Biology subjects

Meena, R. K.

Publications and source records attributed to Meena, R. K..

3 recordsLinked to original sources

bioRxiv2026

Bidirectional coupling among EMT, AXL-RB1 signaling and lineage switch drives resistance to osimertinib and worse clinical outcomes in NSCLC

Acquired resistance to osimertinib remains a major barrier in EGFR-mutant lung adenocarcinoma (LUAD), and in many patients cannot be explained by secondary targetable mutations. This pattern highlights a central role for non-genetic plasticity programs, including epithelial-mesenchymal transition (EMT), drug tolerance, immune evasion, and lineage switch. Here, we used a systems-level framework to define how these processes are coordinated. We constructed a minimal gene regulatory network integrating core EMT regulators with AXL, RB1, PD-L1, and NF-{kappa}B, and analysed its emergent behaviour using dynamical simulations. The network resolved into two mutually inhibitory, self-reinforcing "teams": an epithelial/sensitive team centred on RB1, miR-200, miR-34, p53, and E-cadherin, and a mesenchymal/resistant team centred on ZEB1, SNAIL, AXL, PD-L1, and NF-{kappa}B. Simulations predicted a strong coupling between EMT and osimertinib resistance, which was validated across bulk transcriptomic datasets from NSCLC cell lines, EGFR-mutant patient cohorts, and perturbation experiments. Inducing EMT increased RB1-loss programs, whereas osimertinib exposure induced AXL and EMT programs, supporting bidirectional regulation and reinforcement. Single-cell and spatial transcriptomic analyses further showed that EMT, AXL, PD-L1 activity, and reduced RB1 signaling co-occur within tumors. Clinically, activation of individual axes such as EMT, RB1 loss, or PD-L1 upregulation was associated with worse outcomes, while combined activation produced markedly poorer survival than any single axis alone. Extending the network to incorporate lineage regulators further linked a partial LUAD-to-LUSC shift with EMT, RB1 loss, and resistance. Together, these findings identify a network topology that coordinates multiple plasticity programs driving osimertinib resistance and suggest that disrupting this cooperative architecture may offer a therapeutic strategy in EGFR-mutant LUAD.

cancer biology↗

bioRxiv2026

Time-dependent memory of hypoxia exposure influences tumor invasion dynamics

Cancer cells in hypoxic environments often proliferate less but exhibit enhanced migration relative to their normoxic counterparts. Recent in vitro and in silico studies have characterized the role of hypoxic memory - the ability of cancer cells to retain their hypoxic phenotype even when reoxygenated - in tumor invasion. However, the observations have been limited either to exposing cancer cells to hypoxia for a fixed duration or by assuming a fixed-time persistence of the hypoxic state upon reoxygenation independent of the duration of hypoxia exposure. Thus, time-dependent cell-state changes during hypoxia and their impact on hypoxic memory remains unclear. Here, we first analyze transcriptomic data from breast cancer samples to show that the genes upregulated at transcriptional level and hypomethylated at epigenetic level are enriched in cell invasion, indicating hypoxic memory-driven process of tumor invasion. Next, we used a computational model to investigate how the spatial-temporal dynamics of oxygen levels in a tumor drive time-dependent changes in hypoxic memory and influence tumor invasion dynamics. Our simulation results show that such dynamic hypoxic memory can drive enhanced tumor invasion over a fixed hypoxic memory by a) enriching hypoxic cell density at the tumor front, b) reducing sensitivity of hypoxic cell state to fluctuations in oxygen supply, and c) enhancing effective diffusion of hypoxic cells. Our results highlight the crucial role of dynamic hypoxic memory in shaping tumor invasion dynamics, underscoring the need to elucidate its underlying mechanisms in future studies.

systems biology↗

bioRxiv2025

Interconnected axes of phenotypic plasticity drive coordinated cellular behaviour and worse clinical outcomes in breast cancer

Phenotypic plasticity plays a key role in cancer progression and metastasis, enabling cancer cells to adapt and evolve, but precisely how distinct axes governing phenotypic plasticity interact to shape tumour progression and patient outcomes remains unclear. We investigated five major interconnected axes of plasticity in ER-positive (ER+) breast cancer: Metabolic Reprogramming, Epithelial-to-Mesenchymal Plasticity (EMP), Luminal-Basal (Lineage) Switching, Stemness, and Drug-resistance using network dynamics simulations, integrative bulk and single-cell transcriptomic analyses and patient survival analyses. We show that these axes are not independent but drive one another, forming two mutually inhibiting teams of nodes enabling specified cellular behaviour. One team (favouring high glycolysis, stem-like, basal-like, mesenchymal/hybrid and tamoxifen-resistant phenotype) was found to be associated with aggressive progression and worse survival. On the other hand, the opposing team (favouring high oxidative phosphorylation, non-stem-like, luminal-like, epithelial and tamoxifen-sensitive phenotype) correlated with better outcomes. Importantly, altering one axis of plasticity often drove coordinated responses along other axes and vice versa. Our findings establish phenotypic plasticity in cancer as a coordinated, multi-axis dynamical process, thus suggesting novel strategies to disrupt systems-level reprogramming enabling metastasis and therapeutic resistance.

systems biology↗