About

Dennis E. Discher, Ph.D., is a Professor of Chemical & Biomolecular Engineering at the University of Pennsylvania's Perelman School of Medicine. He is affiliated with the Graduate Groups in Pharmacology and Cell and Molecular Biology. His research expertise includes the study of biomolecular engineering, with a focus on cellular mechanics, biomaterials, and the physical principles underlying cell behavior. His work involves understanding how cells interact with their environment at a molecular level, contributing to advancements in biomedical engineering and cell biology. Dr. Discher's contributions include exploring the mechanical properties of cells and tissues, which have implications for disease understanding and tissue engineering.

Research topics

• Biology
• Computer Science
• Medicine
• Genetics
• Biochemistry
• Computational biology
• Immunology
• Biotechnology
• Internal medicine
• Biomedical engineering
• Cell biology
• Neuroscience
• Cancer research

Selected publications

• BPS2026 – Active-matter tissue sculpting and scaling of visco-elasticity with collagen-fiber densities

  Biophysical Journal · 2026-02-01

  article1st authorCorresponding
  PublisherDOI

• Cell confinement initiates a delayed but heritable loss of chromosomes

  Cell Reports · 2026-03-01

  articleOpen accessSenior author

  Heritable genetic changes continually arise in cancer, especially in solid tumors where cells are sometimes compressed. Rare heritable losses of chromosomes in live cells are quantified here with chromosome reporters (ChReporters), which reveal losses only after imposing a threshold level of confinement. Compression to ∼60% of interphase height ruptures few nuclei compared to deeper compression but perturbs mitotic spindles and prolongs pro/metaphase. Chromosome mis-segregation into micronuclei is discovered only after release from modest confinement, but arrest and death predominate. All such effects are phenocopied by nocodazole washout, which generates a "memory" of prolonged mitosis. The effects also differ from the rapid induction of micronuclei by a spindle-assembly checkpoint inhibitor and by a clinical CDK4/6 inhibitor of cell-cycle entry. Single-cell RNA sequencing confirms chromosome loss days after confinement and reveals dysregulation of chromosome-segregation pathways. Chromosome losses as mitotic memories of confinement ultimately address knowledge gaps in mechanobiology and cancer evolution.

  PublisherOA PDFDOI

• Lipid droplets are rigid and physically suppress phagocytosis, unless cell compression or stretching activates actomyosin

  Molecular Biology of the Cell · 2026-01-28

  articleOpen accessSenior author

  As with many cell types, macrophages are sometimes filled with micron-sized lipid droplets (LD's), but effects on phagocytosis of other cells, particulates, and microbes remain unclear. Here, we show that LDs restructure the cytoskeleton but remain round, consistent with a high interfacial tension; functionally, LD's impair actomyosin-driven uptake, which proves independent of target size. Engulfment of targets starts at the apical surface, but LD's displace apical actomyosin to the basal cortex. Partial rescue occurs tissue-relevant compressive stresses which activate actomyosin. Macrophages that are densely filled with LD's or pre-engulfed rigid beads likewise activate actomyosin, which again rescues phagocytosis relative to sparsely loaded cells. As further evidence of LD rigidity, both LD's and rigid beads impede macrophage migration through small pores, and LD's pressed into a nucleus cause rapid focal rupture independent of actin. LD rigidity thus disrupts cytoskeleton organization and nucleus integrity, suppressing motility processes unless actomyosin is activated by cell compression or stretching.

  PublisherOA PDFDOI

• Cell confinement initiates a delayed but heritable loss of chromosomes

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-03

  articleOpen accessSenior author

  SUMMARY Heritable genetic changes continually arise in cancer, especially in solid tumors where cells sometimes appear compressed. Rare heritable losses of chromosomes in live cells are quantified here with chromosome reporters (ChReporters) that reveal similar levels of loss after imposing a threshold level of confinement. Compression to ∼60% of interphase height ruptures few nuclei compared to deeper compression but perturbs mitotic spindles and prolongs pro/metaphase. Chromosome mis-segregation into micronuclei is discovered only after release from modest confinement, but arrest and death predominate. All such effects are phenocopied by Nocodazole washout that generates a ‘memory’ of prolonged mitosis, and effects differ from the rapid induction of micronuclei by a spindle assembly checkpoint inhibitor and by a clinical CDK4/6-inhibitor of cell cycle entry. Single-cell-RNA-sequencing confirms chromosome loss days after confinement and reveals persistence of chromosome segregation pathways. Chromosome losses as mitotic memories of confinement ultimately address knowledge gaps in mechanobiology and cancer evolution.

  PublisherDOI

• Abstract 766: Physically driven chromosome instabilities spur macrophages to attack cooperatively.

  Cancer Research · 2026-04-03

  article1st authorCorresponding

  Abstract Extracellular matrix often accumulates in and around solid tumors, and such tumors also evolve diverse mutations that drive cancers, confound therapies, and modulate immune interactions. Across cancer types, we observe chromosome number changes associate with collagen-I levels, and our experiments show rare heritable chromosome losses are induced by a stiff 3D matrix around spheroids. Chromosome reporters (ChReporters) reveal losses in as few as ∼0.1% of cells, with a mechanism in spheroids based on distortion of mitotic spindles - which increases with knockdown of the candidate tumor suppressor myosin-II. Chromosomes mis-segregate into micronuclei that increase with matrix stiffness despite suppressed cell division. Drugs that increase micronuclei in 2D and that rely on an unperturbed spindle show no effect in 3D where the spindle is perturbed. Tumors in vivo that are surrounded by stiff collagen likewise show more but varied chromosome loss and slower growth than 2D cultures. High variance of ChReporter-negative colonies further illustrate increased heterogeneity with 3D matrix stiffness and heritable mutations per Luria-Delbruck theory. Physical learning models of evolving chromosome numbers in proliferating cells are developed and fit key statistical trends.Temperature is another physical stressor - as solid tumors tend to be warm - and we show it has similar outcomes as matrix physical properties. Heating is also now part of various therapies as are immune-engineering approaches. We take advantage of Macrophages that often pervade solid tumors where clusters of macrophages are sometimes seen and associate with longer survival of patients. However, clustering mechanisms, responses to stressor above, and impacts on key functions such as phagocytosis remain obscure. Under conditions that maximize cancer cell phagocytosis within cohesive tumors, we uncover pathways that favor dynamic clusters and find a colocalization of tumor-intrusive pseudopodia which we term “intrudopodia.” Cluster formation is favored by M1 macrophages after exposure to interferons and T cell-derived cytokines. M1 macrophages upregulate specific cell-cell adhesion receptors but suppress actomyosin contractility, with both pathways contributing to cluster formation and unleashing pseudopodia. Macrophage neighbors in tumor spheroids indeed coextend intrudopodia between cancer cell junctions—at least when phagocytosis conditions are maximized by checkpoint disruption and other strategies. Intrudopodia from neighbors help detach and individualize cancer cells for rapid engulfment. Cooperative phagocytosis thus overcomes solid tumor cohesion—and might explain why the macrophage clustering factor ITGAL associates with patient survival. Citation Format: Dennis Discher, Markus Sprenger, Joanna Georgiou, Tristan Marchena, Jude Khatib. Physically driven chromosome instabilities spur macrophages to attack cooperatively [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 766.

  PublisherDOI

• Matrix stiffness induces heritable changes in chromosome numbers, consistent with solid tumor heterogeneity

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-30 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Solid tumors often have an abundance of collagen-I that stiffens the tissue, and they are invariably driven by mutations that include chromosome losses and gains. These observations are linked here by showing that 3D matrix stiffness induces heritable changes to a cell ’ s DNA. We use live-cell chromosome reporters (ChReporters) and hydrogels of tunable stiffness to show mitotic compression, micronuclei counts, ChReporter losses and heterogeneity all increase as functions of stiffness. Increased mistakes occur despite suppressed cell division in stiff matrix and minimal size variation between spheroids. Colonies of ChReporter-negative cells within cancer spheroids align with Luria-Delbruck ’ s seminal theory for heritable mutations, which predicts inter-spheroid variances that exceed Poisson statistics. Suppression of the contractility motor Myosin-II also increases chromosome loss in 3D but not 2D and does not affect spheroid growth – thus clarifying Myosin-II ’ s putative role as a tumor suppressor. Consistent with experiments, pan-cancer analyses of clinical data associates chromosome losses and gains with collagen-I levels and genetic variation. Stiff extracellular matrix thus drives mechano-evolution of solid tumors as a Darwin-Lamarck process with heterogeneity that complicates therapy.

  PublisherOA PDFDOI

• Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape

  Nature Nanotechnology · 2025-08-11 · 42 citations

  articleOpen access
  PublisherOA PDFDOI

• Abstract 7465: Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia

  Cancer Research · 2025-04-21

  article1st authorCorresponding

  Abstract Macrophages often pervade solid tumors, but observations that macrophage clusters might associate with patient survival have remained largely unexplored. We observe dynamic macrophage clusters in tumors under conditions that maximize cancer cell phagocytosis, and our reductionist approaches to cluster formation reveal pathways and roles for tumor-intrusive pseudopodia. Aggregates form over hours on low-adhesion substrates after ‘M1’ polarization of macrophages with interferons, including Tcell-derived cytokines, and yet clusters prove fluid on timescales of minutes. Clusters also sort from M2 macrophages which are induced by an interleukin and that disperse on the same substrates. M1’s upregulate cell-cell adhesion receptors but suppress actomyosin contractility, and while both pathways contribute to cluster formation, decreased cortical tension was predicted to unleash pseudopodia. Macrophage neighbors in tumor spheroids indeed extend intrusive pseudopodia or ‘intrudopodia’ in between adjacent cancer cell junctions - at least when phagocytosis conditions are maximized, and coordinated intrudopodia help detach and individualize cancer cells for rapid engulfment. Macrophage clusters thereby provide a cooperative advantage for phagocytosis to overcome solid tumor cohesion. Citation Format: Dennis E. Discher, Lawrence Dooling. Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7465.

  PublisherDOI

• BPS2025 - Mechanical strain causes heritable mutations

  Biophysical Journal · 2025-02-01

  article1st authorCorresponding
  PublisherDOI

• Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia

  Proceedings of the National Academy of Sciences · 2025-07-01 · 8 citations

  articleOpen accessSenior authorCorresponding

  Macrophages often pervade solid tumors, and clusters of macrophages sometimes associate with longer survival of patients. However, clustering mechanisms and impacts on key functions such as phagocytosis remain obscure. Here, under conditions that maximize cancer cell phagocytosis within cohesive tumors, we uncover pathways that favor dynamic clusters and find a colocalization of tumor-intrusive pseudopodia which we term “intrudopodia.” Cluster formation over hours on low-adhesion substrates occurs after macrophage induction to a state colloquially referred to as M1 after exposure to interferons and T cell–derived cytokines. Clusters prove fluid on timescales of minutes and also sort from interleukin-4-treated, so-called M2 macrophages that tend to disperse. M1 macrophages upregulate specific cell–cell adhesion receptors but suppress actomyosin contractility, with both pathways contributing to cluster formation. Decreased cortical tension was not only reflected in a low level of nuclear lamin-A that downregulates cytoskeletal targets of serum response factor and tends to soften the nucleus but was also predicted to unleash pseudopodia. Macrophage neighbors in tumor spheroids indeed coextend intrudopodia between cancer cell junctions—at least when phagocytosis conditions are maximized. Intrudopodia from neighbors help detach and individualize cancer cells for rapid engulfment. Juxtaposition of a macrophage cluster with tumor cell nests defines a broad interface that minimizes cancer cell nearest neighbor interactions and maximizes coordination of macrophage intrudopodia. Cooperative phagocytosis thus overcomes solid tumor cohesion—and might explain why the macrophage clustering factor ITGAL associates with patient survival.

  PublisherDOI

Recent grants

• NIH Grant R21AR056128

  NIH · $364k · 2011

• NIH Grant R21HL128187

  NIH · $426k · 2018

• Nanoscience of Self 2.0: blocking CD47 recognition by phagocytes in blood & solid tumor clearance

  NIH · $3.1M · 2014–2022

• NIH Grant R01EB007049

  NIH · $2.8M · 2015

• NIH Grant R21AI087516

  NIH · $474k · 2013

Frequent coauthors

• Jerome Irianto

  Florida Department of Health

  116 shared

• Roger A. Greenberg

  University of Pennsylvania

  89 shared

• Charlotte R. Pfeifer

  Rockefeller University

  88 shared

• Yuntao Xia

  82 shared

• Lawrence J. Dooling

  81 shared

• Irena L. Ivanovska

  University of Pennsylvania

  72 shared

• Jason C. Andrechak

  University of Pennsylvania

  61 shared

• Michael P. Tobin

  University of Pennsylvania

  56 shared

Education

• Ph.D.

  University of Pennsylvania