RESUMEN
BACKGROUND: Cancer-associated fibroblasts (CAFs) are the prominent cell type in the tumor microenvironment (TME), and CAF subsets have been identified in various tumors. However, how CAFs spatially coordinate other cell populations within the liver TME to promote cancer progression remains unclear. METHODS: We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays. RESULTS: We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells. CONCLUSIONS: We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells.
Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Madre Neoplásicas , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Microambiente Tumoral/genética , Proteómica/métodos , Transcriptoma , Regulación Neoplásica de la Expresión Génica , Genómica/métodos , Proliferación Celular , Perfilación de la Expresión Génica , Línea Celular Tumoral , Pronóstico , MultiómicaRESUMEN
The trade-off between leaf size and number is the basis for plant growth strategies. It is of great significance to study the underlying mechanism of leaf size and number trade-offs for well understanding plant growth strategies. In this study, leaf size was expressed by the dry mass of single leaf, while leafing intensity was expressed by the number of leaves per unit stem volume. We used standardized major axis regression analysis method to examine the trade-off relationship between leaf size and number in Hulunbuir grassland. There was a significant negative isometric-growth trade-off between leaf size and number in Chenqicuogang (typical steppe) and Chenqibayi (meadow steppe). There was a significant negative allometric-growth trade-off between leaf size and number in Xeltala (meadow steppe). The underlying mechanism of the relationship between leaf size and number depended on the leaf and stem biomass allocation mechanism and the changes of the stem tissue density.