Integrating Models to Quantify Environment-Mediated Drug Resistance

Picco, Noemi; Maini, Philip K.; Anderson, Alexander R.A.

doi:10.1158/0008-5472.can-17-0835

Cited by 31 publications

(29 citation statements)

References 48 publications

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“…Given

we intend to use our neurogenesis model to estimate a key quantity of interest that lacks experimental quantification: the founder population,

. For each species of interest, we use Approximate Bayesian Computation (ABC, see Supplemental Information and Picco et al 2017 ) to obtain an estimate of

This method gives the best fit to match the neurogenic output

given the model of choice (constant, or age-dependent, cell cycle length), and the corresponding strategy. Figure 5 B shows the estimates of

for the 3 species and 2 models.…”

Section: Resultsmentioning

confidence: 99%

Mathematical Modeling of Cortical Neurogenesis Reveals that the Founder Population does not Necessarily Scale with Neurogenic Output

et al. 2018

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The mammalian cerebral neocortex has a unique structure, composed of layers of different neuron types, interconnected in a stereotyped fashion. While the overall developmental program seems to be conserved, there are divergent developmental factors generating cortical diversity amongst species. In terms of cortical neuronal numbers, some of the determining factors are the size of the founder population, the duration of cortical neurogenesis, the proportion of different progenitor types, and the fine-tuned balance between self-renewing and differentiative divisions. We develop a mathematical model of neurogenesis that, accounting for these factors, aims at explaining the high diversity in neuronal numbers found across species. By framing our hypotheses in rigorous mathematical terms, we are able to identify paths of neurogenesis that match experimentally observed patterns in mouse, macaque and human. Additionally, we use our model to identify key parameters that would particularly benefit from accurate experimental investigation. We find that the timing of a switch in favor of symmetric neurogenic divisions produces the highest variation in cortical neuronal numbers. Surprisingly, assuming similar cell cycle lengths in primate progenitors, the increase in cortical neuronal numbers does not reflect a larger size of founder population, a prediction that has identified a specific need for experimental quantifications.

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“…Given

we intend to use our neurogenesis model to estimate a key quantity of interest that lacks experimental quantification: the founder population,

. For each species of interest, we use Approximate Bayesian Computation (ABC, see Supplemental Information and Picco et al 2017 ) to obtain an estimate of

This method gives the best fit to match the neurogenic output

given the model of choice (constant, or age-dependent, cell cycle length), and the corresponding strategy. Figure 5 B shows the estimates of

for the 3 species and 2 models.…”

Section: Resultsmentioning

confidence: 99%

Mathematical Modeling of Cortical Neurogenesis Reveals that the Founder Population does not Necessarily Scale with Neurogenic Output

et al. 2018

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“…This includes the modeling of bone as a reservoir of latent TGF-β that is released and activated during tumor-induced osteolysis, which in turn impacts the osteoblast:osteoclast balance in the remodeling unit. (56) In addition, the role of cancer-associated fibroblasts (57) and immune cells (58) in tumor cell metastasis has been modeled, which is of particular interest given the diverse cellular environment of the bone metastatic niche.…”

Section: Ex Vivo Bone Modelsmentioning

confidence: 99%

Modeling the Human Bone–Tumor Niche: Reducing and Replacing the Need for Animal Data

Rao

Edwards

2020

JBMR Plus

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Bone is the most common site for cancer metastasis. Understanding the interactions within the complex, heterogeneous bone–tumor microenvironment is essential for the development of new therapeutics. Various animal models of tumor‐induced bone disease are routinely used to provide valuable information on the relationship between cancer cells and the skeleton. However, new model systems exist that offer an alternative approach to the use of animals and might more accurately reveal the cellular interactions occurring within the human bone–tumor niche. This review highlights replacement models that mimic the bone microenvironment and where cancer metastases and tumor growth might be assessed alongside bone turnover. Such culture models include the use of calcified regions of animal tissue and scaffolds made from bone mineral hydroxyapatite, synthetic polymers that can be manipulated during manufacture to create structures resembling trabecular bone surfaces, gel composites that can be modified for stiffness and porosity to resemble conditions in the tumor–bone microenvironment. Possibly the most accurate model system involves the use of fresh human bone samples, which can be cultured ex vivo in the presence of human tumor cells and demonstrate similar cancer cell–bone cell interactions as described in vivo. In addition, the use of mathematical modeling and computational biology approaches provide an alternative to preliminary animal testing. The use of such models offers the capacity to mimic significant elements of the human bone–tumor environment, and complement, refine, or replace the use of preclinical models. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…Previous mathematical models designed to study cooperative or competitive interactions between tumor and immune cells have quantified the proliferation response of the immune system to changing tumor burden [30][31][32] and response to therapy 33 . Others have used agent-based models 34 or hematoxylin and eosin-stained images 35 to show the importance of spatial organization of heterogeneous immune-evasive "hotspots" within a tumor, especially in the context of competition for shared resources (e.g.…”

Section: Ductal Carcinomas As a Case Of Changing Contextmentioning

confidence: 99%

Macrophage-mediated immunoediting drives ductal carcinoma evolution: Space is the game changer

Gatenbee

West

Baker

et al. 2019

Preprint

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Under normal conditions, the immune system is capable of rapidly detecting and eliminating potentially dangerous entities, including tumor cells. Due to intense selection pressure imposed by the immune response, tumor cells often evolve strategies to avoid elimination in a process known as immunoediting. It is less known how the evolutionary response to immune predation is altered by context. We explore the evolution of immune escape strategies in ductal cancers, a natural case in which to study evolution in different contexts: inside and outside of ducts. We highlight the role of macrophages as a source of "public goods," releasing diffusible factors (reactive oxygen species and growth factors). Immunohistochemistry reveals differences between macrophage densities of invasive ductal carcinomas and non-invasive ductal carcinomas in situ. For the first time, immunohistochemistry (IHC) imaging data comparing DCIS to IDC were used to initialize mechanistic agent-based models of evolutionary dynamics. By using IHC to map the initial conditions of a growing tumor, we show that spatial competition and structure influence transient dynamics during invasion. These dynamics are context-dependent, a conclusion that may be missed from interpreting imaging or non-spatial modeling alone. Before invasion, the presence of macrophages correlate with shorter ductal breach times. After invasion, tumors may employ a "pioneer-engineer" strategy where pioneering immunoresistant cells on the tumor's edge stimulate the release of M1-macrophage-derived reactive oxygen species, degrading surrounding stroma. Behind the invasive edge, the engineering immunosuppressive cells promote the release of M2-macrophage-derived growth factors, providing a long-term immune escape strategy. Together, mathematical modeling and image analysis highlight the crucial role tumor-associated macrophages play in immune escape and invasion, both inside and outside of ducts. 2/1513/15 14/15

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Integrating Models to Quantify Environment-Mediated Drug Resistance

Cited by 31 publications

References 48 publications

Mathematical Modeling of Cortical Neurogenesis Reveals that the Founder Population does not Necessarily Scale with Neurogenic Output

Mathematical Modeling of Cortical Neurogenesis Reveals that the Founder Population does not Necessarily Scale with Neurogenic Output

Modeling the Human Bone–Tumor Niche: Reducing and Replacing the Need for Animal Data

Macrophage-mediated immunoediting drives ductal carcinoma evolution: Space is the game changer

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