Stem cell programs in cancer initiation, progression, and therapy resistance

Abstract

Over the past few decades, substantial evidence has convincingly revealed the existence of cancer stem cells (CSCs) as a minor subpopulation in cancers, contributing to an aberrantly high degree of cellular heterogeneity within the tumor. CSCs are functionally defined by their abilities of self-renewal and differentiation, often in response to cues from their microenvironment. Biological phenotypes of CSCs are regulated by the integrated transcriptional, post-transcriptional, metabolic, and epigenetic regulatory networks. CSCs contribute to tumor progression, therapeutic resistance, and disease recurrence through their sustained proliferation, invasion into normal tissue, promotion of angiogenesis, evasion of the immune system, and resistance to conventional anticancer therapies. Therefore, elucidation of the molecular mechanisms that drive cancer stem cell maintenance, plasticity, and therapeutic resistance will enhance our ability to improve the effectiveness of targeted therapies for CSCs. In this review, we highlight the key features and mechanisms that regulate CSC function in tumor initiation, progression, and therapy resistance. We discuss factors for CSC therapeutic resistance, such as quiescence, induction of epithelial-to-mesenchymal transition (EMT), and resistance to DNA damage-induced cell death. We evaluate therapeutic approaches for eliminating therapy-resistant CSC subpopulations, including anticancer drugs that target key CSC signaling pathways and cell surface markers, viral therapies, the awakening of quiescent CSCs, and immunotherapy. We also assess the impact of new technologies, such as single-cell sequencing and CRISPR-Cas9 screening, on the investigation of the biological properties of CSCs. Moreover, challenges remain to be addressed in the coming years, including experimental approaches for investigating CSCs and obstacles in therapeutic targeting of CSCs.

Keywords: CSC-targeting therapies; cancer stem cells; epigenetics; metabolism; therapy resistance; transcriptional and posttranslational regulation; tumor microenvironment.

Figure 1

Mechanism of N⁶-methyladenosine (m⁶A) modification and its roles in CSCs. (A) m⁶A is regulated by writers, erasers, and readers. “Writers” refer to the m⁶A methyltransferase complex including METTL3, METTL14, WTAP, and RMB15. “Erasers” are m⁶A demethylases including ALKBH5 and FTO. “Readers” are proteins that recognize m⁶A, including YTH domain containing proteins (YTHDF1/2/3 and YTHDC1/2), IGF2BP1/2/3, and other factors such as hnRNPG and eIF3. The binding of these “readers” to m⁶A mediates downstream RNA processes, including stability, splicing, nuclear export, translation, and phase separation potential of targeted mRNAs. (B) The m⁶A modification and its regulators play critical roles in cancer stem cell maintenance and tumorigenicity.

Figure 2

The TME consists of a heterogeneous population of cells including CSCs, dormant cancer cells, TAMs, T cells, other immune cells, and various secretory factors such as cytokines and growth factors.