Apc-mutant cells act as supercompetitors in intestinal tumour initiation

Targeting the coronavirus nucleocapsid protein through GSK-3 inhibition

“…Lithium has a narrow therapeutic window, however, and the concentration needed to inhibit N phosphorylation and to impair infectivity of SARS-CoV-2 and other coronaviruses in cell culture ( 6 , 8 , 18 – 20 ) is above the therapeutic range in humans [peak level ∼2 mM, trough levels ∼1 mM ( 16 )] and the level that induces behavioral changes in model organisms. For example, 1 mM lithium is sufficient to inhibit GSK-3 in humans ( 33 ), alter GSK-3–dependent behaviors in mice ( 32 , 44 ), and activate Wnt signaling in the mouse intestine ( 45 , 46 ), whereas the IC 50 for inhibition of N phosphorylation and inhibition of SARS-CoV-2 replication, as well as inhibition of phosphorylation of established GSK-3 substrates, in cultured cells is ∼10 mM. It is not clear why higher concentrations were needed to inhibit GSK-3 in cell culture compared to in vivo studies but, given the narrow therapeutic window for lithium in bipolar disorder, alternative GSK-3 inhibitors may be better tolerated in clinical settings involving coronavirus infection.…”

Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas

“…Although Apc- mutant adenomas are independent of Wnt ligands ( 15 , 58 ), we found that several Wnt antagonists were decreased after Apc ; Lef1 deletion. This observation may be functionally significant, as a recent study showed that the secreted Wnt antagonist Notum produced by the Apc -mutant adenomas inhibits Wnt signaling in the neighboring WT ISCs ( 59 , 60 ). We found that LEF1 expression was restricted to ligand-independent CRCs, whereas it was not expressed in the ligand-dependent CRCs.…”

Colorectal Cancer Stem Cells: An Overview of Evolving Methods and Concepts

“…Further complexity is added to the picture by the finding that cCSCs are able to deliver inhibitory signals to normal intestinal cells, both directly and by inducing stromal cells to secrete specific factors. In this frame, two studies recently described the capability of Apc-mutated adenoma cells to inhibit stem cell activity of non-mutated cells within the same crypt and adjacent crypts through secretion of soluble Wnt antagonists [ 107 ]. Among these factors, a prominent role is played by NOTUM, whose pharmacological inhibition blocks adenoma formation [ 28 ].…”

“…As a final note, the growing impact of computational methods in research on cancer cell biology, and CSCs in particular, deserves a special mention. The analysis and management of the enormous amount of data generated by multi-omic techniques are in fact made possible only by the continuous development of dedicated algorithms, and most of the recent studies mentioned in this review have heavily taken advantage of increasingly sophisticated computational approaches (see for example [ 84 , 88 , 106 , 107 , 132 , 136 ]). Recent applications include meta-approaches able to integrate data derived from multiple different analytical tools, such as scDNA- and scRNA-sequencing [ 97 ].…”