Autophagy induction can increase or decrease anticancer drug efficacy. Anticancer drug-induced autophagy induction is poorly characterized in osteosarcoma (OS). In this study, we investigated the impact of autophagy inhibition on camptothecin (CPT)-induced cytotoxicity in OS.

Purpose: The genetic intratumoral heterogeneity observed in human osteosarcomas poses challenges for drug development and the study of cell fate, plasticity, and differentiation, which are processes linked to tumor grade, cell metastasis, and survival. Experimental Design: To pinpoint errors in osteosarcoma differentiation, we transcriptionally profiled 31,527 cells from a tissue-engineered model that directs mesenchymal stem cells toward adipogenic and osteoblastic fates. Incorporating preexisting chondrocyte data, we applied trajectory analysis and non-negative matrix factorization to generate the first human mesenchymal differentiation atlas. Results: This “roadmap” served as a reference to delineate the cellular composition of morphologically complex osteosarcoma tumors and quantify each cell’s lineage commitment. Projecting a bulk RNA-sequencing osteosarcoma dataset onto this roadmap unveiled a correlation between a stem-like transcriptomic phenotype and poorer survival outcomes. Conclusions: Our study quantifies osteosarcoma differentiation and lineage, a prerequisite to better understanding lineage-specific differentiation bottlenecks that might someday be targeted therapeutically.

Autophagy is a highly conserved catabolic process induced under various stress conditions to protect the cell from harm and allow survival in the face of nutrient- or energy-deficient states. Regulation of autophagy is complex, as cells need to adapt to a continuously changing microenvironment. It is well recognized that the AMPK and mTOR signaling pathways are the main regulators of autophagy. However, various other signaling pathways have also been described to regulate the autophagic process. A better understanding of these complex autophagy regulatory mechanisms will allow the discovery of new potential therapeutic targets. Here, we present a brief overview of autophagy and its regulatory pathways with emphasis on the epigenetic control mechanisms.