A scheme of the interaction mechanism between normal cells and transformed cells in mammals. A Direct chemical interaction via ligand–receptor interactions. Rasv12 expression induces MHC-I upregulation, and AltR is induced via RUNX2 in surrounding normal cells. MHC-I-stimulated AltR accumulates Filamin via the SHP2-ROCK pathway to apically extrude Ras-transformed cells (above). RasV12 expression upregulates EphA2 via the MEK-ERK pathway. With E-cadherin-based cell–cell interaction, ephrin-A-stimulated EphA2 induces cell repulsion and cell contraction via Src (below). B Indirect interaction via secreted factors. Scribble knockdown induces and secretes FGF21 via the ASK1-p38 pathway in scrb-KD cells, resulting in the generation of mechanical compaction toward scrb-KD cells. Then, scrb-KD cells undergo cell death via the ROCKp38-p53 pathway (above). Extracellular ATP from transformed cells stimulates P2Y1/2 in normal cells to generate ROS via NOX2. Then, ROS induces mitochondrial dysfunction via PDK4 in transformed cells for apical extrusion (middle). Extracellular S1P is sensed by S1PR2 in normal cells, promoting Filamin accumulation via ROCK (below). C Physical interaction. A mechanical sensor on normal cells senses the change in Myosin-II-mediated membrane tension of transformed cells to activate RUNX2, the transcription factor of AltR (left). Mechanical pressure from neighbouring cells causes a lateral shift of N-WASP, resulting in reorganisation of the Actin network in transformed cells for apical extrusion (right)