Matigian, N. | bioRxiv Science

bioRxiv2021

Dominant Effect Of Host Genetics On Skin Microbiota Composition In Homeostasis And Wound Healing

Animal microbiota have complex interactions with hosts and environment that determines its composition. Yet the ability of hosts to determine their microbiota composition is less well studied. In this study, to investigate the role host genetics in determining skin microbiota, we used 30 different mouse strains from the recombinant inbred panel, the Collaborative Cross. Murine skin microbiota composition was strongly dependent on murine strain with > 50% of the variation explained by murine strain. In particular, a quantitative trait locus on chromosome 4 associates both with Staphylococcus abundance and principal-component multi-trait analyses. Additionally, excisional wound associated changes in microbiota composition were not uniform across mouse strains and were host-specific, the genetic background accounting for about 40% of the variation in microbiota. Genetic background also had the highest effect on the healing speed of wounds accounting for over 50% of the variation while mouse age and microbiota composition change accounted only for 20% and 5% of the healing speed despite reaching statistical significance. In conclusion, host genetics has a significant impact on the skin microbiota composition during both homeostasis and wound healing. These findings have long reaching implications in our understanding of associations between microbiota dysbiosis and disease.

systems biology↗

bioRxiv2020

Functional melanoma cell heterogeneity is regulated by MITF-dependent cell-matrix interactions

Phenotypic heterogeneity of cancer cells plays a critical role in shaping treatment response. This type of heterogeneity is organized spatially with specific phenotypes, such as sharply demarcated clusters of proliferating and cell cycle-arrested cells, predominating within discrete domains within a tumor. What determines the occurrence of specific tumor cell phenotypes in distinct microdomains of solid cancers is poorly understood. Here, we show that in melanoma spatial organization of phenotypic heterogeneity is dictated by the expression and activity of MITF. We reveal that this lineage survival oncogene controls ECM composition and organization, and ROCK-driven mechanotransduction through focal adhesion maturation and actin cytoskeleton functionality. In turn, altered tumor microarchitecture and structural integrity impact tumor solid stress which then mediates phenotypic heterogeneity through p27Kip1. Rho-ROCK-myosin signaling is necessary to transmit the effect of the reciprocal cell-ECM regulation into phenotypic heterogeneity. Our findings place cell-ECM crosstalk as a central driver of phenotypic tumor heterogeneity. SignificancePhenotypic heterogeneity is a major culprit of cancer therapy failure. We demonstrate that phenotypic heterogeneity is controlled through tumor cell-ECM crosstalk resulting in altered tumor microarchitecture, mechanotransduction and Rho-ROCK-myosin signaling. Melanoma shares these physical properties with any solid cancer underscoring the importance of our findings for therapeutically targeting this phenomenon.

cancer biology↗