Stochastic Models of Tumor Progression
Tibor Antal
Stochasticity is essential when modeling initiation of tumors, progression of tumors from benign to malignant states, or metastasis formation. Many aspects of these phenomena can be modeled by simple multi-type branching processes, and the results compare fairly well with experimental and clinical data. Other aspects of tumor development needs more refined approaches. Models of developing resistance to chemotherapy, and modeling challenges related to spatial structure and sizes of tumors will also be discussed.
Experimental Studies of Fundamental Cancer Dynamics
Robert Austin
In cancer, there is much more happening than simply uncontrolled growth of cells. If a cancer solid tumor was confined to that single phenotype, simple surgical removal of the tumor, where it is possible, would remove the tumor and the patient would be cured. In fact, when caught early enough this still is the most effective way of curing a patient of cancer. Unfortunately, usually by the time a tumor has become big enough to cause symptoms or become visible, it has turned into something far more deadly. With such a big, sprawling condition no one talk can encompass the totality of the cancer condition, so in this talk we will try to examine some of the population dynamics of cancer as a multi-cellular community under intense stress and selection pressure, and we will try to bring a physicist’s perspective to this talk.
Emergence of microstructural patterns and morphological changes in skin cancers.
Martine Ben Amar
Abstract: Current diagnostic methods for skin cancers are based on some morphological characteristics of the pigmented skin lesions, including the geometry of their contour. We develop a model for the early growth of melanoma accounting for the biomechanical characteristics of the tumour micro-environment, and evaluating their influence on the tumour morphology and its evolution. The spatial distribution of tumour cells and diffusing molecules are explicitly described in a three-dimensional multiphase model, which incorporates general cell-to-cell mechanical interactions, a dependence of cell proliferation on contact inhibition, as well as a local diffusion of nutrients and inhibiting molecules. We derive a 2D model in a lubrication limit accounting for the thin geometry of the
epidermis. We were able to quantify the contour undulations obtained in our simulations occurring in melanoma growth in term of biomechanical factors with analytical techniques (WKB developed for partial differential equations). Finally, comparing the theoretical results with a large amount of clinical data we show that our predictions describe accurately both the morphology of melanoma observed in vivo and its variations with the tumour growth rate. Another aspects useful for the clinical diagnosis of skin cancers is based on the presence of microstructures (e.g. dots, nests) sparsely distributed within the tumour lesion. I will show that these patterns might be originated by a phase separation process. In absence of cellular proliferation, our binary mixture model contains a cell-cell adhesion that leads to a governing equation of the Cahn-Hilliard type. Taking into account a reaction diffusion coupling between nutrient consumption and cellular proliferation, we show, both with analytical and numerical investigations, that two-phase models may undergo a spinodal decomposition even when considering mass exchanges between the phases. The cell-nutrient interaction defines a typical diffusive length in the problem, which is found to control the saturation of a growing separated domain, thus stabilizing the micro-structural pattern. The distribution and the evolution of such emerging cluster morphologies, as predicted by our model, are successfully compared to the clinical observation of micro-structural patterns in tumour lesions.Joint work with Thibaut Balois, Clement Chatelain and Pasquale Ciarletta
Tumor angiogenesis and antiangiogenic cancer therapy
Yihai Cao
Tumor growth and metastasis is dependent on angiogenesis, the process of vascular sprouting from the existing blood vessels. Starvation of tumor cells by inhibition of blood vessel growth in the tumor tissue has been approved as a valid approach for cancer therapy. Despite the clinical success of antiangiogenic cancer therapy, the general beneficial effect of antiangiogenic drugs remain very modest. Many key issues regarding the fundamental mechanisms that underlie antiangiogenic therapy remain unresolved. These include: Why are clinical benefits in most cancer types only seen in combination with chemotherapeutics? Why are a majority of cancer patients intrinsically resistant to antiangiogenic therapy? What are alternative mechanisms underlying clinical benefits? Are there any predictive markers for guiding current clinical practice of antiangiogenic therapy? Along these lines, this lecture will summarize preclinical findings from our work to translate into clinical relevance, with emphasis of fundamental mechanisms of antiangiogenic cancer therapy. Based on preclinical and clinical findings, we propose that off-tumor targets of antiangiogenic drugs would offer a potentially alternative mechanism of survival improvement. Additionally, reduction of chemotoxicity by antiangiogenic agents might also potentially explain why combination with chemotherapy is more effective. We are actively studying the mechanisms underlying tumor angiogenesis, which may provide crucial information for defining new therapeutic targets and for improvement of antiangiogenic cancer therapy.
Complex dynamics of cellular transcriptional response: how do cells get on the fast lane?
Eytan Domany
In response to external stimuli, cells adjust their behavior to a changing environment – for example, they start to divide or migrate. In order to perform these actions, the protein content of the cell must change. To accomplish this, a cell must modify the levels at which the genes that code for these proteins are transcribed. These transcriptional responses to extracellular stimuli are regulated by tuning the rates of transcript production and degradation. I present here the results of a study aimed at deducing the dynamics of these two processes from measurements of the transcriptome, and to elucidate the operational strategy behind this dynamics. By combining a simple theoretical model of transcription with simultaneous measurements of time-dependent precursor mRNA and mature mRNA abundances, we were able to infer unexpected complex stimulation-induced time-dependent transcript production and degradation. In particular, we found that production of many transcripts was characterized by a large dynamic range, which allowed these genes to exhibit an unexpectedly strong and brief pulse of production, thereby accelerating their induction. Surprisingly, we found that the widely used assumption of close correspondence between mRNA abundance and production profiles is incorrect: timing of mRNA maxima does not allow inference of the production pulse. Finally, we discovered that mRNA degradation is regulated in a precisely timed and transcript specific manner. By analyzing data from several kinds of human tumors, we were able to show that the shift of the transcriptome that accompanies the malignant transformation cannot be explained, for many genes, by changing the transcript production rate: the mRNA degradation rate is also modified.
Single-Molecule Denaturation-Mapping of DNA on a nanofluidic chip
Henrik Flyvbjerg
Abstract: This recent physical technique for coarse-grained mapping of long DNA molecules is presented. It is sensitive to sequence variation without enzymatic labeling or a restriction step. It might be the basis for a new mapping technology ideally suited for investigating the long-range structure of entire genomes extracted from single cells.
Growth and instabilities of epithelial tissues
Jean- François Joanny.
Abstract: In this talk, we present some recent results on the growth and mechanical properties of healthy and cancerous tissues. We first show that because of the coupling between cell division and the local stress, a tissue can be considered as a visco-elastic liquid with a relaxation time smaller than the cell division time. We also discuss the role of the insterstitial liquid between the cells. We give examples of the liquid behavior related to the competition for space between two tissues and discuss the stability of the interface between two tissues. In a second part, we discuss the steady state structure of villis which are the protrusions of the surface of the intestine or the colon. We describe the formation of villis as a buckling instability of a polar cell monolayer. The polarity of the layer does not seem to play a role in the intestine where the villis are arranged in a square array but it is important in the colon where they are organized in a hexagonal array. Finally, we discuss other instabilities of tissues for multicellular epithelia and for tube-like cellular structures.
Are biomechanical changes necessary for tumor progression?
Josef Käs
Abstract: With an increasing knowledge in tumor biology an overwhelming complexity becomes obvious which roots in the diversity of tumors and their heterogeneous molecular composition. Nevertheless in all solid tumors malignant neoplasia, i.e. uncontrolled growth, invasion of adjacent tissues, and metastasis, occurs. Physics sheds some new light on cancer by approaching this problem from a functional, materials perspective. Recent results indicate that all three pathomechanisms require changes in the active and passive cellular biomechanics. Malignant transformation causes cell softening for small deformations which correlates with an increased rate of proliferation and faster cell migration. The tumor cell’s ability to strain harden permits tumor growth against a rigid tissue environment. A highly mechanosensitive, enhanced cell contractility is a prerequisite that tumor cells can cross its tumor boundaries and that this cells can migrate through the extracellular matrix. Insights into the biomechanical changes during tumor progression may lead to selective treatments by altering cell mechanics. Such drugs would not cure by killing cancer cells, but slow down tumor progression with only mild side effects and thus may be an option for older and frail patients.
Senescent cells in growing tumors: population dynamics and cancer stem cells
Caterina La Porta & Stefano Zapperi
Tumors are defined by their intense proliferation, but sometimes cancer cells turn senescent and stop replicating. In the stochastic cancer model in which all cells are tumorigenic, senescence is seen as the result of random mutations, suggesting that it could represent a barrier to tumor growth. In the hierarchical cancer model a subset of the cells, the cancer stem cells, divide indefinitely while other cells eventually turn senescent. Here we formulate cancer growth in mathematical terms and obtain predictions for the evolution of senescence. We perform experiments in human melanoma cells which are compatible with the hierarchical model and show that senescence is a reversible process controlled by survivin. We conclude that enhancing senescence is unlikely to provide a useful therapeutic strategy to fight cancer, unless the cancer stem cells are specifically targeted.
Cancer and aging: dangerous ties and overlapping mechanisms
Joao Pedro Magalhaes
Abstract:Cancer is intrinsically linked to aging. The incidence of most (but not all) types of cancer increases dramatically with age. Moreover, genetic and environmental interventions that delay aging in rodents also frequently decreases cancer rates. This suggests some degree of interplay at the mechanistic level either via common processes or because aging influences cancer susceptibility in fundamental ways. Although the underlying molecular mechanisms of aging remain a subject of debate, some evidence points towards a role of DNA damage which is also a major player in cancer. This relationship between the biology of aging and cancer may be particularly relevant at the cellular level. Cell senescence appears to be primarily an antitumor process yet it may also contribute to aging due to the accumulation of senescent cells that disrupts tissue homeostasis. In this context, the roles of telomeres and telomerase in cancer and aging will also be discussed. Lastly, I will discuss species differences in aging and cancer as is an untapped paradigm to study these processes.
Mechanism of mitotic spindle multipolarity independent of centrosome amplification – the role of chromosomal forces
Helder Maiato
Abstract: Loss of spindle pole integrity during mitosis leads to multipolarity independent of centrosome amplification. Multipolar spindle conformation favors incorrect kinetochore-microtubule attachments, compromising faithful chromosome segregation and daughter cell viability. Spindle pole organization influences and is influenced by kinetochore activity, but the molecular nature behind this critical force balance is unknown. CLASPs are microtubule, kinetochore and centrosome-associated proteins whose functional perturbation leads to three main spindle abnormalities: monopolarity, short spindles and multipolarity. The first two reflect a role at the kinetochore-microtubule interface through interaction with specific kinetochore partners, but how CLASPs prevent spindle multipolarity remains unclear. Here we found that human CLASPs ensure spindle pole integrity after bipolarization in response to CENP-E- and Chromokinesin/Kid-mediated forces from misaligned chromosomes. This function is independent of end-on kinetochore-microtubule attachments and involves the recruitment of Ninein to residual pericentriolar satellites. Distinctively, multipolarity arising through this mechanism often persists through anaphase. We propose that CLASPs and Ninein confer spindle pole resistance to traction forces exerted during chromosome congression, thereby preventing irreversible spindle multipolarity and aneuploidy.
Modeling the mechanical response of synthetic and bio-inspired structures
M. Carmen Miguel
The microscopic processes governing the mechanical response of several synthetic and bio-inspired structures of current interest in materials science, such as in colloidal composites or in fiber networks, have much to do with their underlying topology. Here we would like to illustrate several models and simulation techniques that can be used to find the correlations between mechanical behavior and topological properties. Colloidal particles absorbed onto liquid interfaces have been reported as efficient stabilizers of emulsions and foams in fields as diverse as optics and the food industry. They also offer new opportunities of drug encapsulation and drug delivery in biomedical applications. Particles shells produced with current experimental methods vary widely in size, shape, and stability. Several mechanical regimes and particle arrangements are thus expected for different geometries, some of which have already been identified in experiments and in simulations. On the other hand, filamentous proteins in the cytoskeleton are crucial to many cellular functions and dysfunctions. These fibers together with various cross-linking proteins may form an intricate three-dimensional network that, as such, can be characterized by its topological structure. Through the statistical analysis of the adjacency and laplacian matrices of cross-linked bundles of filamentous proteins, we unveil their spectrum, connectivity properties, and response functions.
The role of p53 in the life of stem cells
Varda Rotter
Abstract: p53 deficiency enhances the efficiency of somatic cell reprogramming to a pluripotent state. As p53 is usually mutated in human tumors and many mutated forms of p53 gain novel activities, here we studied the influence of mutant p53 on somatic cell reprogramming. Our data indicate a novel gain-of-function property for mutant-p53, which markedly enhanced the efficiency of the reprogramming process compared to p53 deficiency. Importantly, this novel activity of mutant p53 induced alterations in the characteristics of the reprogrammed cells; while p53-knockout cells reprogrammed with only Oct4 and Sox2 maintained their pluripotent capacity in vivo, reprogrammed cells expressing mutant p53 lost this capability, and gave rise to malignant tumors. This novel gain-of-function of mutant p53 is not attributed to its effect on proliferation, as both p53-knockout and mutant p53 cells displayed similar proliferation rates. In addition, we demonstrate an oncogenic activity of Klf4, as its overexpression in either p53-knockout or mutant p53 cells induced aggressive tumors. Overall, our data show that reprogrammed cells with the capacity to differentiate into the three germ layers in vitro can form malignant tumors, suggesting that in genetically unstable cells such as those in which p53 is mutated, reprogramming may result in the generation of cells with malignant tumor-forming potential.
MONALISA: Molecular Nanotechnology for life science applications
Giacinto Scoles
I will review briefly three activities in progress in the laboratories connected within the Monalisa network. These laboratories are: MONALISA@uniud,MONALISA@cro MONALISA@sissa, MONALISA@elettra and MONALISA@iom-cnr. The glue that keeps these labs collaborating is a ERC senior grant of which the PI and co-PI are Profs. G. Scoles (uniud) and G. Toffoli (cro)The other three PIs are respectively A. Laio (sissa) L.Casalis (elettra) and M. Lazzarino (iom-cnr). The first project that I will discuss concerns the high speed detection of biomolecules using mechanical oscillators called pillars that are vertical cuntilivers that oscillate at about 5 to 10 Mhz of resonant frequency, Acting as microbalances they change the oscillating frequency when a layer of biomelecules is adsorbed on their top surface. The common difficulty connected with the broadening of the resonance of the oscillators when the latter operate in water has been solved by fabricating many pillars next to each other, coating their side surfaces with hydrophobic mo;ecules and using the resulting super hydrophobic effect to let the water wet the upper surface without penetrating in between pillars resulting in a almost negligible broadening of the resonant oscillation peak. Typical sensitivity of this kind of device is at present about 1.000 protein which correspond to about 100 ettograms. The second device I will discuss is a device which is based on nanografting techniques and studies the reaction of restriction enzymes, on double stranded DNA nanostructures nanografted into a monolayer of PEG molecules. If time will permit the third device which I will discuss is a device for the low-cost and high throughput measurement of circulating tumor cells in the peripheral blood of cancer patients.
Modeling interactions of membranes: The nucleation and growth of adhesion domains of ligand-receptor bonds
Ana Suncana Smith
Initially, physical consequences of a formation of a single ligand-receptor bond will be discussed and, renormalized binding affinity of a binding pair of molecules determined. The consequence of forming a bond within an adhesion domain will be calculated and membrane transmitted cooperative effects analyzed. The conditions for the stability of domains will be determined. Furthermore, a theoretical framework to model the dynamical aspects of adhesion will be introduced and the problem of nucleation and growth of the adhesion domains addressed. The results of theoretical modeling will be compared to extensive Langevin simulations. A coarse grained Monte Carlo scheme will be introduced within which the formation of domains can be studied on time and length scales typical for the experiments.