Dear Colleagues,

The major cause of cancer-associated deaths is metastatic disease, rather than primary malignancy. Cancer cells can infrequently disseminate from primary tumors and subsequently seed new colonies in distant tissues, via a multistep process of genetic and/or epigenetic alterations, widely known as invasion–metastasis cascade. This sequential course mainly involves: (a) intravasation of escapers into the circulation, (b) tumor-cell protection against physical stress (hydrodynamic flow) and immune (neutrophil) attack, and (c) extravasation of the survivors through trans-endothelial migration. One central superprogram being contextually engaged in cancer metastasis is termed epithelial-to-mesenchymal transition (EMT). A series of master EMT-inducing transcription factors, such as Zeb1, Twist, Slug, and Snail, orchestrate and coordinate the loss of epithelial (usually, E-Cadherin-dependent) features, and the simultaneous acquisition of specific mesenchymal (usually, Vimentin-dependent) properties, thus endowing cancer cells with multiple malignant traits. Heterotypic signals, including TGF-βs and Wnts, released from the nearby, “reactive”, stroma that is composed of (myo)fibroblasts, endothelial, lymphoid, and myeloid cells, can activate the previously silent EMT route. Remarkably, it is the phenotypic plasticity of a “partial EMT” (“hybrid” in between EMT and MET (mesenchymal-to-epithelial transition)) state that seems to enhance tumor progression and metastasis. EMT commitment can also confer upon cancer cells important stem-cell attributes that usually serve as critical prerequisites for metastatic colonization. However, the biological underpinnings of adaptive mechanisms that control organ-specific tropism of metastatic cells remain poorly understood. Hitherto, no genetic mutation has been identified to be associated with progression to metastasis. Hence, despite the general principles of metastasis that have begun to emerge, detailed molecular circuitries, with oncogenic control nodes, are necessitated to be promptly elucidated, regarding the “causalities and regulations” of: (a) metastatic heterogeneity, (b) clonal origin of metastasis, (c) metastatic evolution, (d) organ microenvironment, (e) “intermediate EMT” programming, (f) radio- and/or chemotherapy resistance, (g) cancer-cell stemness, (h) metastatic dormancy, (i) metastatic signature, (j) metastatic stochasticity, and (k) metastatic determinism.

Special Statement: This Special Issue of “Causalities and Regulations of Tumor Metastasis” is dedicated to the memory of Professor Isaiah J. Fidler who passed away on 8 May 2020 (1936–2020). He was a pioneer in the field of tumor metastasis. Prof. Fidler published over 800 publications in peer-reviewed journals in a career of more than 50 years. He received countless awards that recognized his excellence and valued expertise in metastasis research.

Dr. Dimitrios J. Stravopodis
Guest Editor

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• cancer
• chemoresistance
• EMT
• heterogeneity
• MET
• metastasis
• signaling
• stemness
• stroma