Skeletal muscle atrophy is a common debilitating feature of many systemic diseases, including cancer. Here we examined the effects of inducing expression of an oncogenic version of the Met receptor (Tpr-Met) in terminally differentiated skeletal muscle. A responder mouse containing the Tpr-Met oncogene and GFP (green fluorescent protein) as a reporter was crossed with a transactivator mouse expressing tTA under the control of the muscle creatine kinase promoter. Tpr-Met induction during fetal development and in young adult mice caused severe muscle wasting, with decreased fiber size and loss of myosin heavy chain protein. Concomitantly, in the Tpr-Met-expressing muscle the mRNA of the E3 ubiquitin ligases atrogin-1/MAFbx, MuRF1, and of the lysosomal protease cathepsin L, which are markers of skeletal muscle atrophy, was significantly increased. In the same muscles phosphorylation of the Met downstream effectors Akt, p38 MAPK, and IκBα was higher than in normal controls. Induction of Tpr-Met in differentiating satellite cells derived from the double transgenics caused aberrant cell fusion, protein loss, and myotube collapse. Increased phosphorylation of Met downstream effectors was also observed in the Tpr-Met-expressing myotubes cultures. Treatment of these cultures with either a proteasomal or a p38 inhibitor prevented Tpr-Met-mediated myotube breakdown, establishing accelerated protein degradation consequent to inappropriate activation of p38 as the major route for the Tpr-Met-induced muscle phenotype.

Endothelial-to-mesenchymal transition (EndMT) is a dynamic cellular process characterized by a phenotypic-functional switch of cells from endothelial-to-mesenchymal traits. Many studies have identified EndMT as a key driver of tumor growth and progression. EndMT supports tumor cell proliferation by creating a tumor microenvironment that facilitates cancer cell survival. Notably, EndMT is an important source of cancer-associated fibroblasts, leads to immune dysregulation and immune escape, and supports metastasis and resistance to therapy. Hence, understanding the intricate relationship between EndMT and cancer progression offers exciting new avenues for therapeutic intervention. This review aims to describe the central role of EndMT in tumor progression, highlighting the molecular mechanisms underlying this endothelial alteration and its significant involvement at all stages of tumor progression.

Genomic-oriented oncology has improved tumor classification, treatment options, and patient outcomes. However, genetic heterogeneity, tumor cell plasticity, and the ability of cancer cells to hijack the tumor microenvironment (TME) represent a major roadblock for cancer eradication. Recent biotechnological advances in organotypic cell cultures have revolutionized biomedical research, opening new avenues to explore the use of cancer organoids in functional precision oncology, especially when genomics alone is not a determinant. Here, we outline the potential and the limitations of tumor organoids in preclinical and translational studies with a particular focus on lung cancer pathogenesis, highlighting their relevance in predicting therapy response, evaluating treatment toxicity, and designing novel anticancer strategies. Furthermore, we describe innovative organotypic coculture systems to dissect the crosstalk with the TME and to test the efficacy of different immunotherapy approaches, including adoptive cell therapy. Finally, we discuss the potential clinical relevance of microfluidic mini-organ technology, capable of reproducing tumor vasculature and the dynamics of tumor initiation and progression, as well as immunomodulatory interactions among tumor organoids, cancer-associated fibroblasts (CAFs) and immune cells, paving the way for next-generation immune precision oncology.

Sarcomas are a large family of rare and heterogeneous mesenchymal tumors, which respond poorly to available systemic treatments. Translation of preclinical findings into clinical applications has been slow, limiting improvements in patients' outcomes and ultimately highlighting the need for a better understanding of sarcoma biology to develop more effective, subtype-specific therapies. To this end, reliable preclinical models are crucial, but the development of 3D in vitro sarcoma models has been lagging behind that of epithelial cancers. This is primarily due to the rarity and heterogeneity of sarcomas, and lack of widespread knowledge regarding the optimal growth conditions of these in vitro models. In this review, we provide an overview of currently available sarcoma tumoroid models, together with guidelines and suggestions for model development and characterization, on behalf of the FORTRESS (Forum For Translational Research in Sarcomas) international research working group on 3D sarcoma models.

Extremely low frequency magnetic field exposure affects DnaK and GroEL expression in E. coli cells with impaired heat shock response