Lineage Plasticity in Cancer: The Tale of a Skin-Walker

SIMPLE SUMMARY: Lineage plasticity is the ability of cells to transform from one cell type to another and is an important part for tissue repair and for maintenance of homeostasis. Unfortunately, the very same processes can be corrupted in cancer when the molecular checkpoints controlling the process are compromised; as a result of which treatment resistance and disease recurrence can emerge. It can be triggered by treatment received and has been seen across solid and liquid tumors. This review discusses the factors that control different manifestations of lineage plasticity in various cancer types and more importantly, discusses ideas to potentially revert this phenomenon. ABSTRACT: Lineage plasticity, the switching of cells from one lineage to another, has been recognized as a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here, we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of epithelial-mesenchymal transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.