The Lomakin Lab
Background information: The Luria-Delbrück experiment (1943) famously showed that stress resistance in biological cells can arise from pre-existing random mutations rather than being induced by stress itself. Yet growing evidence indicates that many cellular systems can also acquire stress resistance or tolerance through reversible, non-genetic phenotypic shifts (Levin & Rozen. Nature Reviews Microbiology, 2006; Berman & Krysan. Nature Reviews Microbiology, 2020; and Arozarena & Wellbrock. Nature Reviews Cancer, 2019). Understanding these non-genetic mechanisms is therefore an important emerging frontier. Our previous work (Lomakin et al. Science, 2020; García-Arcos et al. Developmental Cell, 2024; and Ju et al. Nature Cell Biology, 2024) showed that human cancer cells exposed to acute mechanical stress can exploit intrinsic physicochemical mechanisms to resist, and ultimately evade, this form of environmental challenge. One crucial mechanistic trigger of this response is altered surface tension in large organelles, especially the nucleus, together with the associated stretch-sensitive mechanochemical signaling (Lomakin et al. Science, 2020; see also: Venturini et al. Science, 2020; Shen & Niethammer. Science, 2020; and Long & Lammerding. Developmental Cell, 2021). Fascinatingly, the initial size of an organelle can predetermine how strongly a cell responds to a mechanical perturbation of the same magnitude. For example, nuclei in cells at different stages of the cell cycle differ intrinsically not only in biochemical composition but also in size, and therefore in their sensitivity to environmental mechanical stress (Lomakin et al. Science, 2020). This may serve as a source of phenotypic heterogeneity within a stressed cell population (Fig. 1).
Figure 1 (prepared using the BIORender App).
More broadly, this illustrates that stress-adaptive behaviors can emerge from systems-level properties of cells and from signaling pathways reshaped under stress, rather than solely from hard-wired genetic or transcriptional programs. Intriguingly, comparative studies suggest that induced mechanostress evasion is evolutionarily ancient, as even choanoflagellates, unicellular relatives of animals, can mount a related response under strong spatial confinement (Brunet et al. eLife, 2021). Yet in vertebrate cells, the nuclear domain appears to play a far more central role in sensing, signaling, and metabolic regulation. This suggests that, with multicellularity, the nucleus became more than a genetic container: it emerged as a privileged hub for monitoring cellular stress. We therefore propose that perturbations of the nuclear domain may also be sensed in other contexts, including drug-induced stress, where they could help drive adaptive survival programs. Indeed, recent research (Hunter et al. Nature, 2025) points to the possibility that drug tolerance may emerge from nuclear mechanochemical remodeling.
Biomedical relevance: Many pathogenic and opportunistic cells in the human body repeatedly face disruptions of cellular homeostasis throughout the host’s lifetime. Chemotherapeutic pressure further magnifies these challenges. Yet even under aggressive treatment, such cells often evade extinction, revealing evolved mechanisms of stress tolerance and survival. This is why drug resistance remains a growing challenge in microbiology and a tragedy in oncology. One reason the problem remains unresolved is that, even for widely used drugs, we still do not fully understand how cells sense drug-induced perturbations and coordinate adaptive responses across molecular, subcellular, cellular, and multicellular scales. Recent mechanistic studies suggest that even the most commonly used onco-chemotherapeutics and antibiotics can perturb molecular processes (and even affect off-target cells) in ways far beyond what textbook models of drug action would predict (see, e.g., Lin et al. Science Translational Medicine, 2019 and Sawaed et al. Science Advances, 2024). In other words, drugs may fail in the clinic not only because their targets are altered by preexisting or de novo mutations, but also because they trigger underappreciated indirect or off-target effects that can themselves promote adaptation to drug stress. Addressing this challenge will require deeper mechanistic insight into how drugs interact with and perturb living cells, and how these perturbations are translated into adaptive behavior. More broadly, it calls for pharmacology to evolve into a more interdisciplinary science that bridges molecular biology, cell biology, biophysics, and systems-level analysis in order to drive discovery and innovation.
Preliminary findings from the lab & Research objective: To address the problem of drug-induced stress tolerance in a hypothesis-agnostic manner, we started from the premise that drugs perturb entire gene and protein networks rather than single targets (Hopkins. Nature Chemical Biology, 2008). We therefore applied multi-omics profiling to determine how the molecular programs that govern cellular phenotype adapt under drug pressure. Using this approach, we found that cancer cells tolerating the broad-spectrum chemotherapeutics taxoids enter a metabolically dormant (Dhimolea et al. Cancer Cell, 2021 and Lin & Zhu. Cancer Cell, 2021), stress-resilient state by preferentially downregulating evolutionarily ancient (unicellular) networks related to protein synthesis. At the same time, these cells strongly upregulate evolutionarily younger (multicellular) programs converging on the regulation of nuclear morphogenesis. Indeed, nuclear domain alteration is among the earliest observable stress responses in cells surviving sublethal taxoid stress (Belhadj et al. Aging Cell, 2023 and Hale et al. Journal of Cell Science, 2026). Given that cancer cells frequently repurpose ancient fitness programs to navigate environmental shifts (Trigos et al. PNAS, 2017), we propose that they interpret drug-induced perturbations of the nuclear domain as a systems-level signal of compromised homeostasis. This signal triggers a strategic trade-off: the suppression of energetically costly unicellular growth in favor of multicellular programs linked to nuclear remodeling, survival, and phenotypic plasticity.
Building on the principles of network pharmacology, where drug efficacy emerges from modulation of protein networks rather than isolated protein targets (Hopkins. Nature Chemical Biology, 2008), we propose that drug action extends across broader biological scales (Fig. 2). In this view, drugs perturb organellar and sub-organellar networks as integrated functional units. Because organelles are physicochemically constrained compartments governed by boundary conditions, shifts in their geometry, composition, and inter-organelle interactions can serve as hidden drivers of metabolic and signaling reorganization, thereby shaping adaptive cell remodeling and cell-to-cell heterogeneity. Our research program seeks to uncover the quantitative molecular and (sub)cellular rules underlying this layer of regulatory control.
Figure 2 (prepared using the BIORender App).
Approach: We hypothesize that the acquisition of heterogeneous subcellular organization may itself be a key stress-survival response during adaptive phenotype remodeling. By changing organelle architecture, protein-network organization, and nucleo-cytoplasmic domain structure, perturbed cells shift their internal boundary conditions, thereby altering molecular fluxes, reaction environments, signaling, and metabolic coupling (Fig. 2). These layers of adaptation to perturbation remain largely hidden in -omics assays, even at single-cell resolution, because such methods profile molecular states more readily than the spatial and temporal organization in which those states operate. Addressing this problem requires approaches that capture and quantify subcellular organization together with key molecular stress-response markers, enabling reconstruction of the causal chain from perturbation to an emergent cell phenotype.
Figure 3 (prepared using the GOOGLE Gemini App).
Our long-standing expertise lies in developing precisely such quantitative microscopy-based strategies, which, when combined with creative experimentation, theoretical modeling, modern -omics approaches, and physico-chemical analyses (Fig. 3), place us in a strong position to tackle this question. One platform we are currently developing is ORBIT — Organelle-Resolved Bioimaging of Induced Tolerance. Combining open-source tools with commercial instruments, including in collaboration with Thermo Fisher Scientific Inc., this approach leverages AI-guided quantitative microscopy and bioimage informatics to analyze protein complexes, organelles, cells, and cellular communities before, during, and after drug perturbation, with the goal of reconstructing the evolution and uncovering the mechanistic logic of stress tolerance. Embracing interdisciplinary team science, we further complement our strengths with the expertise of collaborators in experimental and theoretical biophysics, as well as metabolomics and molecular genetics.
Finally, we assess the generality of the mechanisms we uncover by conducting comparative stress-response studies across evolutionarily distant species. To this end, we use designer strains of Saccharomyces cerevisiae that have been genetically engineered to respond to human drugs (the “YEAST_ON_DRUGS” system).
Four pillars for building a successful long-term project: In one of her public lectures, Julie A. Theriot, an American cell biologist and co-author of Physical Biology of the Cell, outlined a set of principles for building a durable long-term research program. These principles closely align with our own approach:
(i) Choose a phenomenologically rich biological system;
(ii) Use precise and well-controlled perturbations, ideally varying one parameter at a time;
(iii) Ensure a good view of the system, with informative probes across scales and robust quantitative readouts;
(iv) Build falsifiable models that make quantitative predictions, and refine them through an iterative theory-experiment cycle.
Our approaches and projects will interest scholars focused on quantitative cell biology and biophysics, bioinformatics, microscopy and bioimage informatics, pharmacobiology, drug resistance mechanisms, cancer & aging research, and comparative cell biology.
Medical University of Vienna
Center for Pathobiochemistry and Genetics
