Dr. Maxime Bouchard
Rosalind & Morris Goodman Cancer Research Centre
Department of Biochemistry
Canada Research Chair in developmental genetics of the urogenital system, Government of Canada
Our research program is centered on epithelial morphogenesis and homeostasis. Based on the fascinating parallel between embryo development and cancer, we address crucial questions central to both fields such as stem cells, apoptosis and cell plasticity in the mouse urogenital system (kidney, ureter, prostate). This powerful model provides relatively simple features allowing a comprehensive cell biological approach to vertebrate organogenesis, neonatal malformations and cancer recurrence. Our work directly impacts castrate-resistant prostate cancer (stem cell, apoptosis) and Congenital Anomalies of the Kidney and Urinary Tract. Our main research themes are: Stem cell homeostasis and lineage specification in development, regeneration and cancer; Epithelial cell plasticity during embryonic kidney development and prostate cancer; Apoptotic cell signaling in morphogenesis and regeneration.
Our team primarily used genetic mouse models in combination with ex vivo, cellular and biochemical assays to elucidate the molecular mechanisms underlying developmental and neoplastic diseases of the urinary tract and prostate.
Molecular network of urogenital system development
Congenital malformations of the urogenital system (UGS) are found in one per 500 live births, and therefore constitute one of the most frequent birth defects. They include a number of developmental anomalies at the level of the kidney (e.g. hydronephrosis, hypoplasia, adysplasia) or the urinary tract (e.g. duplex kidneys, ectopic ureter-bladder connections). These malformations often lead to severe renal dysfunction. The central aspects of urogenital system (UGS) morphogenesis include the formation of the pro/ mesonephros (earliest embryonic renal tissue), induction and growth of the metanephros (definitive kidney) and maturation of the urinary tract. Reports from our laboratory and others, revealed the important role played by Pax and Gata transcription factors in urogenital system development. The search for transcriptional targets of these proteins revealed a hierarchy between Pax2/8, Gata3 and other known transcriptional regulators of UGS development. In addition, Pax and Gata factors regulate the expression of effector proteins such as the signaling molecule Ret (Figure 1) involved in the morphogenesis, growth and differentiation of UGS components. We try to elucidate the gene regulatory network by which cellular adhesion, proliferation, cell survival and cell shape changes achieve the complex process of urogenital system morphogenesis.
Urinary tract maturation
Several of the malformations affecting the urogenital system result from a failure to complete distal ureter maturation, the morphogenetic process by which the newly formed ureter separates from the nephric duct (primordium of the vas deferens), to reach its final position within the bladder wall (Figure 2). Surprisingly, relatively little is known about the morphological, cellular and molecular aspects underlying distal ureter maturation. Our team recently identified two members of the Leukocyte-Antigen-Related Receptor Protein Tyrosine Phosphatases (LAR-RPTPs), namely RPTP-σ (PTPRS) and LAR (PTPRF), as required for normal UGS morphogenesis (Figure 3). RPTP-σ;LAR double-mutant embryos indeed exhibit UGS defects such as hydronephrosis, hydroureter and ureterocele. These are typical cases of obstructive nephropathies resulting from distal ureter maturation defects. In the absence of RPTP-σ and LAR, the apoptotic program necessary for distal ureter maturation fails to occur normally, resulting in inappropriate tissue survival and maturation delay. This exciting observation raises a number of key questions such as the identity of the RPTP substrates and interaction partners involved in the apoptotic process and whether RPTPs act upstream or downstream of the apoptotic trigger. Hence, a central goal of this research program is to understand the crucial role of LAR-family of receptor tyrosine phosphatases in the regulation of apoptosis-triggered distal ureter maturation and to identify the signaling pathways they modulate.
Prostate stem cells in development, regeneration and cancer
Another major interest of our laboratory is the role of stem cells in prostate development, regeneration and cancer. Prostate cancer, which is the most prevalent cancer in men, presents major therapeutic challenges as it frequently recurs in a form that is insensitive to hormone-withdrawal therapy (i.e. castrate–resistant tumors), and develops resistance to therapeutic treatment such as Abiraterone and Enzalutamide. We previously identified a crucial role for the transcription factor Gata3 in the prevention of prostate cancer progression. As castrate-resistant prostate cancer is thought to emerge from cancer stem cells, we believe Gata3 plays a role in stem cell homeostasis. In line with this, we recently showed an important role for Gata3 in prostate development through the regulation of spindle orientation in stem/progenitor cells (Figure 3).