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

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.

Keywords: epithelial-mesenchymal plasticity; lineage plasticity; metastasis; therapy resistance; tumor progression.

Figure 1

Lineage plasticity promotes tumor progression, therapy resistance and metastasis. Cancer cells can dynamically alter their identity as a result of genetic/epigenetic alterations or in order to adapt to the drug-induced stress and varying microenvironmental cues. This ability, termed as lineage plasticity, enables them to switch between different cell states through processes such as dedifferentiation or transdifferentiation. During dedifferentiation, differentiated cancer cells become less specialized and acquire stem/progenitor cell-like characteristics. Through transdifferentiation, cancer cells can convert from one differentiated lineage to another, i.e., from luminal adenocarcinoma cells to neuroendocrine/small cell or squamous cells as observed in lung, prostate and pancreatic cancer. Cancer cells have also been found to adopt endothelial cell characteristics to form vascular channels through a process called vasculogenic mimicry or mesenchymal phenotype through the process of epithelial-mesenchymal transition. This lineage plasticity is increasingly being recognized as a key player in quiescence, therapeutic resistance and metastasis in cancer.

Figure 2

Genetic, epigenetic and microenvironmental factors involved in regulating lineage plasticity. The genetic factors include the loss of tumor suppressors and gain of oncogenes and overexpression of several transcription factors, eventually resulting in the enabling of the cellular reprogramming. In addition, altered expression of epigenetic modulators and microenvironmental components also play an important role in facilitating the switching of cellular identity in response to various stresses.

Figure 3

Therapeutic strategies to target the lineage plasticity. Schematic showing the approaches used to target cancer lineage plasticity. Lineage plasticity can be prevented by directly inhibiting the mediators regulating cellular plasticity (by inhibiting cancer cell-associated proteins (HDACs KDM, IL6-STAT3 signaling) and microenvironment-derived factors (PDGF-CC)). Another approach is to eliminate the new cell fate adopted by the cells through lineage switching (e.g., using cytotoxic drug-conjugated antibody against CLDN6). The third approach is to reverse the lineage plasticity of cancer cells (e.g., by inhibiting the epigenetic modulators such as EZH2 or by blocking EMT mediators like TGFβ). Another strategy that has recently gained attention is to exploit the intrinsic cellular plasticity of the tumor cells by transdifferentiating them into alternate cell lineages that are post-mitotic and thereby rerouting the lineage plasticity. Combining chemo/targeted therapy along with the transdifferentiating drug will facilitate the effective eradication of tumor cells.