Biology subjects

Dewan, P.

Publications and source records attributed to Dewan, P..

4 recordsLinked to original sources

bioRxiv2025

Glassy dynamics in active epithelia emerge from an interplay of mechanochemical feedback and crowding.

Glassy dynamics in dense epithelial cells remain a subject of debate, as theory predicts its emergence only at unrealistically low cellular activity, yet experimental studies have shown glassy dynamics at physiologically active conditions. In this study, we address this paradox by integrating experimental observations in epithelial monolayers with an active vertex model. We demonstrate that while crowding is essential, it is not sufficient for glassy dynamics to emerge. A mechanochemical feedback loop (MCFL-1), mediated by cell shape changes through the contractile actomyosin network is required to drive glass transition in dense epithelial tissues. Such mechanochemical feedback is captured experimentally via a crosstalk between actin-based cell clustering and dynamic heterogeneity, as well as via force induced actin reorganization in epithelial cells. Incorporating MCFL into the vertex model reveals contrasting results from those previously predicted by theories-we show that the MCFL can counteract cell division-induced fluidisation and enable glassy dynamics to emerge through active cell-to-cell communication. Furthermore, our analysis reveal, for the first time, the existence of novel collective mechanochemical oscillations that arise from the crosstalk of MCFL-1 with oscillatory MCFL-2, capturing ERK mediated cell shape changes. Together, we demonstrate that an interplay between crowding and active mechanochemical feedback enables the emergence of glass-like traits and collective biochemical oscillations in epithelial tissues with active cell-to-cell contacts.

biophysics↗

bioRxiv2025

Differential interfacial tension between oncogenic and wild-type populations forms the mechanical basis of tissue-specific oncogenesis in epithelia

Why does the same oncogenic mutation drive tumor formation in some tissues but not in others? While cancer driver mutations are well-documented, their tissue-specific effects remain largely attributed to genetic factors, leaving the biophysical aspects underexplored. Here, we demonstrate that mechanical interactions, specifically interfacial tension between newly transformed and wildtype epithelial cells are critical in determining survival and growth of HRasV12 oncogenic mutants in human mammary and bronchial epithelia, leading to contrasting outcomes in the two tissues. In mammary epithelium, isolated oncogenic cells are extruded-a typical mechanism of defense against cancer in epithelia-while oncogenic groups become spatially confined in a kinetically arrested, jammed state, marked by an actomyosin belt at the interface. In contrast, bronchial epithelium permits persistent spreading of the same oncogenic cells, which form long protrusions regardless of colony size. Furthermore, oncogenic clusters in these two tissues exhibit distinct biophysical properties, including variations in cell shapes, intracellular pressure, cell-cell tension, and cellular motility. Using a cell shape-tension coupled bi-disperse vertex model, we reveal that differences in interfacial tension at mutant-wild-type boundaries dictate whether oncogenic cells are eliminated, restrained, or expanded and that modulating the heterotypic interfacial tension alters mutant cell fate within the epithelium. Together, our findings uncover a mechanical basis for tissue-specific oncogenesis by highlighting how differential cellular mechanics at the oncogenic-host cell interface regulate tumor initiation and progression.

biophysics↗

bioRxiv2024

Reduced Filaggrin expression induces dysregulated intracellular signalling in atopic eczema

Atopic eczema (AE) is the most common inflammatory dermatosis, affecting up to 20% of children. Loss of function mutations in the Filaggrin (FLG) gene are the most strongly implicated genetic risk factor for AE, but little is known about the signalling pathways altered in response to loss of FLG. To explore the downstream effects of loss of FLG on the cellular environment, we combined RNAseq analysis of siRNA knockdown of normal human keratinocytes and analysis of tape strip (TS) samples from AE patients who were clinically phenotyped and genotyped for FLG mutation status. RNA-seq analysis revealed an increase in BMP signalling following FLG KD, which we validated in vivo using TS samples and biopsies. Recombinant BMP2 or BMP6 increased FLG and suprabasal keratin expression in vitro. Phosphoproteomic analysis identified 237 significantly differentially phosphorylated proteins following FLG KD. Kinase enrichment analysis identified downregulation of ERK1/2 and AKT1 signalling which was confirmed in AE biopsies. cFOS was downregulated following FLG KD and correlated with FLG expression in repository datasets. cFOS was downregulated following BMP6 treatment, implying that cFOS may be an important link between FLG and BMP signalling. Finally, proteomic analysis of TS samples identified altered desmosomal expression and phosphorylation following either loss of FLG or increased BMP signalling. Therefore, we have identified a SMAD1/Filaggrin/AKT axis as a potential therapeutic avenue in AE.

cell biology↗

bioRxiv2018

Delays, behaviour and transmission: modelling the impact of effective private provider engagement on tuberculosis control in urban India

In India, the country with the worlds largest burden of tuberculosis (TB), most patients first seek care in the private healthcare sector, which is fragmented and unregulated. Ongoing initiatives are demonstrating effective approaches for engaging with this sector, and form a central part of Indias recent National Strategic Plan: here we aimed to address their potential impact on TB transmission in urban settings, when taken to scale. We developed a mathematical model of TB transmission dynamics, calibrated to urban populations in Mumbai and Patna, two major cities in India where pilot interventions are currently ongoing.\n\nWe found that, when taken to sufficient scale to capture 75% of patient-provider interactions, the intervention could reduce incidence by upto 21.3% (95% Bayesian credible interval (CrI) 13.0 - 32.5%) and 15.8% (95% CrI 7.8 - 28.2%) in Mumbai and Patna respectively, between 2018 and 2025. There is a stronger impact on TB mortality, with a reduction of up to 38.1% (95% CrI 20.0 - 55.1%) in the example of Mumbai. The incidence impact of this intervention alone may be limited by the amount of transmission that has already occurred by the time a patient first presents for care: model estimates suggest an initial patient delay of 4-5 months before first seeking care, followed by a diagnostic delay of 1-2 months before ultimately initiating TB treatment. Our results suggest that the transmission impact of such interventions could be maximised by additional measures to encourage early uptake of TB services.

systems biology↗