About

Andre Levchenko is the John C. Malone Professor of Biomedical Engineering at Yale University. His research focuses on systems biology, signal transduction, and cell-cell communication, with particular interests in cell decision making, microfluidics, micro- and nano-fabrication, and stem cell engineering. Levchenko has made significant contributions to understanding the dynamics of biochemical signaling networks, including MAP kinase signaling modules and NF-κB signaling, as well as intercellular transfer mechanisms mediating multidrug resistance in tumor cells. His work also explores the structural and functional regulation of cardiac tissue constructs, neuronal growth cone engineering, and the information transduction capacity of biochemical signaling networks. Throughout his career, Levchenko has been recognized with numerous awards and honors, including election as a Fellow of the American Institute for Medical and Biological Engineering, and has contributed extensively to the scientific community through publications and participation in influential conferences.

Research topics

• Biology
• Computer Science
• Cell biology
• Neuroscience
• Psychology
• Cognitive science
• Biochemistry
• Artificial Intelligence
• Genetics
• Evolutionary biology
• Endocrinology
• Physics
• Medicine
• Intensive care medicine
• Biophysics
• Cancer research
• Computational biology
• Internal medicine
• Theoretical computer science

Selected publications

• The hierarchical timescale hypothesis: Functional and structural convergence of biological networks and artificial neural nets

  Cell Systems · 2026-02-01

  articleSenior author
  PublisherDOI

• Disruption of WNT/Notch signaling in pancreatic cancer reveals tumors depend on the intricate equilibrium of malignant cell states

  Developmental Cell · 2026-03-23

  articleOpen access
  PublisherOA PDFDOI

• CRISPR screen of human pancreatic cancer xenografts identifies a KLF5 proliferation vulnerability through epigenetic modifiers NCAPD2 and MTHFD1

  Molecular Cancer · 2026-02-10 · 1 citations

  articleOpen access

  One of the major conundrums of cancer research and treatment is that the metastases that lead to death in most patients do not appear to involve additional driver mutations. Previously, we reported widespread loss of heterochromatin with activation of pro-metastatic genes in the subset of cells of primary pancreatic tumors that gave rise to liver and lung metastases. Here we hypothesized that this change in chromatin could create unique vulnerabilities in distant metastases. Using a CRISPR screen of human patient-derived xenografts from metastases and primary tumors, we identified KLF5 as essential for metastatic cell proliferation but not primary tumor growth. Further, we found that KLF5 induced epigenetic modifier genes, including NCAPD2 and MTHFD1, which themselves facilitated expression of specific genes driving migration and epithelial-mesenchymal transition, including TGFBR2, VIM, EMP1, and ITGB1. Inhibition of expression of these modifier genes restored heterochromatin in the specific regions that distinguish the primary and metastatic tumors. We backed up this causal chain of evidence with rigorous additional knockdown experiments with the modifier genes, and single cell RNA and chromatin experiments, and we also replicated the main findings in a second set of paired primary and distant metastasis xenograft lines. Finally, KLF5 expression was strongly associated with patient survival and human PDAC cell plasticity in a dataset of 70 PDAC patients and KLF5 expression was increased in the majority of lung, liver and peritoneal metastases compared to the matched primary tumor, confirming its importance in PDAC metastasis and mortality. In summary, we have identified a cascade of epigenetic modulators, modifiers and mediators that maintains the widespread heterochromatin loss supporting metastatic cell proliferation in human pancreatic cancer (see Graphical Abstract). KLF5 modulates epigenetic modifications driving PDAC metastatic proliferation and plasticity

  PublisherDOI

• Cancer signaling beyond the genes

  Current Opinion in Cell Biology · 2026-04-17

  articleOpen access1st authorCorresponding

  Cancer is still largely interpreted through the lens of genetic mutations, which continues to shape most therapeutic strategies. Yet single cell analyses reveal limits to this view: phenotypic heterogeneity is pervasive even among genetically identical cancer cells, and many canonical driver mutations are also present in non-malignant tissues. These paradoxes can be reconciled by viewing cancer as a new tissue state characterized by aberrant cellular information processing, where mutations act as context-dependent modifiers of the signaling codes. We advance a framework in which input-specific signaling dynamics determine phenotypic outcomes, while oncogenic mutations bias and blur these dynamics rather than acting as simple "on-off" switches. In this view, therapeutic success depends on restoring the fidelity of dynamic signal encoding and decoding rather than merely inhibiting isolated pathway components.

  PublisherDOI

• A Neyman-Pearson Framework for Modeling Cellular Decision Making Using Single-Cell TNF–NF-κB Signaling Data

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-31

  articleOpen access

  Abstract Cells make hard calls under noise. When signaling is abnormal, those calls can go wrong and drive pathological conditions and diseases. In this research, we develop a Neyman–Pearson (NP) detection-theory framework that maximizes probability of detection ( P D ) for a chosen false alarm probability ( P FA ), without requiring prior probabilities, using experimental single-cell measurements of NF-κB responses to tumor necrosis factor (TNF), a critical pathway involved in cell survival, apoptosis, immune signaling, and stress response, in wild-type and A20-deficient fibroblasts. We model log-responses as (multi)variate Gaussian and compute optimal thresholds, P D – P FA trade-offs, and ROC curves at 30 minutes and 4 hours. The NP framework captures expected biology: P D increases with TNF dose; wild-type cells outperform A20 -/- at matched conditions; and combining two time points (bivariate analysis) improves detection (e.g., for 0.0052 vs. 0.2 ng/mL, P D rises from 0.71 (30 minutes) and 0.42 (4 hours) to 0.80 at P FA = 0.1). The analysis recovers expected biology (higher TNF causes higher detectability; negative feedback lowers late responses) and flags cases where decision quality degrades (e.g., perturbations that blunt separation between conditions). The same recipe extends to multivariate readouts without changing the logic. Overall, the NP detection framework provides a compact, quantitative score of pathway performance and failure. It turns noisy single-cell readouts into actionable decision metrics that compare doses, time points, and perturbations, and ultimately, can help explain when and how cellular decisions drift toward pathology.

  PublisherOA PDFDOI

• Interplay between cytokine and FGF2 signaling in induction of entosis and vasculogenic mimicry response in glioblastoma

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-10

  preprintSenior authorCorresponding

  Summary Tumor vascularization is critical to survival of cancer cells, but is frequently perturbed leading to disorganized angiogenesis and emergence of alternative means of delivery of oxygen and nutrients, such as vasculogenic mimicry (VM). Understanding of VM and its relationship to endothelial vascularization has been hampered by the lack of comprehensive combination of in vivo clinical data and relevant in vitro models. We address this challenge by analyzing glioblastoma (GBM) tumors and clinically isolated cancer cells. This analysis strongly suggests a key role of macrophage-induced controlled cell death in emergence of VM. The results further point to entosis of cancer cells as a critical intermediate state in this process, enabled by mechano-chemical cell heterogeneity. We find evidence that macrophages can regulate endothelial angiogenesis and VM as two alternative vascularization mechanisms. These results reveal mechanistic underpinnings of VM and pave the way to predictive analysis of tumor progression.

  PublisherDOI

• Cas12a-knock-in mice for multiplexed genome editing, disease modelling and immune-cell engineering

  Nature Biomedical Engineering · 2025-03-20 · 22 citations

  articleOpen access

  The pleiotropic effects of human disease and the complex nature of gene-interaction networks require knock-in mice allowing for multiplexed gene perturbations. Here we describe a series of knock-in mice with a C57BL/6 background and with the conditional or constitutive expression of LbCas12a or of high-fidelity enhanced AsCas12a, which were inserted at the Rosa26 locus. The constitutive expression of Cas12a in the mice did not lead to discernible pathology and enabled efficient multiplexed genome engineering. We used the mice for the retrovirus-based immune-cell engineering of CD4+ and CD8+ T cells, B cells and bone-marrow-derived dendritic cells, for autochthonous cancer modelling through the delivery of multiple CRISPR RNAs as a single array using adeno-associated viruses, and for the targeted genome editing of liver tissue using lipid nanoparticles. We also describe a system for simultaneous dual-gene activation and knockout (DAKO). The Cas12a-knock-in mice and the viral and non-viral delivery vehicles provide a versatile toolkit for ex vivo and in vivo applications in genome editing, disease modelling and immune-cell engineering, and for the deconvolution of complex gene interactions. Knock-in mice conditionally or constitutively expressing Cas12 variants enable a wide range of ex vivo and in vivo applications requiring multiplexed genome engineering.

  PublisherOA PDFDOI

• YAP controls cell migration and invasion through a Rho GTPase switch.

  PubMed · 2025-05-27 · 6 citations

  articleOpen accessSenior author

  Delineating the mechanisms that control the movement of cells is central to understanding diverse physiological and pathophysiological processes. The transcriptional coactivator YAP is important during development and associated with cancer metastasis. Here, we found that YAP promoted cell migration by modulating a Rho family guanosine triphosphatase (GTPase) switch involving Rac1 and RhoA, which are key regulators of cytoskeletal dynamics. YAP transcriptionally transactivated the gene encoding the Rac1 guanine nucleotide exchange factor TRIO by directly binding to its intronic enhancer. This led to the activation of Rac1 and inhibition of RhoA, which increased cell migration and invasion in vitro and in vivo. This YAP-dependent program was observed across many cell types, including human breast epithelial cells and astrocytes, but it was particularly enhanced in a patient-specific manner in glioblastoma (GBM), the most common malignant brain tumor. Additionally, YAP-TRIO signaling activated STAT3, a transcription factor implicated in invasive growth in cancer, suggesting potential for cross-talk with this pathway to exacerbate invasive behavior. Clinically, hyperactivation of YAP, TRIO, and STAT3 gene signatures in GBM were associated with poor survival outcomes in patients. Our findings suggest that the YAP-TRIO-Rho-GTPase signaling network regulates invasive cell spread in both physiological and pathological contexts.

  PublisherOA PDFDOI

• Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines

  Cell stem cell · 2025-05-01 · 23 citations

  article
  PublisherDOI

• Oscillatory signal decoding within the ERK cascade

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-28

  preprintOpen access

  ABSTRACT Extracellular-signal-regulated kinase (ERK) integrates multiple growth factor and hormone stimuli to control essential cellular processes such as proliferation, survival, and migration. In electrically excitable cells, the ERK pathway also interfaces with intracellular Ca 2+ dynamics to achieve non-canonical, cell-type specific functions, having been implicated in neuronal synaptic plasticity, cardiac hypertrophy, and pancreatic insulin secretion. Yet how the classical Ras/MEK/ERK cascade responds to and decodes dynamic Ca 2+ signals at its multiple levels to regulate cellular function is poorly understood. Here, we investigated the dynamics of Ca 2+ -induced ERK pathway activation in a pancreatic β-cell line using genetically encoded fluorescent biosensors. By carefully manipulating Ca 2+ input signals and directly monitoring the activity dynamics of individual ERK pathway components, we reveal that β-cell Ca 2+ oscillations undergo sequential signal processing along the ERK cascade, mediated by the characteristic response kinetics at each pathway step. We further demonstrate that the ERK cascade and possibly other Ca 2+ -responsive pathways operate within a hybrid network architecture to achieve both hierarchical and parallel processing of β-cell Ca 2+ oscillations, providing important insights into dynamic signal decoding by this crucial signaling network.

  PublisherOA PDFDOI

Recent grants

• Collaborative Research: Multicellular Communication in Gradient Sensing

  NSF · $220k · 2015–2018

• NIH Grant U01CA155758

  NIH · $1.8M · 2017

• NIH Grant R01CA065145

  NIH · $8.3M · 2013

• NIH Grant R01GM084332

  NIH · $1.2M · 2014

• NIH Grant R21EB008562

  NIH · $178k · 2010

Frequent coauthors

• Alfredo Quiñones‐Hinojosa

  Jacksonville College

  120 shared

• Hugo Guerrero-Cázares

  Mayo Clinic in Florida

  108 shared

• Christopher L. Smith

  University of Pennsylvania

  95 shared

• Kshitiz Gupta

  University of Connecticut

  82 shared

• Kaisorn L. Chaichana

  WinnMed

  79 shared

• Olindi Wijesekera

  76 shared

• Mingxin Zhu

  Ocean University of China

  75 shared

• Qian Li

  71 shared

Labs

• Yale Biomedical EngineeringPI

Awards & honors

• Computational Molecular Biology Post-Doctoral Fellowship fro…
• Invited Participant in the National Academies Inaugural Keck…
• Inaugural Distinguished Guest lecturer, Molecular and Cellul…
• Featured as an Outstanding Young Scientist in a special issu…
• American Asthma Foundation Early Excellence Award (2010)