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Robert A Gatenby

Publications and source records attributed to Robert A Gatenby.

18 recordsLinked to original sources
PubMed2026

Integrated Genomic and Epigenomic Analysis Reveals Epigenetic Plasticity in Disease Progression and Multidrug Resistance in Multiple Myeloma.

UNLABELLED: Multiple myeloma is marked by recurrent cytogenetic abnormalities and mutations that accumulate as the disease progresses. In this study, we sought to elucidate the transitions driving tumorigenesis and therapy resistance in multiple myeloma using a unique cohort of nearly 900 patients spanning premalignant to late-stage refractory multiple myeloma, comprehensively characterized at molecular and clinical levels. Waves of epigenetic dysregulation drove these critical transitions. In this paradigm, genomic and cytogenetic events unlocked epigenetic plasticity, reshaping multiple myeloma cell biology to evade tumor microenvironment constraints and therapeutic pressures. Functional perturbation studies in an isogenic proteasome inhibitor-resistant cell line model demonstrated enhanced reliance on transcriptional cofactors, supporting a mechanistic link between chromatin plasticity and therapy adaptation. Collectively, these findings support a unifying framework in which genomic heterogeneity unlocks gene regulatory plasticity, enabling plasma cells (PC) to evade microenvironmental constraints and therapeutic pressure. These results provide a mechanistic explanation for sequential relapse without new genomic alterations and nominate epigenetic plasticity-mediated PC adaptation as a therapeutic vulnerability in the heterogeneous genetic background of multiple myeloma. SIGNIFICANCE: Assembly and analysis of a multiple myeloma cohort spanning the continuum from premalignant to late relapse that integrates bulk transcriptomics with single-cell multiomic data provides insights into disease progression and epigenetic plasticity.

Multiple Myeloma↗
PubMed2006

Information theory in living systems, methods, applications, and challenges.

Living systems are distinguished in nature by their ability to maintain stable, ordered states far from equilibrium. This is despite constant buffeting by thermodynamic forces that, if unopposed, will inevitably increase disorder. Cells maintain a steep transmembrane entropy gradient by continuous application of information that permits cellular components to carry out highly specific tasks that import energy and export entropy. Thus, the study of information storage, flow and utilization is critical for understanding first principles that govern the dynamics of life. Initial biological applications of information theory (IT) used Shannon's methods to measure the information content in strings of monomers such as genes, RNA, and proteins. Recent work has used bioinformatic and dynamical systems to provide remarkable insights into the topology and dynamics of intracellular information networks. Novel applications of Fisher-, Shannon-, and Kullback-Leibler informations are promoting increased understanding of the mechanisms by which genetic information is converted to work and order. Insights into evolution may be gained by analysis of the the fitness contributions from specific segments of genetic information as well as the optimization process in which the fitness are constrained by the substrate cost for its storage and utilization. Recent IT applications have recognized the possible role of nontraditional information storage structures including lipids and ion gradients as well as information transmission by molecular flux across cell membranes. Many fascinating challenges remain, including defining the intercellular information dynamics of multicellular organisms and the role of disordered information storage and flow in disease.

Computational Biology↗
PubMed2006

Metabolic changes during carcinogenesis: potential impact on invasiveness.

Successful adaptation to varying microenvironmental constraints plays a crucial role during carcinogenesis. We develop a hybrid cellular automation approach to investigate the cell-microenvironmental interactions that mediate somatic evolution of cancer cells. This allows investigation of the hypothesis that regions of premalignant lesions develop a substrate-limited environment as proliferation carries cells away from blood vessels which remain separated by the intact basement membrane. We find that selective forces in tumoural regions furthest from the blood supply act to favour cells whose metabolism is best suited to respond to local changes in oxygen, glucose and pH levels. The model predicts three phases of somatic evolution. Initially, cell survival and proliferation is limited due to diminished oxygen levels. This promotes adaptation to a second phase of growth dominated by cells with constitutively up-regulated glycolysis, less reliant on oxygen for ATP production. Increased glycolysis induces acidification of the local environment, limiting proliferation and inducing cell death through necrosis and apoptosis. This promotes a third phase of cellular evolution, with emergence of phenotypes resistant to acid-induced toxicity. This emergent cellular phenotype has a significant proliferative advantage because it will consistently acidify the local environment in a way that is toxic to its competitors but harmless to itself. The model's results suggest this sequence is essential in the transition from self-limited premalignant growth to invasive cancer, and, therefore, that this transition may be delayed or prevented through novel strategies directed towards interrupting the hypoxia-glycolysis-acidosis cycle.

Adenosine Triphosphate↗
PubMed2006

Acid-mediated tumor invasion: a multidisciplinary study.

The acid-mediated tumor invasion hypothesis proposes altered glucose metabolism and increased glucose uptake, observed in the vast majority of clinical cancers by fluorodeoxyglucose-positron emission tomography, are critical for development of the invasive phenotype. In this model, increased acid production due to altered glucose metabolism serves as a key intermediate by producing H(+) flow along concentration gradients into adjacent normal tissue. This chronic exposure of peritumoral normal tissue to an acidic microenvironment produces toxicity by: (a) normal cell death caused by the collapse of the transmembrane H(+) gradient inducing necrosis or apoptosis and (b) extracellular matrix degradation through the release of cathepsin B and other proteolytic enzymes. Tumor cells evolve resistance to acid-induced toxicity during carcinogenesis, allowing them to survive and proliferate in low pH microenvironments. This permits them to invade the damaged adjacent normal tissue despite the acid gradients. Here, we describe theoretical and empirical evidence for acid-mediated invasion. In silico simulations using mathematical models provide testable predictions concerning the morphology and cellular and extracellular dynamics at the tumor-host interface. In vivo experiments confirm the presence of peritumoral acid gradients as well as cellular toxicity and extracellular matrix degradation in the normal tissue exposed to the acidic microenvironment. The acid-mediated tumor invasion model provides a simple mechanism linking altered glucose metabolism with the ability of tumor cells to form invasive cancers.

Acidosis↗
PubMed2005

Power laws of complex systems from extreme physical information.

Many complex systems obey allometric, or power, laws y=Y x(a) . Here y > or = 0 is the measured value of some system attribute a , Y> or =0 is a constant, and x is a stochastic variable. Remarkably, for many living systems the exponent a is limited to values n/4 , n=0, +/-1, +/-2.... Here x is the mass of a randomly selected creature in the population. These quarter-power laws hold for many attributes, such as pulse rate (n=-1) . Allometry has, in the past, been theoretically justified on a case-by-case basis. An ultimate goal is to find a common cause for allometry of all types and for both living and nonliving systems. The principle I-J=extremum of extreme physical information is found to provide such a cause. It describes the flow of Fisher information J-->I from an attribute value a on the cell level to its exterior observation y . Data y are formed via a system channel function y identical to f (x,a) , with f (x,a) to be found. Extremizing the difference I-J through variation of f (x,a) results in a general allometric law f (x,a) identical to y=Y x(a) . Darwinian evolution is presumed to cause a second extremization of I-J , now with respect to the choice of a . The solution is a=n/4 , n=0,+/-1,+/-2..., defining the particular powers of biological allometry. Under special circumstances, the model predicts that such biological systems are controlled by only two distinct intracellular information sources. These sources are conjectured to be cellular DNA and cellular transmembrane ion gradients.

Algorithms↗
PubMed2005

The role of acidity in solid tumour growth and invasion.

Acidic pH is a common characteristic of human tumours. It has a significant impact on tumour progression and response to therapies. In this paper, we develop a simple model of three-dimensional tumour growth to examine the role of acidosis in the interaction between normal and tumour cell populations. Both vascular and avascular tumour dynamics are investigated, and a number of different behaviours are observed. Whilst an avascular tumour always proceeds to a benign steady state, a vascular tumour may display either benign or invasive dynamics, depending on the value of a critical parameter. Analysis of the model allows us to assess novel therapies directed towards changing the level of acidity within the tumour.

Cell Proliferation↗
PubMed2004

Information dynamics in carcinogenesis and tumor growth.

The storage and transmission of information is vital to the function of normal and transformed cells. We use methods from information theory and Monte Carlo theory to analyze the role of information in carcinogenesis. Our analysis demonstrates that, during somatic evolution of the malignant phenotype, the accumulation of genomic mutations degrades intracellular information. However, the degradation is constrained by the Darwinian somatic ecology in which mutant clones proliferate only when the mutation confers a selective growth advantage. In that environment, genes that normally decrease cellular proliferation, such as tumor suppressor or differentiation genes, suffer maximum information degradation. Conversely, those that increase proliferation, such as oncogenes, are conserved or exhibit only gain of function mutations. These constraints shield most cellular populations from catastrophic mutator-induced loss of the transmembrane entropy gradient and, therefore, cell death. The dynamics of constrained information degradation during carcinogenesis cause the tumor genome to asymptotically approach a minimum information state that is manifested clinically as dedifferentiation and unconstrained proliferation. Extreme physical information (EPI) theory demonstrates that altered information flow from cancer cells to their environment will manifest in-vivo as power law tumor growth with an exponent of size 1.62. This prediction is based only on the assumption that tumor cells are at an absolute information minimum and are capable of "free field" growth that is, they are unconstrained by external biological parameters. The prediction agrees remarkably well with several studies demonstrating power law growth in small human breast cancers with an exponent of 1.72+/-0.24. This successful derivation of an analytic expression for cancer growth from EPI alone supports the conceptual model that carcinogenesis is a process of constrained information degradation and that malignant cells are minimum information systems. EPI theory also predicts that the estimated age of a clinically observed tumor is subject to a root-mean square error of about 30%. This is due to information loss and tissue disorganization and probably manifests as a randomly variable lag phase in the growth pattern that has been observed experimentally. This difference between tumor size and age may impose a fundamental limit on the efficacy of screening based on early detection of small tumors. Independent of the EPI analysis, Monte Carlo methods are applied to predict statistical tumor growth due to perturbed information flow from the environment into transformed cells. A "simplest" Monte Carlo model is suggested by the findings in the EPI approach that tumor growth arises out of a minimally complex mechanism. The outputs of large numbers of simulations show that (a) about 40% of the populations do not survive the first two-generations due to mutations in critical gene segments; but (b) those that do survive will experience power law growth identical to the predicted rate obtained from the independent EPI approach. The agreement between these two very different approaches to the problem strongly supports the idea that tumor cells regress to a state of minimum information during carcinogenesis, and that information dynamics are integrally related to tumor development and growth.

Information Theory↗
PubMed2004

Why do cancers have high aerobic glycolysis?

If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.

Acidosis↗
PubMed2003

An evolutionary model of carcinogenesis.

A quantitative model of carcinogenesis based on methods from population biology and game theory demonstrates normal cells in vivo occupy a ridge-shaped maximum in a well-defined tissue fitness landscape, a novel configuration that allows cooperative coexistence of multiple cellular populations. This state, although necessary for development of functioning multicellular organisms, is subject to invasion by fitter, mutant phenotypes permitting somatic evolution of cancer. The model demonstrates carcinogenesis is an emergent phenomenon requiring a sequence of evolutionary steps as cellular proliferation follows successful adaptation to varying environmental constraints. In the initial development of preneoplastic lesions, cellular proliferation is controlled exclusively by interactions with other cells, the extracellular matrix, and soluble or insoluble growth factors so that gain of function mutations in oncogenes, loss of function mutations in tumor suppressor genes, and disruption of normal senescence pathways will permit clonal expansion. This provides explicit selection mechanisms for the mutations depicted in the classical Fearon-Vogelstein model of colorectal carcinogenesis. The model demonstrates neoplastic cellular proliferation can also be promoted by alterations in the somatic landscape that reduce inhibitory signals produced by the normal cells and extracellular matrix. This is consistent with experimental evidence for a strong microenvironmental influence in tumorigenesis independent of genomic changes in the neoplastic populations. However, we find that these changes alone produce only self-limited neoplastic growth because cellular crowding alters system dynamics so that proliferation is dependent on substrate availability. Consequent cellular competition for critical nutrients results in Darwinian selection pressures favoring phenotypes that increase substrate delivery (e.g., angiogenesis) or uptake (e.g., amplify membrane transporters). These previously unknown substrate dynamics in the later stages of carcinogenesis provide a mechanism for evolution of cellular properties typically found in invasive cancers including the angiogenic and glycolytic phenotypes.

Animals↗
PubMed2003

The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models.

Malignant cells characteristically exhibit altered metabolic patterns when compared with normal mammalian cells with increased reliance on anaerobic metabolism of glucose to lactic acid even in the presence of abundant oxygen. The inefficiency of the anaerobic pathway is compensated by increased glucose flux, a phenomenon first noted by Otto Warburg approximately 80 years ago and currently exploited for 2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging in clinical radiology. The latter has demonstrated the glycolytic phenotype is a near-universal phenomenon in human cancers. The potential role of the glycolytic phenotype in facilitating tumor invasion has been investigated through mathematical models of the tumor-host interface. Modified cellular automaton and diffusion reaction models demonstrate protons will diffuse from the tumor into peritumoral normal tissue subjecting nontransformed cells adjacent to the tumor edge to an extracellular pH significantly lower than normal. This leads to normal cell death via p53-dependent apoptosis pathways, as well as degradation of the interstitial matrix, loss of intercellular gap junctions, enhanced angiogenesis, and inhibition of the host immune response to tumor antigens. Transformed cells maintain their proliferative capacity in acidic extracellular pH because of mutations in p53 or some other component in the apoptosis pathways. This allows tumor cells to remain proliferative and migrate into the peritumoral normal tissue producing the invasive phenotype. Mathematical models of invasive cancer based on tumor-induced acidification are consistent with extant data on tumor microenvironment and results from clinical positron emission tomography imaging, including the observed correlation between tumor invasiveness and glucose utilization. Novel treatment approaches focused on perturbation of the tumor microenvironment are predicted from the mathematical models and are supported by recent clinical data demonstrating the benefits of azotemia and metabolic acidosis in survival of patients with metastatic renal cancer. The evolutionary basis for adoption of the glycolytic phenotype during carcinogenesis remains unclear because it appears to confer significant competitive disadvantages on the tumor cells due to of inefficient energy production and expenditure of resources to remove the acid byproducts. We propose that the glycolytic phenotype represents a successful adaptation to environmental selection parameters because it confers the ability to invade. That is, the glycolytic phenotype allows the cell to move from the microenvironment of a premalignant lesion to adjacent normal tissue. There it competes with normal cells that are less fit than the populations within the tumor in a microenvironment of relative substrate abundance. The consequent unrestrained proliferation allows the glycolytic phenotype to emerge simultaneous with the transition from a premalignant lesion to an invasive cancer.

Animals↗
PubMed2003

Application of quantitative models from population biology and evolutionary game theory to tumor therapeutic strategies.

Quantitative models from population biology and evolutionary game theory frame the tumor-host interface as a dynamical microenvironment of competing tumor and normal populations. Through this approach, critical parameters that control the outcome of this competition are identified and the conditions necessary for formation of an invasive cancer are defined. Perturbations in these key parameters that destabilize the cancer solution of the state equations and produce tumor regression can be predicted. The mathematical models demonstrate significant theoretical limitations in therapies based solely on cytotoxic drugs. Because these approaches do not alter critical parameters controlling system dynamics, the tumor population growth term will remain positive as long as any individual cells are present so that the tumor will invariably recur unless all proliferative cells are killed. The models demonstrate that such total effectiveness is rendered unlikely by the genotypic heterogeneity of tumor populations (and, therefore, the variability of their response to such drugs) and the ability of tumor cells to adapt to these proliferation constraints by evolving resistant phenotypes. The mathematical models support therapeutic strategies that simultaneously alter several of the key parameters in the state equations. Furthermore, the models demonstrate that administration of cytotoxic therapies will, by reducing the tumor population density, create system dynamics more conducive to perturbations by biological modifiers.

Biological Evolution↗
PubMed2002

The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy.

Cytoreductive nephrectomy prior to systemic therapy significantly increases survival in patients with metastatic renal cancer. This result is generally ascribed to the benefits of resection of the primary tumor including reduction of tumor burden, removal of a source for growth factors and metastases, and enhanced immune response. On the basis of mathematical models of tumor invasion, we propose that the observed effects of cytoreductive nephrectomy may be caused by resection of the kidney rather than the cancer. The models predict that the graded metabolic acidosis associated with mild renal failure after unilateral nephrectomy may alter the dynamics of the tumor-host interface sufficiently to reduce and even reverse the rate of invasion. A review of patient data from the surgical arm of the Southwest Oncology Group (SWOG) 8949(2) trial demonstrates significantly improved survival in patients who experienced postoperative increase in blood urea nitrogen (BUN) and creatinine compared with those who did not (17-month survival versus 4-month survival; P = 0.0007). This is generally consistent with the predictions of the mathematical models. If confirmed, these results suggest novel and broadly applicable tumor therapies.

Acidosis↗
PubMed2002

Application of information theory and extreme physical information to carcinogenesis.

Cellular information dynamics during somatic evolution of the malignant phenotypes are complex and poorly understood. Accumulating, random genetic mutations and, therefore, loss of genomic information appears necessary for carcinogenesis. However, additional control parameters can be inferred because unconstrained mutagenesis would ultimately produce cellular information degradation incompatible with life. Similarly, the stability of some genomic segments, such as those controlling proliferation and metabolism, indicates the presence of selective mutational constraints. By applying Information Theory and Extreme Physical Information (EPI) analysis, we demonstrate that the phenotypic characteristics and growth pattern of cancer populations are emergent properties resulting from the nonlinear dynamics of accumulating, random genetic mutations and tissue selection factors. Maximum quantitative loss of transgenerational information is demonstrated in genomic segments encoding negative or neutral evolutionary properties. This is most evident in the progressive dedifferentiation observed during carcinogenesis and may terminate in a differentiation "information catastrophe" producing decoherent cellular morphology and function. In contrast, microenvironmental selection pressures preserve genomic information controlling properties that confer selective growth advantages even in the presence of a high background mutation rate. Thus, phenotypic traits characteristically retained by tumor populations can be identified as critical selection parameters favoring clonal proliferation. The information model of carcinogenesis is tested by applying EPI analysis to predict tumor growth dynamics. We found that cellular proliferation attributable to information degradation will produce power law tumor growth with an exponent of 1.62. Data from six published studies that use sequential mammograms to measure the volume of small, untreated human breast cancers demonstrate power law tumor growth with a mean exponent value of 1.73 +/- 0.23. Other predictions including exponential growth of tumor cells in vitro are also supported by experimental observations. The nonlinear dynamics of stochastic information loss constrained by somatic evolution indicate that carcinogenesis will not be associated with any predictable, fixed sequence of genomic alterations. Rather, sporadic clinical cancers are emergent structures produced by multiple, fundamentally nondeterministic genetic pathways.

Animals↗
PubMed1996

Fibroblast Enhancement of Tumor Invasion in a Tumor-Host Interface Recapitulated in-vitro.

Tumor cells and fibroblasts were isolated from the tumor-host interface of a colon 4047 tumor growing subcutaneously in a Fischer 344 rat. The populations were co-cultured to recapitulate the tumor-host interface in vitro. The co-cultured populations grew in a predictable pattern with tumor cells forming nodules surrounded by fibroblasts. Population dynamic experiments demonstrated the fibroblasts enhanced the growth of the tumor cells but tumor inhibited and ultimately destroyed the fibroblasts. Video microscopic examination of the fibroblasts demonstrated intense membrane ruffling adjacent to the tumor nodules followed by membrane fragmentation and detachment. Immunohistochemical staining for gelatinase A was markedly positive within the fibroblasts surrounding the tumor nodules; but negative within the tumor and in fibroblasts when tumor was absent. This technique recapitulates many aspects of the tumor-host interface in vitro and may be a useful model for evaluating several aspects of tumor-host interaction.

Journal Article↗
PubMedDate not supplied

pH imaging. A review of pH measurement methods and applications in cancers.

Acid-base balance is altered in a variety of common pathologies, including COPD, ischemia, renal failure, and cancer. Because of robust cellular pH homeostatic mechanisms, most of the pathological alterations in pH are expressed as changes in the extracellular, systemic pH. There are data to indicate that altered pH is not simply an epiphenomenon of metabolic or physiologic imbalance but that chronic pH alterations can have important sequelae. MRSI and MRI measurements indicate that pH gradients of up to 1.0 pH unit can exit within 1-cm distance. Although measurement of blood pH can indicate systemic problems, it cannot pinpoint the lesion or quantitatively assess the magnitude of excursion from normal pHe. Hence, there is a need to develop pHe measurement methods with high spatiotemporal resolution. The two major approaches being investigated include magnetization transfer methods and relaxation methods. pH-dependent MT effects can observed with endogenous signals or exogenously applied CEST agents. While endogenous signals have the advantage of being fully noninvasive and relatively straightforward to apply, they lack a full biophysical characterization and dynamic range that might be afforded by future CEST agents. pH-dependent relaxivity also requires the injection or infusion of exogenous contrast reagents. In both MT and relaxographic approaches, the magnitude of the effect, and, thus, the ability to quantify pHe, depends on a spatially and temporally varying concentration of the CR. A number of approaches have been proposed to solve this problem and, once it is solved, pH imaging methods will be applicable to human clinical pathologies.

Acid-Base Equilibrium↗