Only when external resistance or matrix rigidity surpasses a defined “mechanical threshold,” and downstream modules (such as Rho, Hippo–YAP, mitogen-activated protein kinase[MAPK], and metabolic enzymes) are correctly coupled, can Piezo1–Ca2+ signals shift from a “relaxed mode” to a “tensional mode,” thereby driving tumor cell migration, drug resistance, and metastasis. This evidence concerns the gene YAP1 and neoplasm.