Biology subjects

Subbalakshmi, A. R.

Publications and source records attributed to Subbalakshmi, A. R..

8 recordsLinked to original sources

bioRxiv2026

Decoding stress-induced adaptation of cancer cells in spatial confinement by integrating live-cell imaging and mathematical modeling

The adaptive strategies employed by cancer cells to combat stress when grown in 2D cultures have been extensively studied, including applying evolutionary game theory. However, relatively little is known about these strategies when the cells are grown in confinement that resemble the tumor microenvironment more closely. Here, we used cisplatin-sensitive and -tolerant lung cancer cells that were grown as monotypic or heterotypic spheroids in a microfluidics system and monitored in real time. Competition and cooperation between these cells were modeled by estimating the parameters through the best fit of observed measurements using a modified version of the Cellular Potts model. The results indicated that the two sensitive and tolerant populations exhibited different cooperative and competitive strategies under changing environmental conditions. Importantly, we found that in addition to initial cell type composition, the population fitness was governed by the spatial organization, intercellular interactions, and dynamic remodeling of the local microenvironment by these cells. Further, tolerant cells exhibited similarities to a persister trait and appeared to cooperate with sensitive cells, enabling them to evade chemotherapy.

cancer biology↗

bioRxiv2026

Systems-level analysis identifies IRF6 as an inhibitor of epithelial-mesenchymal transition

BackgroundEpithelial-mesenchymal transition (EMT) and its reverse process Mesenchymal-Epithelial Transition (MET) are crucial during metastasis and therapy resistance. While the dynamics and master regulators of EMT are well-studied, the transcription factors that can prevent EMT or promote MET are relatively less understood. ResultsHere, by integrating bulk and spatial transcriptomic data analysis from cell lines and patient samples, with mechanism-based dynamical modelling, we identify IRF6 as a factor that strongly associates with an epithelial phenotype and is often inhibited during EMT. In vitro experiments in multiple cancer cell lines demonstrate the progression to a mesenchymal phenotype upon IRF6 knock-down, suggesting a role as an inhibitor of EMT. Finally, we observe that IRF6 expression levels correlates with worse patient survival in a subset of solid tumour types. ConclusionOur integrated computational-experimental systems-level analysis suggests that IRF6 is frequently downregulated during EMT and can also prevent the progression towards a complete EMT, underscoring its role as an MET stabilizing factor.

systems biology↗

bioRxiv2025

Mitochondrial Dynamics Through the Lens of Nonlinear Chemical Oscillations: A Theoretical Exploration Inspired by the Belousov-Zhabotinsky Reaction

In biology, oscillations are observed across a wide spectrum of processes and systems. Oscillatory systems are typically leveraged to transmit information within cells. However, they can also serve to transmit information between organisms underscoring their fundamental role in regulating transitions, maintaining stability, and responding to environmental stimuli. In this study, we explore mitochondrial fission and fusion dynamics through the framework of the Belousov-Zhabotinsky (BZ) reaction, a hallmark of non-equilibrium system that exhibits periodic changes in reactant concentrations through autocatalysis and feedback regulation. We observed that mitochondrial changes followed an oscillatory dynamic where the fission, fusion and intermediary factors undergo oscillations. Also, by modelling comparison with publicly available datasets of diseased condition before and after therapy, we observed similarities, where under diseased condition there is increased concentration of the fission and fusion factors but upon treatment the concentration of the intermediary factors increase. Also, patient survival data analysis showed that increase in fission and fusion factors correlated with increased deaths but when there is increase in the intermediary factor concentration, we see better patient survival. These results highlight the possibility of targeting mitochondrial dynamics as a potential strategy for therapeutic development for diseases such as cancer where mitochondrial dynamics is dysregulated.

systems biology↗

bioRxiv2022

The ELF3 transcription factor is associated with an epithelial phenotype and represses epithelial-mesenchymal transition

Epithelial-mesenchymal plasticity (EMP) involves bidirectional transitions between epithelial, mesenchymal and multiple intermediary hybrid epithelial/mesenchymal phenotypes. While the process of epithelial-mesenchymal transition (EMT) and its associated transcription factors are well-characterised, the transcription factors that promote mesenchymal-epithelial transition (MET) and stabilise hybrid E/M phenotypes are less well understood. Here, we analyse multiple publicly-available transcriptomic datasets at bulk and single-cell level and pinpoint ELF3 as a factor that is strongly associated with an epithelial phenotype and is inhibited during EMT. Using mechanism-based mathematical modelling, we also show that ELF3 inhibits the progression of EMT, suggesting ELF3 may be able to counteract EMT induction, including in the presence of EMT-inducing factors, such as WT1. Our model predicts that the MET induction capacity of ELF3 is stronger than that of KLF4, but weaker than that of GRHL2. Finally, we show that ELF3 levels correlates with worse patient survival in a subset of solid tumor types, suggesting cell-of-origin or lineage specificity in the prognostic capacity of ELF3.

cancer biology↗

bioRxiv2021

KLF4 induces Mesenchymal-Epithelial Transition (MET) by suppressing multiple EMT-inducing transcription factors

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, FOXC2 - are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2, GRHL1/2). Here, using mechanism-based mathematical modeling, we show that the transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote phenotypic shift toward a more epithelial state, an observation suggested by 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 EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at an epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.

cancer biology↗

bioRxiv2020

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

Epithelial-mesenchymal plasticity comprises of reversible transitions among epithelial, hybrid epithelial/mesenchymal (E/M) and mesenchymal phenotypes, and underlies various aspects of aggressive tumor progression such as metastasis, therapy resistance and immune evasion. The process of cells attaining one or more hybrid E/M phenotypes is termed as partial EMT. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either fully epithelial or mesenchymal state. Thus, identifying regulators of hybrid E/M phenotypes is essential to decipher the rheostats of phenotypic plasticity and consequent accelerators of metastasis. Here, using a computational systems biology approach, we demonstrate that SLUG (SNAIL2) - an EMT-inducing transcription factor - can inhibit cells from undergoing a complete EMT and thus stabilizing them in hybrid E/M phenotype(s). It expands the parametric range enabling the existence of a hybrid E/M phenotype, thereby behaving as a phenotypic stability factor (PSF). Our simulations suggest that this specific property of SLUG emerges from the topology of the regulatory network it forms with other key regulators of epithelial-mesenchymal plasticity. Clinical data suggests that SLUG associates with worse patient prognosis across multiple carcinomas. Together, our results indicate that SLUG can stabilize hybrid E/M phenotype(s).

cancer biology↗

bioRxiv2020

NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype

Metastasis remains the cause of over 90% of cancer-related deaths. Cells undergoing metastasis use phenotypic plasticity to adapt to their changing environmental conditions and avoid therapy and immune response. Reversible transitions between epithelial and mesenchymal phenotypes - Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) - form a key axis of phenotypic plasticity during metastasis and therapy resistance. Recent studies have shown that the cells undergoing EMT/MET can attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes, the process of which is termed as partial EMT/MET. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either epithelial or mesenchymal state. Thus, it is crucial to identify the factors and regulatory networks enabling such hybrid E/M phenotypes. Here, employing an integrated computational-experimental approach, we show that the transcription factor NFATc can inhibit the process of complete EMT, thus stabilizing the hybrid E/M phenotype. It increases the range of parameters enabling the existence of a hybrid E/M phenotype, thus behaving as a phenotypic stability factor (PSF). However, unlike previously identified PSFs, it does not increase the mean residence time of the cells in hybrid E/M phenotypes, as shown by stochastic simulations; rather it enables the co-existence of epithelial, mesenchymal and hybrid E/M phenotypes and transitions among them. Clinical data suggests the effect of NFATc on patient survival in a tissue-specific or context-dependent manner. Together, our results indicate that NFATc behaves as a non-canonical phenotypic stability factor for a hybrid E/M phenotype.

cancer biology↗

bioRxiv2019

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

Tumor heterogeneity and cisplatin resistance are a major cause of tumor relapse and poor survival. Here we show that in lung adenocarcinoma (LUAD), paxillin (PXN) and integrin beta 4 (ITGB4) are associated with tumor progression, and cisplatin resistance. Silencing PXN and ITGB4 render cisplatin tolerant cells sensitive, and immunologically neutralizing ITGB4 improves sensitivity. The N-terminal half of PXN is intrinsically disordered and interacts with ITGB4 to regulate expression of USP1 and VDAC1 which are required for maintaining genomic stability and mitochondrial function in LUAD. By virtual screening an FDA-approved compound library, we identified compounds that interact with PXN in silico and attenuate cisplatin resistance in LUAD cells. RNAseq analysis identified a double negative feedback loop between ITGB4 and microRNA miR-1-3p, suggesting that bistability could lead to stochastic switching between cisplatin-sensitive and resistant states in these cells. The data highlight an alternate, non-genetic, mechanism underlying chemoresistance in lung cancer.

cancer biology↗