Changes in Stem Cell Regulation and Epithelial Organisation during Carcinogenesis and Disease Progression in Gynaecological Malignancies

Simple Summary Recent advances in our understanding of the stem cell potential in adult tissues have far-reaching implications for cancer research, and this creates new opportunities for the development of new therapeutic strategies. Here we outline changes in stem cell biology that characterize main gynaecological malignancies, ovarian, endometrial, and cervical cancer, and focus on specific differences between them. We highlight the importance of the local niche environment as a driver of malignant transformation in addition to mutations in key cancer-driving genes. Patient-derived organoids capture in vitro main aspects of cancer tissue architecture and stemness regulatory mechanisms, thus providing a valuable new platform for a personalized approach in the treatment of gynecological malignancies. This review summarizes the main achievement and formulates remaining open questions in this fast-evolving research field. Abstract Gynaecological malignancies represent a heterogeneous group of neoplasms with vastly different aetiology, risk factors, molecular drivers, and disease outcomes. From HPV-driven cervical cancer where early screening and molecular diagnostics efficiently reduced the number of advanced-stage diagnosis, prevalent and relatively well-treated endometrial cancers, to highly aggressive and mostly lethal high-grade serous ovarian cancer, malignancies of the female genital tract have unique presentations and distinct cell biology features. Recent discoveries of stem cell regulatory mechanisms, development of organoid cultures, and NGS analysis have provided valuable insights into the basic biology of these cancers that could help advance new-targeted therapeutic approaches. This review revisits new findings on stemness and differentiation, considering main challenges and open questions. We focus on the role of stem cell niche and tumour microenvironment in early and metastatic stages of the disease progression and highlight the potential of patient-derived organoid models to study key events in tumour evolution, the appearance of resistance mechanisms, and as screening tools to enable personalisation of drug treatments.