http://CompModelMatch.org

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Web page: http://CompModelMatch.org

Project Status: Not specified

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Finding Your Inner Modeler IV

An online collaborative project incubator for quantitative cell biologists and computational modelers

MEETING OVERVIEW

• Keynotes by Angela DePace, Wallace Marshall, and Rob Phillips
• Project pesentations* by selected cell biologist/modeler pairs
• Feedback and advice from a panel of computational experts
• Meet-a-Modeler opportunities to consult with experts one-on-one
• Poster session, lightning talks, and Pecha Kucha
• Virtual speed networking, inter- and intradisciplinary group chats
• NSF
...

Project: http://CompModelMatch.org

Public web page: https://go.hub.ki/innermodeler

Start date: 2nd Aug 2021

End date: 6th Aug 2021

CompModelMatch

Country:  United States

City: Not specified

Web page: http://CompModelMatch.org

Spontaneous cell fusions as a mechanism of parasexual recombination in tumour cell populations.
Finding Your Inner Modeler IV

Abstract (Expand)

The initiation and progression of cancers reflect the underlying process of somatic evolution, in which the diversification of heritable phenotypes provides a substrate for natural selection, resulting … in the outgrowth of the most fit subpopulations. Although somatic evolution can tap into multiple sources of diversification, it is assumed to lack access to (para)sexual recombination-a key diversification mechanism throughout all strata of life. On the basis of observations of spontaneous fusions involving cancer cells, the reported genetic instability of polypoid cells and the precedence of fusion-mediated parasexual recombination in fungi, we asked whether cell fusions between genetically distinct cancer cells could produce parasexual recombination. Using differentially labelled tumour cells, we found evidence of low-frequency, spontaneous cell fusions between carcinoma cells in multiple cell line models of breast cancer both in vitro and in vivo. While some hybrids remained polyploid, many displayed partial ploidy reduction, generating diverse progeny with heterogeneous inheritance of parental alleles, indicative of partial recombination. Hybrid cells also displayed elevated levels of phenotypic plasticity, which may further amplify the impact of cell fusions on the diversification of phenotypic traits. Using mathematical modelling, we demonstrated that the observed rates of spontaneous somatic cell fusions may enable populations of tumour cells to amplify clonal heterogeneity, thus facilitating the exploration of larger areas of the adaptive landscape (relative to strictly asexual populations), which may substantially accelerate a tumour's ability to adapt to new selective pressures.

Authors: D. Miroshnychenko, E. Baratchart, M. C. Ferrall-Fairbanks, R. V. Velde, M. A. Laurie, M. M. Bui, A. C. Tan, P. M. Altrock, D. Basanta, A. Marusyk

Date Published: 20th Jan 2021

Publication Type: Journal

The harsh microenvironment in early breast cancer selects for a Warburg phenotype.
Finding Your Inner Modeler IV

Abstract (Expand)

The harsh microenvironment of ductal carcinoma in situ (DCIS) exerts strong evolutionary selection pressures on cancer cells. We hypothesize that the poor metabolic conditions near the ductal center … foment the emergence of a Warburg Effect (WE) phenotype, wherein cells rapidly ferment glucose to lactic acid, even in normoxia. To test this hypothesis, we subjected low-glycolytic breast cancer cells to different microenvironmental selection pressures using combinations of hypoxia, acidosis, low glucose, and starvation for many months and isolated single clones for metabolic and transcriptomic profiling. The two harshest conditions selected for constitutively expressed WE phenotypes. RNA sequencing analysis of WE clones identified the transcription factor KLF4 as potential inducer of the WE phenotype. In stained DCIS samples, KLF4 expression was enriched in the area with the harshest microenvironmental conditions. We simulated in vivo DCIS phenotypic evolution using a mathematical model calibrated from the in vitro results. The WE phenotype emerged in the poor metabolic conditions near the necrotic core. We propose that harsh microenvironments within DCIS select for a WE phenotype through constitutive transcriptional reprogramming, thus conferring a survival advantage and facilitating further growth and invasion.

Authors: M. Damaghi, J. West, M. Robertson-Tessi, L. Xu, M. C. Ferrall-Fairbanks, P. A. Stewart, E. Persi, B. L. Fridley, P. M. Altrock, R. A. Gatenby, P. A. Sims, A. R. A. Anderson, R. J. Gillies

Date Published: 19th Jan 2021

Publication Type: Journal

Investigating Inter- and Intrasample Diversity of Single-Cell RNA Sequencing Datasets.
Finding Your Inner Modeler IV

Abstract (Expand)

Tumor heterogeneity can arise from a variety of extrinsic and intrinsic sources and drives unfavorable outcomes. With recent technological advances, single-cell RNA sequencing has become a way for … researchers to easily assay tumor heterogeneity at the transcriptomic level with high resolution. However, ongoing research focuses on different ways to analyze this big data and how to compare across multiple different samples. In this chapter, we provide a practical guide to calculate inter- and intrasample diversity metrics from single-cell RNA sequencing datasets. These measures of diversity are adapted from commonly used metrics in statistics and ecology to quantify and compare sample heterogeneity at single-cell resolution.

Authors: M. C. Ferrall-Fairbanks, P. M. Altrock

Date Published: 14th Sep 2020

Publication Type: InBook

Reassessing enzyme kinetics: Considering protease-as-substrate interactions in proteolytic networks.
Finding Your Inner Modeler IV

Abstract (Expand)

Enzymes are catalysts in biochemical reactions that, by definition, increase rates of reactions without being altered or destroyed. However, when that enzyme is a protease, a subclass of enzymes that … hydrolyze other proteins, and that protease is in a multiprotease system, protease-as-substrate dynamics must be included, challenging assumptions of enzyme inertness, shifting kinetic predictions of that system. Protease-on-protease inactivating hydrolysis can alter predicted protease concentrations used to determine pharmaceutical dosing strategies. Cysteine cathepsins are proteases capable of cathepsin cannibalism, where one cathepsin hydrolyzes another with substrate present, and misunderstanding of these dynamics may cause miscalculations of multiple proteases working in one proteolytic network of interactions occurring in a defined compartment. Once rates for individual protease-on-protease binding and catalysis are determined, proteolytic network dynamics can be explored using computational models of cooperative/competitive degradation by multiple proteases in one system, while simultaneously incorporating substrate cleavage. During parameter optimization, it was revealed that additional distraction reactions, where inactivated proteases become competitive inhibitors to remaining, active proteases, occurred, introducing another network reaction node. Taken together, improved predictions of substrate degradation in a multiple protease network were achieved after including reaction terms of autodigestion, inactivation, cannibalism, and distraction, altering kinetic considerations from other enzymatic systems, since enzyme can be lost to proteolytic degradation. We compiled and encoded these dynamics into an online platform (https://plattlab.shinyapps.io/catKLS/) for individual users to test hypotheses of specific perturbations to multiple cathepsins, substrates, and inhibitors, and predict shifts in proteolytic network reactions and system dynamics.

Authors: M. C. Ferrall-Fairbanks, C. A. Kieslich, M. O. Platt

Date Published: 11th Feb 2020

Publication Type: Journal

Re: Simulation analysis for tumor radiotherapy based on three-component mathematical models.
Finding Your Inner Modeler IV

Abstract

Not specified

Authors: M. C. Ferrall-Fairbanks, D. J. Glazar, R. J. Brady, G. J. Kimmel, M. U. Zahid, P. M. Altrock, H. Enderling

Date Published: 31st May 2019

Publication Type: Journal

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Finding Your Inner Modeler IV Poster
Finding Your Inner Modeler IV

An online collaborative project incubator for quantitative cell biologists
and computational modelers

MEETING OVERVIEW
• Keynotes by Angela DePace, Wallace Marshall, and Rob Phillips
• Project presentations by selected cell biologist/modeler pairs
• Feedback and advice from a panel of computational experts
• Meet-a-Modeler opportunities to consult with experts one-on-one
• Poster session, lightning talks, and Pecha Kucha
• Virtual speed networking, inter- and intradisciplinary group chats
• NSF
...

Creators: David Stone, Elizabeth Sztul

Submitter: Michael Blinov

Download
Finding Your Inner Modeler NSF abstract
Finding Your Inner Modeler IV

Abstract of NSF award for Finding Your Inner Modeler workshop series

Creator: David Stone

Submitter: Michael Blinov

Download
Finding Your Inner Modeler IV Agenda
Finding Your Inner Modeler IV

An online collaborative project incubator for quantitative cell biologists
and computational modelers

MEETING OVERVIEW
• Keynotes by Angela DePace, Wallace Marshall, and Rob Phillips
• Project presentations by selected cell biologist/modeler pairs
• Feedback and advice from a panel of computational experts
• Meet-a-Modeler opportunities to consult with experts one-on-one
• Poster session, lightning talks, and Pecha Kucha
• Virtual speed networking, inter- and intradisciplinary group chats • NSF
...

Creator: David Stone

Submitter: Michael Blinov

Download
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