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• W4313887583 abstract "Abstract Background Despite intensive research, cancer remains a major health problem. The difficulties in treating cancer are due to the complex nature of this disease, including high levels of heterogeneity within tumours. Intra-tumour heterogeneity creates the conditions for inter-clonal competition and selection, which should result in selective sweeps and a reduction in levels of heterogeneity. However, in addition to competing, cancer clones could also cooperate with each other, and the positive effects of these interactions on the fitness of clones can actually contribute to maintaining the heterogeneity of tumours. Consequently, understanding the evolutionary mechanisms and pathways involved in such behaviours is of great significance for cancer treatment. This is particularly relevant for metastasis, which is the most lethal phase during cancer progression. To explore if and how genetically distant clones can cooperate during invasion, this study used three genetically distant cancer cell lines with different metastatic potentials. Results We found that (i) the conditioned media from the invasive lines increased the migration and invasion potential of the poorly metastatic line, and (ii) this inter-clonal interaction involved the TGF-β1 signalling pathway. Furthermore, when a highly and poorly metastatic lines were co-cultured, the invasive potential of both lines was enhanced, and this outcome was dependent on the co-option of the less aggressive clone into expressing a malignant phenotype. Based on our findings, we propose a two-tier model whereby highly metastatic clones can co-opt (through autocrine-paracrine crosstalk) weakly metastatic clones into expressing an invasive phenotype, which in turn augments the invasion ability of the former (i.e., a “help me help you” strategy). Conclusions We suggest that such synergistic cooperative interactions can easily emerge via crosstalk involving metastatic clones able to constitutively secrete molecules that induce and maintain their own malignant state (producer-responder clones) and clones that have the ability to respond to those signals (responder clones) and express a synergistic metastatic behaviour, regardless of the degree of overall genetic/genealogical relatedness. Taking into account the lack of therapies that directly affect the metastatic process, interfering with such cooperative behaviours that tumour cells engage in during the early steps in the metastatic cascade could provide additional strategies to increase patient survival." @default.
• W4313887583 created "2023-01-10" @default.
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• W4313887583 date "2023-01-09" @default.
• W4313887583 modified "2023-09-27" @default.
• W4313887583 title "Synergistic inter-clonal cooperation involving crosstalk, co-option and co-dependency can enhance the invasiveness of genetically distant cancer clones" @default.
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• W4313887583 doi "https://doi.org/10.21203/rs.3.rs-2394919/v1" @default.
• W4313887583 hasPublicationYear "2023" @default.
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