Editorial: Catch Me If You Can: Cellular Plasticity in Tumor Progression and Drug Resistance - Fatoftheland (2024)

Cellular plasticity is a broad term that encompasses the reversible mechanisms by which cells acquire different identities in response to homeostatic imbalances and cellular stress (Huyghe et al., 2024). In human malignancies, cellular plasticity is abnormally activated at all stages of premalignant and malignant progression (Quintanal-Villalonga et al., 2020). This activation provides cancer cells with a dynamic capacity to fluctuate between different states, allowing them to adapt to changing microenvironmental conditions and therapeutic pressures (Boumahdi and de Sauvage, 2020). Given its profound impact on the maintenance of tumor development, cellular plasticity is now recognized as a hallmark of cancer (Hanahan, 2022).

Over decades of research, numerous insights have been gained into how plasticity promotes intratumor heterogeneity, immune evasion, drug resistance, and metastatic spread in cancer. Despite these advances, the intricate molecular networks that govern cellular plasticity are only partially understood. Ongoing research continues to reveal novel molecular mechanisms and interactors that contribute to this process (Torborg et al., 2022). For example, accumulating evidence has highlighted the role of non-coding RNAs, epigenetic modifications, and signaling pathways in regulating cellular plasticity. These discoveries not only deepen our understanding of cancer biology but also identify novel potential targets for therapeutic intervention (Mehta and Stanger, 2024).

This Research Topic represents a collective effort, aimed at collecting and discussing the most recent findings that elucidate the role of cellular plasticity in tumor progression and evolution. By exploring the latest developments in this field, we aim to shed light on the complex interplay between cancer cells and the tumor microenvironment (TME), and potentially identify new vulnerabilities for targeting this hallmark of cancer.

The article by Cammareri and Myant reviews recent developments and transcriptomic mechanisms of metaplasia and epithelial-to-mesenchymal transition (EMT), two important examples of protective cellular plasticity in response to microenvironmental damage. Metaplasia, the adaptive process by which one mature cell type transforms into another, is discussed in the context of chronic inflammation of the esophagus and pancreas. The authors emphasize its important role in the development of epithelial dysplasia and the pathogenesis of esophageal and pancreatic adenocarcinoma. EMT, the process that allows cells to switch between epithelial and mesenchymal phenotypes (Haerinck et al., 2023), is also explored. The article summarizes recent findings and experimental models and discusses the intricate interplay between drug administration—a key inducer of EMT—and how EMT in turn contributes to drug resistance.

Metabolic plasticity has also emerged as an important mechanism promoting cancer cell adaptability to environmental stressors and therapeutic pressures (McGuirk et al., 2020). However, metabolic rewiring varies across tumors and therapy types, highlighting the need for systematic studies to develop effective therapies. To fill this gap, the review by Pendleton et al. examines the role of permanent and plastic mitochondrial adaptations in therapy resistance. The article summarizes experimental models of therapy-induced metabolic adaptation, with an emphasis on the clinical implications of targeting both permanent and plastic metabolic states. The authors highlight that oxidative phosphorylation in therapy-resistant cancer cells is dependent on multiple energy sources, underscoring that inhibiting these pathways is a promising strategy in preclinical studies. The review also discusses future directions and caveats for translating these findings into clinical practice, providing a valuable perspective for developing novel therapeutic strategies.

Focusing on the specific interactors that orchestrate cellular plasticity, the review article by Liao et al. delves into the multifaceted role of LINK-A, a long non-coding RNA that is frequently dysregulated in human malignancies. The authors elucidate the molecular pathways regulated by LINK-A, in particular the HIF1α pathway, and how this novel interactor promotes various aspects of cellular plasticity, such as metabolic reprogramming, cell migration, invasion, and drug resistance. The review underscores the crucial role of LINK-A expression in the interplay between cancer cells and cell populations within the TME, exploring mechanisms of immune evasion and suppression. Furthermore, it discusses the potential translational significance of LINK-A expression, highlighting recent achievements in using LINK-A as a prognostic biomarker for clinical aggressiveness and poor prognosis, which can be evaluated in tumor samples and sera from patients with different tumor types.

The article by Lei et al. systematically examines the role of extracellular vesicles (EVs) in cancer cell plasticity and their contribution to the metastatic spread of gastric cancer. EVs are membrane-enveloped vesicles released by almost all cell types and contain nucleic acids, proteins, and lipids that modulate the biological functions of recipient cells. Not surprisingly, gastric cancer cells exploit this intercellular communication mechanism to shape the environment into a pro-metastatic niche. The review investigates the significance of gastric cancer-derived EVs in immunosuppression, angiogenesis, and phenotype switching within the TME. In addition, the authors describe and discuss the role of EVs derived from cancer-associated fibroblasts and mesenchymal stem cells in promoting the metastatic potential of cancer cells, highlighting the bidirectional role of EVs in tumor progression mechanisms.

The original study by Chong et al. investigates the growth dynamics of breast cancer spheroids under varying extracellular matrix (ECM) conditions. Their findings highlight how variations in ECM pressure on cancer cells affect cell proliferation, induce apoptosis, and promote a switch to a mesenchymal phenotype, underscoring the critical role of matrix concentration and stiffness in modulating tumor expansion. A novel aspect of the study is the development of an algorithm to characterize the shear stress exerted by the expanding spheroids on the agarose matrix. The authors identified two distinct cell populations on the spheroid surface: one that generates lower expansion forces, likely corresponding to non-dividing cells, and the other that exerts higher forces, corresponding to dividing cells. The insights gained from this study are thoroughly discussed in the context of current literature and pave the way for developing more effective cancer treatments by targeting the biomechanical interactions within the tumor microenvironment.

The physical interaction between cancer cells and their microenvironment is further explored in the original report by Paxson et al. Recognizing that advanced prostate cancer extends beyond the fibromuscular capsule of the organ, exposing cells to a contractile environment, the study investigates how mechanical stress promotes the plasticity of prostate cancer cells, potentially affecting their sensitivity to therapeutic agents. Using a mouse-human tumor xenograft model, they isolated an aggressive, muscle-invasive cell population with distinct biophysical properties and a unique transcriptomic profile. High-throughput screening of several compounds revealed an altered therapeutic vulnerability profile of muscle-invasive cells compared to controls. These findings suggest potential treatment strategies that target the epigenetic landscape of aggressive tumors. Future research will focus on identifying effective combinations of epigenetic modifiers to eradicate metastatic cells at an early stage.

Overall, articles in this Research Topic present a comprehensive overview of cancer cellular plasticity, providing new insights and critical perspectives on its role in tumor development and treatment resistance. The collective findings emphasize the importance of a thorough understanding of cellular plasticity to design effective cancer therapies. We express our gratitude to the authors and reviewers for their dedicated contributions, and we hope that the articles in this volume inspire future innovative research.

Contributions by authors

GR: Writing – original draft, Writing – review/editing. IS: Writing – original draft, Writing – review/editing. JC: Writing – original draft, Writing – review/editing. SL: Writing – original draft, Writing – review/editing.

Financing

The authors declare that they received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

Any claims made in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, editors, and reviewers. Any product that may be reviewed in this article, or claim that may be made by the manufacturer, is not guaranteed or endorsed by the publisher.

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