detail to provide sufficient data in preclinical models to assess their potential for drug development. Our data provide new mechanistic insights into the pathogenesis of endometriosis with respect to the clinically most relevant phenotypic representations. Preclinical data for novel therapeutic approaches were generated, including miRNA drugs, novel natural drugs, and novel inhibitors of endometriotic stem cells. The re-purposing of drugs such as DCA, the successful eveluation of natural compounds such as rosmarinic acid and wogonin, gamma-secretase inhibitors and microRNA-based reagents serve as examples. We have published 13 Open Access manuscripts in well-reputed scientific journals so far, and expect a substantial amount of additional publications.
We will have strengthened the European research area by establishing a novel and strong network of European and non-European researchers benefitting considerably from the exchange of expertise and resources, thus strengthening their position as opinion leaders. Importantly, we expect to have strengthened cooperation between academic and non-academic partners for their mutual benefit, and we expect to exploit the translational potential of this project in the fields of quantitative AFM, novel endocrine approaches, as well as miRNA- and natural substance-based endometriosis therapeutics. By this way, the impact on society is expected to be high, as young European researchers receive excellent interdisciplinary training in an important and specialized research area for which we expect a high future demand both in the academic community and in industry. By closing important knowledge gaps in the area of endometriosis research, we expect to make a major contribution to the preclinical development of more efficient drugs and diagnostics.
We will have strengthened the European research area by establishing a novel and strong network of European and non-European researchers benefitting considerably from the exchange of expertise and resources, thus strengthening their position as opinion leaders. Importantly, we expect to have strengthened cooperation between academic and non-academic partners for their mutual benefit, and we expect to exploit the translational potential of this project in the fields of quantitative AFM, novel endocrine approaches, as well as miRNA- and natural substance-based endometriosis therapeutics. By this way, the impact on society is expected to be high, as young European researchers receive excellent interdisciplinary training in an important and specialized research area for which we expect a high future demand both in the academic community and in industry. By closing important knowledge gaps in the area of endometriosis research, we expect to make a major contribution to the preclinical development of more efficient drugs and diagnostics.