Abstract
Simple SummaryCancer is expected to be the leading cause of death due to noncommunicable diseases in the 21st century. Cancer-related mortality is largely due to metastasis. Cancer cells undergoing metastasis exhibit Epithelial–Mesenchymal Plasticity where they can transition from an epithelial to mesenchymal (EMT) or from a mesenchymal to epithelial (MET) phenotype. These transitions are crucial for the success of various stages of metastasis. Both these processes are modulated by multiple EMT-inducing and MET-inducing factors acting in concert. While EMT inducers are well-recognized, MET inducers are relatively poorly investigated. Here, we investigated the role of KLF4 through mechanism-based mathematical models and transcriptomic data analysis and identified it to be a potential MET inducer by suppressing one or more EMT inducers directly and/or indirectly.Epithelial–Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs)—TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, and FOXC2—are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2 and GRHL1/2). Here, using mechanism-based mathematical modeling, we show that transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote a phenotypic shift toward a more epithelial state, an observation suggested by the negative correlation of KLF4 with EMT-TFs and with transcriptomic-based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating the EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at the epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with the patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.
Highlights
Cancer is expected to surpass all noncommunicable disease-related deaths in the21st century, making it a major global public health threat [1]
A key hallmark exhibited by these cells is phenotypic plasticity, i.e., their ability to dynamically switch between phenotypes, empowering them to adapt to the ever-changing microenvironments that they face during metastasis [5,6]
To do do this this we investigated the dynamics of the interaction between Krüppel-like factor 4 (KLF4) and a core Epithelial–Mesenchymal Transition (EMT) regulatory we investigated the dynamics of the interaction between KLF4 and a core EMT regulatory circuit comprised of four players: circuit comprised of four players: three EMT-inducing transcription factors (EMT-TFs)—ZEB1/2, SNAIL, and SLUG—and three EMT-inducing transcription factors (EMT-TFs)—ZEB1/2, SNAIL, and SLUG—and an EMT-inhibiting microRNA family
Summary
Cancer is expected to surpass all noncommunicable disease-related deaths in the21st century, making it a major global public health threat [1]. Cancer is expected to surpass all noncommunicable disease-related deaths in the. Most cancer-related deaths can be attributed to the process of metastasis [2]. Metastasis is a highly inefficient process with attrition rates as high as >99.5% [4]; only a miniscule percentage of metastasizing cells comprise the successful seeding of secondary tumor(s). A key hallmark exhibited by these cells is phenotypic plasticity, i.e., their ability to dynamically switch between phenotypes, empowering them to adapt to the ever-changing microenvironments that they face during metastasis [5,6]. It is critical to decode the mechanisms of phenotypic plasticity in order to unravel the dynamics of metastasis and develop therapeutic strategies targeting this insurmountable clinical challenge
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
