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Results Results Method (Figure 1) * Stage 1 (Invadopodia Formation) Invasive cells are plated on a thick layer of matrigel, about tens to hundred of microns thick * Stage 2 (Invadopodia Elongation) Invadopodia elongate before the invasive cell penetrates the underlying tissue; where cells are not chemoattracted and made to migrate in the x-y plane * Stage 3 (Cell Entrance into the Stromal Compartment) Cells degrade a thin matrigel layer before passing through the empty pores of the filter Method (Figure 1) * Stage 1 (Invadopodia Formation) Invasive cells are plated on a thick layer of matrigel, about tens to hundred of microns thick * Stage 2 (Invadopodia Elongation) Invadopodia elongate before the invasive cell penetrates the underlying tissue; where cells are not chemoattracted and made to migrate in the x-y plane * Stage 3 (Cell Entrance into the Stromal Compartment) Cells degrade a thin matrigel layer before passing through the empty pores of the filter Abstract The basement membrane (BM) acts as a physiological barrier to maintain tissue homeostasis. Studies (e.g. Cancer Cell Invasion) have shown that BM transmigration is a conserved three-stage process. Firstly, invadopodia-like protrusions form at the ventral surace of invasive cells; later one protrrusion elongates that lastly drives the infiltration of cells into the underlying compartment. Abstract The basement membrane (BM) acts as a physiological barrier to maintain tissue homeostasis. Studies (e.g. Cancer Cell Invasion) have shown that BM transmigration is a conserved three-stage process. Firstly, invadopodia-like protrusions form at the ventral surace of invasive cells; later one protrrusion elongates that lastly drives the infiltration of cells into the underlying compartment. Stage 1 Cancer cells degrade the matrix by producing dark spots in the fluorescent background. Invadopodia are then defined as actin puncta that localize to sites of matrix degradation Stage 1 Cancer cells degrade the matrix by producing dark spots in the fluorescent background. Invadopodia are then defined as actin puncta that localize to sites of matrix degradation Stage 2 Invadopodia penetrated into the matrix only superficially and merely elongated more than 2 μm Stage 2 Invadopodia penetrated into the matrix only superficially and merely elongated more than 2 μm Stage 3 Cancer cells, after breaching the BM, penetrate the underlying stroma mostly composed of a collagen I network, which molecular composition and stiffness differ form the BM Stage 3 Cancer cells, after breaching the BM, penetrate the underlying stroma mostly composed of a collagen I network, which molecular composition and stiffness differ form the BM Figure 1 Figure 1 Conclusion Invasive cancer cells use all three cytoskeleton networks to execute their infiltration into the stromal compartment. They turn on cytoskeleton-related genes that are expressed mesodermal or neural crest cells during embryonic development. Cancer cells seem to simply reactivate latent morphogenic programs already encoded in their genome to counteract physiological barriers and promote cancer progression. As a result, many queries arise on the invasion cascade. A better understanding of the initial step of the invasion cascade will bring new ideas for design of efficient drugs to stop or at least to limit the metastatic speed. Conclusion Invasive cancer cells use all three cytoskeleton networks to execute their infiltration into the stromal compartment. They turn on cytoskeleton-related genes that are expressed mesodermal or neural crest cells during embryonic development. Cancer cells seem to simply reactivate latent morphogenic programs already encoded in their genome to counteract physiological barriers and promote cancer progression. As a result, many queries arise on the invasion cascade. A better understanding of the initial step of the invasion cascade will bring new ideas for design of efficient drugs to stop or at least to limit the metastatic speed.