Surface remodeling and inversion of cell-matrix interactions underlie community recognition and dispersal in Vibrio cholerae biofilms.

Biofilms are ubiquitous surface-associated bacterial communities embedded in an extracellular matrix. It is commonly assumed that biofilm cells are glued together by the matrix; however, how the specific biochemistry of matrix components affects the cell-matrix interactions and how these interactions vary during biofilm growth remain unclear. Here, we investigate cell-matrix interactions in Vibrio cholerae, the causative agent of cholera.

Beyond the pair approximation: Modeling colonization population dynamics.

The process of range expansion (colonization) is one of the basic types of biological dynamics, whereby a species grows and spreads outwards, occupying new territories. Spatial modeling of this process is naturally implemented as a stochastic cellular automaton, with individuals occupying nodes on a rectangular grid, births and deaths occurring probabilistically, and individuals only reproducing onto unoccupied neighboring spots. In this paper we derive several approximations that allow prediction of the expected range expansion dynamics, based on the reproduction and death rates.

The role of telomere shortening in carcinogenesis: A hybrid stochastic-deterministic approach.

Genome instability is a characteristic of most cancers, contributing to the acquisition of genetic alterations that drive tumor progression. One important source of genome instability is linked to telomere dysfunction in cells with critically short telomeres that lack p53-mediated surveillance of genomic integrity. Here we research the probability that cancer emerges through an evolutionary pathway that includes a telomere-induced phase of genome instability.

Cellular Hierarchy as a Determinant of Tumor Sensitivity to Chemotherapy.

Chemotherapy has been shown to enrich cancer stem cells in tumors. Recently, we demonstrated that administration of chemotherapy to human bladder cancer xenografts could trigger a wound-healing response that mobilizes quiescent tumor stem cells into active proliferation. This phenomenon leads to a loss of sensitivity to chemotherapy partly due to an increase in the number of tumor stem cells, which typically respond to chemotherapy-induced cell death less than more differentiated cells.

Complex Dynamics of Virus Spread from Low Infection Multiplicities: Implications for the Spread of Oncolytic Viruses.

While virus growth dynamics have been well-characterized in several infections, data are typically collected once the virus population becomes easily detectable. Earlier dynamics, however, remain less understood. We recently reported unusual early dynamics in an experimental system using adenovirus infection of human embryonic kidney (293) cells.

Telomeres open a window on stem cell division.

Measuring the length distribution of telomeres can reveal information about biological processes that are otherwise difficult to analyze experimentally.

Quantifying replicative senescence as a tumor suppressor pathway and a target for cancer therapy.

To study quantitatively replicative senescence as a tumor suppressor mechanism, we investigate the distribution of a growing clonal cell population restricted by Hayflick's limit. We find that in the biologically relevant range of parameters, if the imbalance between cell division and death is moderate or low (high death-to-birth ratio), senescence offers significant protection against cancer by halting abnormal cell proliferation at early pre-diagnostic stages of tumor development. We also find that by the time tumors are typically detected, there is a high probability that telomerase is activated, even if the cell of origin was telomerase negative.

Characterizing inhibited tumor growth in stem-cell-driven non-spatial cancers.

Healthy human tissue is highly regulated to maintain homeostasis. Secreted negative feedback factors that inhibit stem cell division and stem cell self-renewal play a fundamental role in establishing this control. The appearance of abnormal cancerous growth requires an escape from these regulatory mechanisms.

Preventing clonal evolutionary processes in cancer: Insights from mathematical models.

Clonal evolutionary processes can drive pathogenesis in human diseases, with cancer being a prominent example. To prevent or treat cancer, mechanisms that can potentially interfere with clonal evolutionary processes need to be understood better. Mathematical modeling is an important research tool that plays an ever-increasing role in cancer research.

Cancer-associated mutations in healthy individuals: assessing the risk of carcinogenesis.

Mutations associated with hematopoietic malignancies have been repeatedly identified in healthy individuals. For certain cases, such as the t(14;18) translocation and monoclonal B-cell lymphocytosis, no clear link between the presence of aberrant cells and the later development of cancer has been established. Intriguingly, longitudinal studies suggest that these abnormalities persist for long periods of time in some individuals, but in others are transient in which they disappear completely.

Minimizing the risk of cancer: tissue architecture and cellular replication limits.

Normal somatic cells are capable of only a limited number of divisions, which prevents unlimited cell proliferation and the onset of tumours. Cancer cells find ways to circumvent this obstacle, typically by expressing the enzyme telomerase and less often by alternative recombination strategies. Given this fundamental link between cellular replication limits and cancer, it is important to understand how a tissue's architecture affects the replicative capacity of a cell population.

Tumor growth dynamics: insights into evolutionary processes.

Identifying the types of event that drive tumor evolution and progression is crucial for understanding cancer. We suggest that the analysis of tumor growth dynamics can provide a window into tumor biology and evolution by connecting them with the types of genetic change that have occurred. Although fundamentally important, the documentation of tumor growth kinetics is more sparse in the literature than is the molecular analysis of cells.

Stem cell control, oscillations, and tissue regeneration in spatial and non-spatial models.

Normal human tissue is organized into cell lineages, in which the highly differentiated mature cells that perform tissue functions are the end product of an orderly tissue-specific sequence of divisions that start with stem cells or progenitor cells. Tissue homeostasis and effective regeneration after injuries requires tight regulation of these cell lineages and feedback loops play a fundamental role in this regard. In particular, signals secreted from differentiated cells that inhibit stem cell division and stem cell self-renewal are important in establishing control.

Evolutionary dynamics of feedback escape and the development of stem-cell-driven cancers.

Cancers are thought to arise in tissue stem cells, and similar to healthy tissue, are thought to be maintained by a small population of tumor stem or initiating cells, whereas the majority of tumor cells are more differentiated with limited replicative potential. Healthy tissue homeostasis is achieved by feedback loops, and particular importance has been attached to signals secreted from differentiated cells that inhibit stem-cell division and stem-cell self-renewal, as documented in the olfactory epithelium and other tissues. Therefore, a key event in carcinogenesis must be escape from these feedback loops, which is studied here using evolutionary computational models.

Quantitative theory of telomere length regulation and cellular senescence.

In normal somatic cells, telomere length shortens with each cell replication. This progressive shortening is associated with cellular senescence and apoptosis. Germ cells, stem cells, and the majority of cancer cells express telomerase, an enzyme that extends telomere length and, when expressed at sufficient levels, can immortalize or extend the life span of a cell line.