Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 12% survival rate, highlighting the need for novel therapies. c-MYC overexpression, driven by upstream mutations and amplifications, reprograms tumor metabolism and promotes proliferation, migration and metastasis. This study identifies ELOVL6, a fatty acid elongase regulated by c-MYC, as a potential therapeutic target. Using PDAC mouse models and cell lines, we show that c-MYC directly upregulates ELOVL6 during tumor progression. Genetic or chemical inhibition of ELOVL6 reduces proliferation and migration by altering fatty acid composition, affecting membrane rigidity, permeability and pinocytosis. These changes increase Abraxane uptake and show a synergistic effect when combined with ELOVL6 inhibition in vitro. In vivo, ELOVL6 interference significantly suppresses tumor growth and improves Abraxane response, prolonging survival. These findings position ELOVL6 as a promising target for improving PDAC treatment outcomes.

Red blood cell (RBC) membrane flickering arises from the interplay between thermal fluctuations, cytoskeletal elasticity, and metabolically driven non-equilibrium processes, making it a sensitive reporter of membrane mechanical state. Here, we introduce a computational microscopy framework that integrates bright-field morphometry with high-speed flickering spectroscopy to phenotype single-cell RBC mechanics under flavonoid exposure. As a proof of concept, human erythrocytes from a single donor were incubated with structurally distinct flavonoids (quercetin, apigenin, and rutin) prepared at sub-hemolytic concentrations, ensuring preservation of membrane integrity. Static shape descriptors and dynamic fluctuation spectra were extracted from segmented cell contours and analyzed through Fourier-mode decomposition to obtain compound-specific mechanical signatures. While gross morphology remained largely discocytic across conditions, flavonoid treatment induced reproducible alterations in flickering spectra and effective mechanical parameters, revealing distinct dynamical phenotypes that depend on flavonoid structure. In particular, aglycone flavonoids exhibited modulation patterns that differed from the glycosylated compound, consistent with differential membrane interactions. The combined analysis of geometry and dynamics provided enhanced discriminative power compared to either modality alone. These results establish computational microscopy as a sensitive, label-free approach to map compound-specific perturbations of RBC membrane mechanics and flickering, with potential applications in membrane biophysics, drug–membrane interaction screening, and single-cell mechanical phenotyping.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, marked by a survival rate of only 12%. Consequently, the exploration of novel therapeutic strategies becomes a critical clinical imperative. Among the genetic alterations contributing to PDAC, c-MYC overexpression arises due to upstream mutations, amplifications, and copy number alterations. c-MYC serves as a key regulator in the tumor’s metabolic reprogramming, playing a pivotal role in proliferation, migration, and metastasis. This study delves into the investigation of the role of the elongase ELOVL6 in c-MYC-induced cell transformation and its potential as a therapeutic target in PDAC. Here, we demonstrate that c-MYC regulates lipid elongation to promote cell transformation, offering a new avenue for therapeutic intervention. Initially, we show the direct regulation of ELOVLs expression by c-MYC in various PDAC mouse models and cell lines, elucidating its upregulation during transformation and tumor progression. Genetic or chemical inhibition of ELOVL6 results in decreased proliferation and migration, accompanied by alterations in fatty acid elongation. These changes in fatty acid composition led to modifications in membrane rigidity, permeability, and thickness, which collectively affect micropinocytosis and macropinocytosis. Importantly, we observe an increase in Abraxane uptake and a synergistic effect when combined with ELOVL6 interference in vitro . In vivo validation demonstrates that ELOVL6 inhibition significantly reduces tumor growth and enhances the response to Abraxane, thereby increasing overall survival. Altogether, these results position ELOVL6 as a promising therapeutic target in the treatment of PDAC.

The cell nucleus is increasingly recognized as a mechanosensitive organelle whose mesoscale mechanical heterogeneity (100 nm 10 um) is inseparable from genome regulation yet remains weakly integrated into systems biology and omics frameworks. Here we synthesize experimental and theoretical advances that define a nuclear mechanome: a multidimensional state of mechanical observables spanning lamins, chromatin, nucleoplasm and condensates, and varying across space, time, and cells. We review how intranuclear gradients, chromatin domains and phase-separated bodies generate viscoelastic, poroelastic and plastic niches that shape transcription, replication, DNA repair, epigenetic metabolism, and clonal selection, with particular emphasis on cancer, laminopathies and ageing. We survey invasive, optical and high throughput mechanophenotyping techniques, together with continuum, shell polymer, mesoscopic and non-equilibrium models, as a toolkit for mechanomic mapping. Finally, we outline a research agenda towards standardized mechanical descriptors, tissue-level mechano multi omic atlases and mechanotherapeutic strategies that explicitly target nuclear mechanotypes as potential biomarkers that can define cellular identity, explain plasticity, and help predict pathological states or the evolution of several diseases.