Decoding intestinal crypt morphogenesis: From tissue mechanics to tumor initiation

Intestinal cancers are among the most prevalent epithelial malignancies and constitute a major clinical burden, largely due to late diagnosis and difficulty of predicting disease progression. Tumorigenesis mainly initiates within intestinal crypts, which harbor stem cell (SC) and sustain lifelong epithelial renewal. Extensive work has defined the molecular regulation of SC identity and proliferation but the principles governing crypt morphogenesis and tumoral drift remain far less understood. Crypt integrity relies on precise tissue architecture, cell behavior, and mechanical homeostasis. Disruption of these parameters represents an early and decisive step toward malignant transformation. While the genetic and histopathological landscapes of intestinal cancer are well characterized, earliest cellular and tissue-level events that destabilize crypts are poorly understood. Moreover, intestinal crypts are dynamic structures that undergo continuous remodeling through crypt fission, a process essential for postnatal growth and adult tissue maintenance. During fission, a mature crypt splits into two daughter crypts. Fission dysfunctions lead to aberrant crypts, that seed microadenomas. Although early work suggested that division orientation defects can promote abnormal fission, the underlying mechanisms remain poorly defined. Emerging evidence indicates that SCs/niche cells organization may jointly drive crypt remodeling. Notably, mechanical inflation can induce crypt branching in organoids, but in vivo this occurs primarily under pathological conditions, underscoring the importance of mechanical control. Thus, despite its physiology and pathological significance, crypt fission is still a little-known and insufficiently studied biological process.

Altogether, these gaps critically limit our ability to identify early markers of intestinal cancer and to develop rational preventive strategies. Addressing them is essential to uncover how physical and biological processes cooperate during crypt morphogenesis to maintain intestinal homeostasis—and how their failure initiates tumorigenesis. For that purpose, we developed an integrated approach combining intestinal models (2D/3D organoids, mouse genetics, and human samples) with molecular analyses, quantitative live imaging adapted to 3D tissues and biophysical analyses. More precisely, we examine how genetic programs, cytoskeletal mechanics, and tissue architecture collectively sustain intestinal function, and how their breakdown promotes pre-tumoral evolution.

Delphine DELACOUR is a CNRS Research Director, group leader at the Institute for Developmental Biology of Marseille (IBDM, Marseille, France). She made key discoveries in cell adhesion, division, cytoskeletal dynamics in mammals. She also made major contributions in molecular mechanisms underlying mechanical regulation of epithelial integrity.  She has expertise in studying epithelial cell and tissue dynamics, particularly in the mammalian intestine, using 2D and 3D cultures. In 2017, she received the Prize for Research on Rare Intestinal Diseases from the Groupama Foundation. The accomplished work established the team in the domain of epithelial cell mechanics and tissue integrity maintenance in mammalian epithelial intestine.