Herbert Levine

Rice University · Department of Bioengineering

Epithelial-mesenchymal plasticity (EMP) is a cell-fate switching program that enables cells to adopt a spectrum of phenotypes ranging from epithelial (E) to mesenchymal (M) and hybrid E/M states. Hybrid E/M phenotypes are considered optimal for cancer metastasis due to their association with metastatic initiation and traits such as stemness, drug r...

Abnormal metabolism is a hallmark of cancer. Initially recognized through the observation of aerobic glycolysis in cancer nearly a century ago. Also, we now know that mitochondrial respiration is also used by cancer for progression and metastasis. However, it remains largely unclear the mechanisms by which cancer cells mix and match different metab...

Exploring the complexity of the epithelial-to-mesenchymal transition (EMT) unveils a diversity of potential cell fates; however, the exact timing and mechanisms by which early cell states diverge into distinct EMT trajectories remain unclear. Studying these EMT trajectories through single-cell RNA sequencing is challenging due to the necessity of s...

Transcription has a mechanical component, as the translocation of the transcription machinery or RNA polymerase (RNAP) on DNA or chromatin is dynamically coupled to the chromatin torsion. This posits chromatin mechanics as a possible regulator of eukaryotic transcription, however, the modes and mechanisms of this regulation are elusive. Here, we fi...

Reliable prediction of T cell specificity against antigenic signatures is a formidable task, complicated by the immense diversity of T cell receptor and antigen sequence space and the resulting limited availability of training sets for inferential models. Recent modeling efforts have demonstrated the advantage of incorporating structural informatio...

Understanding cancer metabolism is crucial for deciphering various cancer hallmarks, including metastasis and immunosuppression. This study investigated the intricate interplay of catabolic processes involving glucose, fatty acids, and glutamine in cancer cells. Recent evidence highlights the dual reliance of cancer cells on glycolysis and oxidativ...

Background Epithelial-to-mesenchymal transition (EMT) is a developmental program that consists of the loss of epithelial features concomitant with the acquisition of mesenchymal features. Activation of EMT in cancer facilitates the acquisition of aggressive traits and cancer invasion. EMT plasticity (EMP), the dynamic transition between multiple hy...

Transcription has a mechanical component, as the translocation of the transcription machinery or RNA polymerase (RNAP) on DNA or chromatin is dynamically coupled to the chromatin torsion. This posits chromatin mechanics as a possible regulator of eukaryotic transcription, however, the modes and mechanisms of this regulation are elusive. Here, we fi...

Exploring the complexity of the epithelial-to-mesenchymal transition (EMT) unveils a diversity of potential cell fates; however, the exact timing and intricate mechanisms by which early cell states diverge into distinct EMT trajectories remain unclear. Studying these EMT trajectories through single cell RNA sequencing is challenging due to the nece...

Tumors develop in a complex physical, biochemical, and cellular milieu, referred to as the tumor microenvironment. Of special interest is the set of immune cells that reciprocally interact with the tumor, the tumor-immune microenvironment (TIME). The diversity of cell types and cell–cell interactions in the TIME has led researchers to apply concept...

Reliable prediction of T cell specificity against antigenic signatures is a formidable task, complicated primarily by the immense diversity of T cell receptor and antigen sequence space and the resulting limited availability of training sets for inferential models. Recent modeling efforts have demonstrated the advantage of incorporating structural...

Recent years have seen a tremendous growth of interest in understanding the role that the adaptive immune system could play in interdicting tumor progression. In this context, it has been shown that the density of adaptive immune cells inside a solid tumor serves as a favorable prognostic marker across different types of cancer. The exact mechanism...

The Notch pathway, an example of juxtacrine signaling, is an evolutionary conserved cell-cell communication mechanism. It governs emergent spatiotemporal patterning in tissues during development, wound healing and tumorigenesis. Communication occurs when Notch receptors of one cell bind to either of its ligands, Delta/Jagged of the neighboring cell...

We offer our opinion on the benefits of integration of insights from active matter physics with principles of regulatory interactions and control to develop a field we term "smart active matter". This field can provide insight into important principles in living systems as well as aid engineering of responsive, robust and functional collectives.

The failure of cancer treatments, including immunotherapy, continues to be a major obstacle in preventing durable remission. This failure often results from tumor evolution, both genotypic and phenotypic, away from sensitive cell states. Here, we propose a mathematical framework for studying the dynamics of adaptive immune evasion that tracks the n...

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, dr...

Tumors develop in a complex physical, biochemical, and cellular milieu, referred to as the tumor microenvironment. Of special interest is the set of immune cells that reciprocally interact with the tumor, the tumor-immune microenvironment (TIME). The diversity of cell types and cell-cell interactions in the TIME has led researchers to apply concept...

We introduce an active version of the recently proposed finite Voronoi model of epithelial tissue. The resultant Active Finite Voronoi (AFV) model enables the study of both confluent and non-confluent geometries and transitions between them, in the presence of active cells. Our results indicate a rich phase diagram which unifies the study of the ro...

Metastasis consists of sequential steps initiated by cancer cells invading from the primary tumor site into neighboring tissues, followed by entry into the circulatory system and completed by extravasation and growth in distal organs where secondary tumors are formed. Circulating tumor cells, thus, encounter and adapt to multiple environmental chan...

A phase field approach is proposed to model the chemotaxis of Dictyostelium discoideum. In this framework, motion is controlled by active forces as determined by the Meinhardt model of chemical dynamics which is used to simulate directional sensing during chemotaxis. Then, the movement of the cell is achieved by the phase field dynamics, while the...

Cell-fate decisions are driven by complex regulatory networks. Despite their complexity, these networks often exhibit low-dimensional dynamics and allow only a limited number of phenotypes. What design principles in network topology allows for these salient features remains unclear. Previously, we demonstrated that networks driving epithelial-mesen...

We offer our opinion on the benefits of integration of insights from active matter physics with principles of regulatory interactions and control to develop a field we term ``smart matter". This field can provide insight into important principles in living systems as well as aid engineering of responsive, robust and functional collectives.

The dogma that cancer is a genetic disease is being questioned. Recent findings suggest that genetic/nongenetic duality is necessary for cancer progression. A think tank organized by the Shraman Foundation's Institute for Theoretical Biology compiled key challenges and opportunities that theoreticians, experimentalists, and clinicians can explore f...

Epithelial-mesenchymal transition (EMT) and its reverse mesenchymal-epithelial transition (MET) are critical during embryonic development, wound healing and cancer metastasis. While phenotypic changes during short-term EMT induction are reversible, long-term EMT induction has been often associated with irreversibility. Here, we show that phenotypic...

We introduce an active version of the recently proposed finite Voronoi model of epithelial tissue. The resultant Active Finite Voronoi (AFV) model enables the study of both confluent and non-confluent...

Regulatory networks as large and complex as those implicated in cell-fate choice are expected to exhibit intricate, very high-dimensional dynamics. Cell-fate choice, however, is a macroscopically simple process. Additionally, regulatory network models are almost always incomplete and/or inexact, and do not incorporate all the regulators and interac...

Epithelial-mesenchymal plasticity (EMP) underlies embryonic development, wound healing, and cancer metastasis and fibrosis. Cancer cells exhibiting EMP often have more aggressive behavior, characterized by drug resistance, and tumor-initiating and immuno-evasive traits. Thus, the EMP status of cancer cells can be a critical indicator of patient pro...

The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as Gene Regulatory Netw...

Cancer metastasis relies on an orchestration of traits driven by different interacting functional modules, including metabolism and epithelial-mesenchymal transition (EMT). During metastasis, cancer cells can acquire a hybrid metabolic phenotype (W/O) by increasing oxidative phosphorylation without compromising glycolysis and they can acquire a hyb...

The Notch pathway, an example of juxtacrine signaling, is an evolutionary conserved cell-cell communication mechanism. It governs emergent spatiotemporal patterning in tissues during development, wound healing and tumorigenesis. Communication occurs when Notch receptors of one cell bind to either of its ligands, Delta/Jagged of neighboring cell. In...

The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene-regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as gene-regulatory netw...

The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as Gene Regulatory Netw...

Biological cells are quintessentially active objects, using their stored energy to power motion. The field of cell motility is quite broad, ranging from bacteria to mammalian cells, from swimming to crawling to more exotic self-propulsion methods, to moving on surfaces or through liquid or via traversing fibrous gels, and to moving individually ver...

The theory of Darwinian evolution can be treated using the formalism of chemical systems where the reactions consist of birth, death and genomic changes. In this chapter we introduce this approach and focus on three important problems that yield insight into evolutionary dynamics. First, we focus on the fixation of single mutations in a population...

Drug persistence is a phenomenon by which a small percentage of cancer cells survive the presentation of targeted therapy by transitioning to a quiescent state. Eventually some of these persister cells can transition back to an active growing state and give rise to resistant tumors. Here we introduce a quantitative genetics approach to drug-exposed...

Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) are critical during embryonic development, wound healing and cancer metastasis. While phenotypic changes during short-term EMT induction are reversible, long-term EMT induction has been often associated with irreversibility. Here, we show that phenotypic...

The failure of cancer treatments, including immunotherapy, continues to be a major obstacle in preventing durable remission. This failure often results from tumor evolution, both genotypic and phenotypic, away from sensitive cell states. Here, we propose a mathematical framework for studying the dynamics of adaptive immune evasion that tracks the n...

Cancer metastasis relies on an orchestration of multiple traits driven by different functional interacting modules including metabolism and epithelial-mesenchymal transition (EMT). Cancer cells can adjust their metabolism during metastasis by increasing oxidative phosphorylation without compromising glycolysis, acquiring a hybrid metabolic phenotyp...

The in vitro reconstructions of human salivary glands in service of their eventual medical use represent a challenge for tissue engineering. Here, we present a theoretical approach to the dynamical formation of acinar structures from human salivary cells, focusing on observed stick-slip radial expansion as well as possible growth instabilities. Our...

The T-cell arm of the adaptive immune system provides the host protection against unknown pathogens by discriminating between host and foreign material. This discriminatory capability is achieved by the creation of a repertoire of cells each carrying a T-cell receptor (TCR) specific to non-self-antigens displayed as peptides bound to the major hist...

Biological cells can exist in a variety of distinct phenotypes, determined by the steady-state solutions of genetic networks governing their cell fate. A popular way of representing these states relies on the creation of landscape related to the relative occupation of these states. It is often assumed that this landscape offers direct information r...

Recent years have seen a tremendous growth of interest in understanding the role that the adaptive immune system could play in interdicting tumor progression. In this context, it has been shown that the density of adaptive immune cells inside a solid tumor serves as a favorable prognostic marker across different types of cancer. The exact mechanism...

Regulatory networks as large and complex as those implicated in cell-fate choice are expected to exhibit intricate, very high-dimensional dynamics. Cell-fate choice, however, is a macroscopically simple process. Additionally, regulatory network models are almost always incomplete and / or inexact, and do not incorporate all the regulators and inter...

Directed cell migration guided by external cues plays a central role in many physiological and pathophysiological processes. The microenvironment of cells often simultaneously contains various cues and the motility response of cells to multiplexed guidance is poorly understood. Here we combine experiments and mathematical models to study the three-...

Hybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and r...

PURPOSE Lehmann et al have identified four molecular subtypes of triple-negative breast cancer (TNBC)—basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor—and an immunomodulatory (IM) gene expression signature modifier. Our group previously showed that the response of TNBC to neoadjuvant systemic chemotherapy (NST) differs by mole...

Multiple RNA polymerases (RNAPs) transcribing a gene have been known to exhibit collective group behavior, causing the transcription elongation rate to increase with the rate of transcription initiation. Such behavior has long been believed to be driven by a physical interaction or 'push' between closely spaced RNAPs. However, recent studies have p...

Cancer metastasis is the leading cause of cancer-related mortality and the process of the epithelial-to-mesenchymal transition (EMT) is crucial for cancer metastasis. Both partial and complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among the oxidative phosphorylation, fatty acid oxidation...

While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the nutrients and the metabolic pathways they are depen...

The epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous w...

The T cell arm of the adaptive immune system provides the host protection against unknown pathogens by discriminating between host and foreign material. This discriminatory capability is achieved by the creation of a repertoire of cells each carrying a T cell receptor (TCR) specific to non-self antigens displayed as peptides bound to the major hist...

Cancer metastasis is the leading cause of cancer-related mortality and the process of Epithelial to Mesenchymal Transition (EMT) is crucial for cancer metastasis. Either a partial or complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among oxidative phosphorylation, fatty acid oxidation and g...

Drug resistance, a major challenge in cancer therapy, is typically attributed to mutations and genetic heterogeneity. Emerging evidence suggests that dynamic cellular interactions and group behavior also contribute to drug resistance. However, the underlying mechanisms remain poorly understood. Here, we present a new mathematical approach with game...

Recent preclinical and clinical data suggests enhanced metastatic fitness of hybrid epithelial/mesenchymal (E/M) phenotypes, but mechanistic details regarding their survival strategies during metastasis remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states. We construct and simulate the dynamics of a minimalistic regul...

The epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesenchymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous w...

Breast cancer is the most commonly diagnosed cancer in the USA. Although advances in treatment over the past several decades have significantly improved the outlook for this disease, most women who are diagnosed with estrogen receptor positive disease remain at risk of metastatic relapse for the remainder of their life. The cellular source of late...

Hypoxia, through hypoxia inducible factor (HIF), drives cancer cell invasion and metastatic progression in various cancer types. In epithelial cancer, hypoxia induces the transition to amoeboid cancer cell dissemination, yet the molecular mechanisms, relevance for metastasis, and effective intervention to combat hypoxia-induced amoeboid reprogrammi...

Directed cell migration guided by external cues plays a central role in many physiological and pathophysiological processes. The microenvironment of cells often simultaneously contains various cues and the motility response of cells to multiplexed guidance is poorly understood. Here we combine experiments and mathematical models to study the three-...

The first stage of the metastatic cascade often involves motile cells emerging from a primary tumor either as single cells or as clusters. These cells enter the circulation, transit to other parts of the body and finally are responsible for growth of secondary tumors in distant organs. The mode of dissemination is believed to depend on the EMT natu...

Epithelial cell clusters often move collectively on a substrate. Mechanical signals play a major role in organizing this behavior. There are a number of experimental observations in these systems which await a comprehensive explanation. These include: the internal strains are tensile even for clusters that expand by proliferation; the tractions on...

Significance The cytoskeleton plays a central role in mechanobiology, serving both as a scaffold to support the cell’s shape and as an engine that allows the cell to exert large-scale mechanical forces. A key feature of the cytoskeleton is that it is dynamic, continually remodeling itself to respond to changing cellular needs. We use computer simul...

Many developmental processes in biology utilize Notch-Delta signaling to construct an ordered pattern of cellular differentiation. This signaling modality is based on nearest-neighbor contact, as opposed to the more familiar mechanism driven by the release of diffusible ligands. Here, exploiting this ``juxtacrine" property, we present an exact trea...

Epithelial-mesenchymal plasticity (EMP) underlies embryonic development, wound healing, and cancer metastasis and fibrosis. Cancer cells exhibiting EMP often have more aggressive behavior, characterized by drug resistance, and tumor-initiating and immuno-evasive traits. Thus, the EMP status of cancer cells can be a critical indicator of patient pro...

Hybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and r...

While tumor infiltration by CD8+ T cells is now widely accepted to predict outcomes, the clinical significance of intratumoral B cells is less clear. We hypothesized that spatial distribution rather than density of B cells within tumors may provide prognostic significance. We developed statistical techniques (fractal dimension differences and a box...

Collective cancer invasion with leader–follower organization is increasingly recognized as a predominant mechanism in the metastatic cascade. Leader cells support cancer invasion by creating invasion tracks, sensing environmental cues and coordinating with follower cells biochemically and biomechanically. With the latest developments in experimenta...

Cancer metastasis remains a primary cause of cancer related mortality. Recent in vitro and in vivo data has indicated the high metastatic fitness of hybrid epithelial/mesenchymal (E/M) states, i.e. their enhanced abilities to initiate tumours at secondary tumour site. Mechanistic details about how such hybrid E/M cells survive the metastatic cascad...

Accurate assessment of T-cell-receptor (TCR)–antigen specificity across the whole immune repertoire lies at the heart of improved cancer immunotherapy, but predictive models capable of high-throughput assessment of TCR–peptide pairs are lacking. Recent advances in deep sequencing and crystallography have enriched the data available for studying TCR...

Significance The epithelial-to-mesenchymal transition (EMT) is a critical cell biological process that occurs during normal embryonic development and cancer progression. Our study combines single-cell RNA-sequencing analysis and mathematical modeling to identify critical regulators of EMT. Detailed analyses of TGF-β1–induced EMT by single-cell RNA-...