Biology subjects

Santos, C. P.

Publications and source records attributed to Santos, C. P..

3 recordsLinked to original sources

bioRxiv2018

Urothelial organoids originate from Cd49f-High stem cells and display Notch-dependent differentiation capacity

The urothelium is a specialized stratified epithelium with unique structural and functional features. Understanding the mechanisms involved in urothelial stem cell biology and differentiation has been limited by the lack of methods for unlimited propagation. Here, we establish normal mouse urothelial organoid (NMU-o) cultures that can be maintained uninterruptedly for >1 year. Organoid growth is dependent on EGF and Wnt activators. High CD49f/ITGA6 expression features a subpopulation of organoid-forming urothelial stem cells expressing basal markers. On induction of differentiation, multilayered organoids show reduced layer number, acquire barrier function, and activate the urothelial program, including expression of uroplakins and tight junction components. Combined pharmacological modulation of PPAR{gamma} and EGFR was most potent driving cell differentiation. Transcriptome analysis of organoids widely validates the system, highlights the transcriptional networks involved, and reveals NOTCH signaling as a novel pathway required for normal urothelial organoid differentiation.

cell biology↗

bioRxiv2017

Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.

cancer biology↗

bioRxiv2017

Hardwired synthetic lethality within the cohesin complex in human cancer cells

Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 act redundantly to support sister chromatid cohesion and cell survival. STAG1 represents a hardwired, context independent vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.

cell biology↗