Engaging plasticity: Differentiation therapy in solid tumors

Abstract

Cancer is a systemic heterogeneous disease that can undergo several rounds of latency and activation. Tumor progression evolves by increasing diversity, adaptation to signals from the microenvironment and escape mechanisms from therapy. These dynamic processes indicate necessity for cell plasticity. Epithelial-mesenchymal transition (EMT) plays a major role in facilitating cell plasticity in solid tumors by inducing dedifferentiation and cell type transitions. These two practices, plasticity and dedifferentiation enhance tumor heterogeneity creating a key challenge in cancer treatment. In this review we will explore cancer cell plasticity and elaborate treatment modalities that aspire to overcome such dynamic processes in solid tumors. We will further discuss the therapeutic potential of utilizing enhanced cell plasticity for differentiation therapy.

Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma

“…Taken together, our results demonstrate the potential clinical utility of Sirt2i in the selective targeting of ATRX-deficient epigenomic dysfunction in both adult and pediatric malignant glioma. The induction by Sirt2i of terminal differentiation in particular echoes analogous established approaches employing epigenetic therapies in myeloid malignancies and recapitulates reported effects of HDAC inhibitors in sarcoma, lung, and prostate cancer models( 44, 45 ).…”

Fatty acid synthase (FASN) signalome: A molecular guide for precision oncology

“…Manipulation of FASN signaling to phenotypically override the unstable cancer genome in neoplastic cells is analogous to the results from differentiationinducing therapy, which aims to convert undifferentiated cancer cells into differentiated cells with low tumorigenicity [120,121,131,132]. However, the observation that the non-catalytic functions of FASN, but not necessarily its biosynthetic activity, control the functional specialization in cell-fate decisions underscores the limitations of using traditional, occupancy-driven small-molecule FASNis for differentiation therapies.…”

Epithelial–mesenchymal plasticity in kidney fibrosis

“…Many mammalian cells can change their phenotype by a process called cellular plasticity (Bar‐Hai & Ishay‐Ronen, 2022; Canciello et al, 2022; Horsley, 2022; Merrell & Stanger, 2016). These cells are capable of differentiation toward mature stage and, on the other hand, can dedifferentiate or transdifferentiate to exhibit new phenotypes (Bar‐Hai & Ishay‐Ronen, 2022; Canciello et al, 2022; Horsley, 2022; Merrell & Stanger, 2016). Epithelial cells also undergo epithelial–mesenchymal plasticity (EMP) with dynamic changes in cellular structure, composition, and function, becoming mixed (hybrid) epithelial/mesenchymal (E/M) phenotypes (Canciello et al, 2022; Yang et al, 2020).…”

“…Many mammalian cells can change their phenotype by a process called cellular plasticity (Bar‐Hai & Ishay‐Ronen, 2022; Canciello et al, 2022; Horsley, 2022; Merrell & Stanger, 2016). These cells are capable of differentiation toward mature stage and, on the other hand, can dedifferentiate or transdifferentiate to exhibit new phenotypes (Bar‐Hai & Ishay‐Ronen, 2022; Canciello et al, 2022; Horsley, 2022; Merrell & Stanger, 2016).…”