Vascular and neuronal development: Intersecting parallelisms and rossroads

Two key events during evolution allowed vertebrates to develop specialized tissues able to perform complex tasks: the formation of a highly branched vascular system ensuring that all tissues receive adequate blood supply, and the development of a nervous system in which nerves branches to transmit electrical signal to peripheral organs. Both networks are laid down in a complex and stereotyped manner, which is tightly controlled by a series of shared developmental cues. Vessels and nerves use similar signals and principles to grow, differentiate and navigate toward their final targets. Moreover, the vascular and the nervous system cross-talk and, when deregulated, they contribute to medically relevant diseases. The emerging evidence that both systems share several molecular pathways not only provides an important link between vascular biology and neuroscience, but also promises to accelerate the discovery of new pathogenetic insights and therapeutic strategies

Body composition and lung cancer-associated cachexia in TRACERx

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial–mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC