Investigation of RUNX1 in Normal Prostate and Prostate Cancer

Abstract

Prostate cancer (PCa) is the most commonly diagnosed cancer in men, and it remains challenging to accurately stratify patients diagnosed with indolent and aggressive forms of PCa, such as castration-resistant PCa. The lack of prognosis biomarkers represents therefore a central challenge to avoid a worsening problem of over diagnosis and treatment. In the recent years, there has been a growing body of literature involving the master regulator of haematopoiesis RUNX1 in non-haematopoietic cancers, including hormone-regulated epithelial tissues, suggesting that this transcription factor could be broadly implicated in the biology and pathology of epithelial tissues. These intriguing new findings led us to propose that RUNX1 plays a role in normal prostate homeostasis and prostate tumorigenesis. To explore this hypothesis, RUNX1 expression was characterised in the mouse prostate. RUNX1 was expressed in a specific subpopulation of proximal luminal cells (PLCs), enriched in the peri-urethral region of the developing and adult prostate, distinct from the previously identified NKX3.1+ luminal castration resistant cells. Functionally, RUNX1+ PLCs are not committed to the secretory function and display facultative stem cell behaviour in organoid assays. Single-cell RNA-sequencing profiling and genetic lineage tracing revealed that RUNX1+ PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, a transcriptionally similar RUNX1+ population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Thus, RUNX1+ PLCs constitutes an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development. Finally, the expression of RUNX1 was investigated in patient samples to evaluate whether RUNX1 could be exploited as a clinical marker of PCa. In benign prostate glands, RUNX1 was low in secretory luminal cells but higher in atrophic epithelia. RUNX1 was rarely expressed in tumours, but a limited number of high-grade tumours exhibited very high RUNX1 levels. However, overall survival analyses revealed poor prognostic performance of RUNX1 used as a single marker or in combination with NKX3.1.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Georges Lacaud (Supervisor) & Esther Baena Chaparro (Supervisor)