Wei Yang
Kavita Shah
Rong Yang- 1Department of Pathology and Cancer Center, Stony Brook University, Stony Brook, NY, United States
- 2Department of Chemistry, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States
- 3Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, China
Editorial on the Research Topic
Cell signaling in cancer metastasis and lineage plasticity
Metastasis, the primary cause of cancer deaths, remains a poorly understood malignant process (Gerstberger et al., 2023). While the last two decades have witnessed the emergence of numerous targeted therapies for metastatic cancers, their effectiveness often diminishes quickly due to the development of drug resistance. Among the drug resistance mechanisms, lineage plasticity, which is the ability of cells to change from one committed developmental pathway to another (Quintanal-Villalonga et al., 2020), is gaining recognition as an important factor. However, the molecular mechanisms underlying tumor cell plasticity remains largely uncharted. The objective of this Research Topic is to delve into recent advancements in understanding the molecular underpinnings of cancer metastasis or lineage plasticity, with the ultimate goal of enhancing our comprehension and management of these life-threatening processes.
Recent research has unveiled One Cut homeobox 2 (ONECUT2) as a pivotal regulator of cancer metastasis and lineage plasticity (Rotinen et al., 2018; Guo et al., 2019; Liu et al., 2021). Intriguingly, Steadman et al. have revealed that ONECUT2 mRNA functions as a master competing endogenous RNA (ceRNA) with its extraordinarily lengthy 3′ untranslated region (UTR) spanning 14,575 nucleotides. Even more fascinating is the discovery that both the ONECUT2 3’ UTR and the ONECUT2 protein activate similar gene networks to promote cancer aggressiveness, indicating a cooperative functional relationship between the two ONECUT2 entities.
The p21-activated kinase-1 (PAK1) is a key player in various biological processes and a critical factor in cancer progression and metastasis (Yao et al., 2020). Saldivar-Ceron et al. have uncovered a novel mechanism by which PAK1 promotes breast tumorigenesis. Their study demonstrates that PAK1/CaMKII signaling is required for the efficient proliferation, migration, and invasion of mammary epithelial cells, suggesting that co-targeting PAK1 and CaMKII holds promise as a therapeutic approach for breast cancer.
In a Hypothesis and Theory article, Harryman et al. propose that the heterogeneity of cell-cell and cell-extracellular matrix adhesion receptors drives aggressive tumor networks and has significant functional implications, particularly in muscle-invasive and lethal carcinomas. They hypothesize the existence of functional epithelial-mesenchymal cooperation (EMC) within early tumor invasive networks, facilitating tumor escape from the primary organ and navigation to metastatic sites. Understanding EMC in the early tumor invasive networks could lead to the identification of early biomarkers for aggressive transitions and the discovery of novel agents to inhibit the EMC phenotype.
H19, the first long non-coding RNA discovered (Brannan et al., 1990), has been found to play a key role in various diseases including cancer. In a comprehensive review article, Wu et al. summarized H19’s key roles in cancer development and progression, as well as its regulatory functions in oncogenic signaling pathways such as the PI3K/Akt, canonical Wnt/β-catenin, canonical NF-κB, MAPK, JAK/STAT, and apoptotic pathways. The accumulating evidence suggests that H19 holds promise as both a therapeutic target and a biomarker for cancer diagnosis, prognosis, and treatment.
In summary, this Research Topic offers insights into the ongoing research advancements in cell signaling related to cancer metastasis and lineage plasticity. These efforts are expected to enhance our understanding of the fundamental mechanisms governing these processes, ultimately paving the way for more effective therapeutic strategies to combat these life-threatening conditions.
Author contributions
WY: Conceptualization, Formal Analysis, Funding acquisition, Investigation, Project administration, Writing–original draft. KS: Funding acquisition, Investigation, Project administration, Writing–review and editing. RY: Funding acquisition, Investigation, Project administration, Writing–review and editing.
Funding
The authors declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Cancer Institute (1R01CA266694-01A1 to WY and 1R01-CA237660 to KS), the Department of Defense (W81XWH2210131 and HT94252310028 to WY), and the Natural Science Foundation of China (NSFC82172691 to RY).
Acknowledgments
We would like to express our gratitude to the authors of the papers published in this Research Topic for their valuable contributions, as well as on the reviewers for their meticulous review. In addition, we thank the dedicated specialists at Frontiers for their unwavering support.
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.
The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Brannan, C. I., Dees, E. C., Ingram, R. S., and Tilghman, S. M. (1990). The product of the H19 gene may function as an RNA. Mol. Cell. Biol. 10, 28–36. doi:10.1128/mcb.10.1.28
Gerstberger, S., Jiang, Q., and Ganesh, K. (2023). Metastasis. Cell. 186, 1564–1579. doi:10.1016/j.cell.2023.03.003
Guo, H., Ci, X., Ahmed, M., Hua, J. T., Soares, F., Lin, D., et al. (2019). ONECUT2 is a driver of neuroendocrine prostate cancer. Nat. Commun. 10, 278. doi:10.1038/s41467-018-08133-6
Liu, D., Zhang, T., Chen, X., Zhang, B., Wang, Y., Xie, M., et al. (2021). ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY. Cell. Death Dis. 12, 1113. doi:10.1038/s41419-021-04410-3
Quintanal-Villalonga, Á., Chan, J. M., Yu, H. A., Pe’er, D., Sawyers, C. L., Triparna, S., et al. (2020). Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat. Rev. Clin. Oncol. 17, 360–371. doi:10.1038/s41571-020-0340-z
Rotinen, M., You, S., Yang, J., Coetzee, S. G., Reis-Sobreiro, M., Huang, W.-C., et al. (2018). ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat. Med. 24, 1887–1898. doi:10.1038/s41591-018-0241-1
Keywords: signaling, metastasis, lineage plasticity, ONECUT2, PAK1, network, LncRNA―long non-coding RNA
Citation: Yang W, Shah K and Yang R (2023) Editorial: Cell signaling in cancer metastasis and lineage plasticity. Front. Cell Dev. Biol. 11:1302659. doi: 10.3389/fcell.2023.1302659
Received: 26 September 2023; Accepted: 04 October 2023;
Published: 13 October 2023.
Edited and reviewed by:
Ana Cuenda, Spanish National Research Council (CSIC), SpainCopyright © 2023 Yang, Shah and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wei Yang, wei.yang@stonybrook.edu