SMAD4 and neoplasm: Given the heterogeneous composition of the tumor microenvironment comprising not only stromal fibroblasts but also smooth muscle cells and various cellular types of immune origin, it is plausible to think that haploinsufficiency at members of the TGF-β signaling pathways such as SMAD4 and LKB1 affects cell to cell communication in different tissues, thus leading to loss of tissue architecture.