Normalizing Input-Output Relationships of Cancer Networks for Reversion Therapy.

Accumulated genetic alterations in cancer cells distort cellular stimulus-response (or input-output) relationships, resulting in uncontrolled proliferation. However, the complex molecular interaction network within a cell implicates a possibility of restoring such distorted input-output relationships by rewiring the signal flow through controlling hidden molecular switches. Here, a system framework of analyzing cellular input-output relationships in consideration of various genetic alterations and identifying possible molecular switches that can normalize the distorted relationships based on Boolean network modeling and dynamics analysis is presented. Such reversion is demonstrated by the analysis of a number of cancer molecular networks together with a focused case study on bladder cancer with in vitro experiments and patient survival data analysis. The origin of reversibility from an evolutionary point of view based on the redundancy and robustness intrinsically embedded in complex molecular regulatory networks is further discussed.

Up-regulated fibronectin in 3D culture facilitates spreading of triple negative breast cancer cells on 2D through integrin ß-5 and Src.

Using MDA-MB-231 cells as a model of triple negative breast cancer (TNBC) and its metastatic sub-cell lines that preferentially metastasize to lung, bone or brain, we found that the mRNA and protein levels of fibronectin (FN) are increased in MDA-MB-231 cells and its lung metastatic derivative, when cultivated in three-dimensional (3D) suspension cultures. The increase of FN expression in 3D was dependent on p38 mitogen-activated protein kinase (MAPK) because it was prevented by treatment of cells with SB203580, an inhibitor of p38MAPK. The up-regulated FN was converted into fibrils, and it enhanced cell spreading when cells cultured in 3D were transferred to two-dimensional (2D) culture. The arginine-glycine-aspartate (RGD) peptides and siRNAs targeting of integrin ß-5 inhibited spreading of cells regardless of the presence of FN on 2D culture dishes. In addition, the levels of phosphorylated Src were found to be increased in 3D and the treatment of cells with SU6656, an inhibitor of Src, decreased the rate of cell spreading on FN. Collectively, these studies demonstrate that increased cellular FN in 3D suspension culture facilitates cancer cell attachment and spreading via integrin ß-5 and Src, suggesting that the increased FN promotes initial attachment of cancer cells to secondary organs after circulation during metastasis.