7,198 research outputs found
Emergence of Anti-Cancer Drug Resistance: Exploring the Importance of the Microenvironmental Niche via a Spatial Model
Practically, all chemotherapeutic agents lead to drug resistance. Clinically,
it is a challenge to determine whether resistance arises prior to, or as a
result of, cancer therapy. Further, a number of different intracellular and
microenvironmental factors have been correlated with the emergence of drug
resistance. With the goal of better understanding drug resistance and its
connection with the tumor microenvironment, we have developed a hybrid
discrete-continuous mathematical model. In this model, cancer cells described
through a particle-spring approach respond to dynamically changing oxygen and
DNA damaging drug concentrations described through partial differential
equations. We thoroughly explored the behavior of our self-calibrated model
under the following common conditions: a fixed layout of the vasculature, an
identical initial configuration of cancer cells, the same mechanism of drug
action, and one mechanism of cellular response to the drug. We considered one
set of simulations in which drug resistance existed prior to the start of
treatment, and another set in which drug resistance is acquired in response to
treatment. This allows us to compare how both kinds of resistance influence the
spatial and temporal dynamics of the developing tumor, and its clonal
diversity. We show that both pre-existing and acquired resistance can give rise
to three biologically distinct parameter regimes: successful tumor eradication,
reduced effectiveness of drug during the course of treatment (resistance), and
complete treatment failure
Modeling Three-dimensional Invasive Solid Tumor Growth in Heterogeneous Microenvironment under Chemotherapy
A systematic understanding of the evolution and growth dynamics of invasive
solid tumors in response to different chemotherapy strategies is crucial for
the development of individually optimized oncotherapy. Here, we develop a
hybrid three-dimensional (3D) computational model that integrates
pharmacokinetic model, continuum diffusion-reaction model and discrete cell
automaton model to investigate 3D invasive solid tumor growth in heterogeneous
microenvironment under chemotherapy. Specifically, we consider the effects of
heterogeneous environment on drug diffusion, tumor growth, invasion and the
drug-tumor interaction on individual cell level. We employ the hybrid model to
investigate the evolution and growth dynamics of avascular invasive solid
tumors under different chemotherapy strategies. Our simulations reproduce the
well-established observation that constant dosing is generally more effective
in suppressing primary tumor growth than periodic dosing, due to the resulting
continuous high drug concentration. In highly heterogeneous microenvironment,
the malignancy of the tumor is significantly enhanced, leading to inefficiency
of chemotherapies. The effects of geometrically-confined microenvironment and
non-uniform drug dosing are also investigated. Our computational model, when
supplemented with sufficient clinical data, could eventually lead to the
development of efficient in silico tools for prognosis and treatment strategy
optimization.Comment: 41 pages, 8 figure
The role of spatial variations of abiotic factors in mediating intratumour phenotypic heterogeneity
We present here a space- and phenotype-structured model of selection dynamics between cancer cells within a solid tumour. In the framework of this model, we combine formal analyses with numerical simulations to investigate in silico the role played by the spatial distribution of abiotic components of the tumour microenvironment in mediating phenotypic selection of cancer cells. Numerical simulations are performed both on the 3D geometry of an in silico multicellular tumour spheroid and on the 3D geometry of an in vivo human hepatic tumour, which was imaged using computerised tomography. The results obtained show that inhomogeneities in the spatial distribution of oxygen, currently observed in solid tumours, can promote the creation of distinct local niches and lead to the selection of different phenotypic variants within the same tumour. This process fosters the emergence of stable phenotypic heterogeneity and supports the presence of hypoxic cells resistant to cytotoxic therapy prior to treatment. Our theoretical results demonstrate the importance of integrating spatial data with ecological principles when evaluating the therapeutic response of solid tumours to cytotoxic therapy
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The role of spatial variations of abiotic factors in mediating intratumour phenotypic heterogeneity
We present here a space- and phenotype-structured model of selection dynamics between cancer cells within a solid tumour. In the framework of this model, we combine formal analyses with numerical simulations to investigate in silico the role played by the spatial distribution of abiotic components of the tumour microenvironment in mediating phenotypic selection of cancer cells. Numerical simulations are performed both on the 3D geometry of an in silico multicellular tumour spheroid and on the 3D geometry of an in vivo human hepatic tumour, which was imaged using computerised tomography. The results obtained show that inhomogeneities in the spatial distribution of oxygen, currently observed in solid tumours, can promote the creation of distinct local niches and lead to the selection of different phenotypic variants within the same tumour. This process fosters the emergence of stable phenotypic heterogeneity and supports the presence of hypoxic cells resistant to cytotoxic therapy prior to treatment. Our theoretical results demonstrate the importance of integrating spatial data with ecological principles when evaluating the therapeutic response of solid tumours to cytotoxic therapy
Blood Vessel Tortuosity Selects against Evolution of Agressive Tumor Cells in Confined Tissue Environments: a Modeling Approach
Cancer is a disease of cellular regulation, often initiated by genetic
mutation within cells, and leading to a heterogeneous cell population within
tissues. In the competition for nutrients and growth space within the tumors
the phenotype of each cell determines its success. Selection in this process is
imposed by both the microenvironment (neighboring cells, extracellular matrix,
and diffusing substances), and the whole of the organism through for example
the blood supply. In this view, the development of tumor cells is in close
interaction with their increasingly changing environment: the more cells can
change, the more their environment will change. Furthermore, instabilities are
also introduced on the organism level: blood supply can be blocked by increased
tissue pressure or the tortuosity of the tumor-neovascular vessels. This
coupling between cell, microenvironment, and organism results in behavior that
is hard to predict. Here we introduce a cell-based computational model to study
the effect of blood flow obstruction on the micro-evolution of cells within a
cancerous tissue. We demonstrate that stages of tumor development emerge
naturally, without the need for sequential mutation of specific genes.
Secondly, we show that instabilities in blood supply can impact the overall
development of tumors and lead to the extinction of the dominant aggressive
phenotype, showing a clear distinction between the fitness at the cell level
and survival of the population. This provides new insights into potential side
effects of recent tumor vasculature renormalization approaches
Bridging scales in cancer progression: Mapping genotype to phenotype using neural networks
In this review we summarize our recent efforts in trying to understand the
role of heterogeneity in cancer progression by using neural networks to
characterise different aspects of the mapping from a cancer cells genotype and
environment to its phenotype. Our central premise is that cancer is an evolving
system subject to mutation and selection, and the primary conduit for these
processes to occur is the cancer cell whose behaviour is regulated on multiple
biological scales. The selection pressure is mainly driven by the
microenvironment that the tumour is growing in and this acts directly upon the
cell phenotype. In turn, the phenotype is driven by the intracellular pathways
that are regulated by the genotype. Integrating all of these processes is a
massive undertaking and requires bridging many biological scales (i.e.
genotype, pathway, phenotype and environment) that we will only scratch the
surface of in this review. We will focus on models that use neural networks as
a means of connecting these different biological scales, since they allow us to
easily create heterogeneity for selection to act upon and importantly this
heterogeneity can be implemented at different biological scales. More
specifically, we consider three different neural networks that bridge different
aspects of these scales and the dialogue with the micro-environment, (i) the
impact of the micro-environment on evolutionary dynamics, (ii) the mapping from
genotype to phenotype under drug-induced perturbations and (iii) pathway
activity in both normal and cancer cells under different micro-environmental
conditions
Dynamic changes during the treatment of pancreatic cancer
This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient\u27s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment
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