Fig. 7. Model for BCL9-dependent upregulation of calcium wave propagation among CRC cells and with the TME.

In wild-type C1 CRC cells (left) (e.g. RKO), the generation of spontaneous calcium transients through voltage-gated calcium channel opening, leads to neurotransmitter release and activation of neighboring cells bearing its receptor (e.g. GPCR) to promote calcium release and wave propagation. Simultaneously, CRC cell stimulation and calcium influx promote BCL9 accumulation around and interaction with paraspeckles, generating a positive feedback loop to stabilize mRNA of calcium associated genes (e.g. CACNA2D1) and ensuring the occurrence of the subsequent calcium transients. Thus, BCL9 translocation into paraspeckles provides C1 CRC cells with neuronal-like properties (e.g. cytoplasmic projections, calcium waves) to enhance communication among tumor cells and cells from the tumor microenvironment; this subsequently promotes tumor progression by enhancing tumor progression, tissue remodeling, stromal cell infiltration (e.g. macrophages, and endothelial cells). In C1 cells lacking BCL9 (right), the neuronal-like properties are lost; this is due to the lack of expression of genes associated with the generation of calcium waves, the disruption of the positive feed-back loop, and the fact that calcium waves are not strong enough to induce neurotransmitter release. This consequently terminates the propagation of calcium waves and communication among tumor cells and with the tumor microenvironment. I.R.C. represents interchromosomal region.