Workshop 7: Stem Cells, Development, and Cancer

(April 13,2015 - April 17,2015 )

Organizers


Heiko Enderling
Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute
Thomas Hillen
Mathematical and Statistical Sciences, University of Alberta
John Lowengrub
Mathematics, University of California, Irvine

Most tissues are hierarchically organized into lineages. A lineage is a set of progenitor-progeny relationships within which progressive changes in cell character occur. Typically, lineages are traced back to a self-perpetuating stem cell (SC), and end with a postmitotic terminal cell. One of the most exciting recent developments in the field of cancer biology is the recognition that lineage progression continues to occur in tumors. In particular there is an increasing body of evidence that like normal tissues, tumor cells that have the potential for unlimited self-renewal give rise in large numbers to cells that lack this potential - the so-called cancer stem cell hypothesis. By focusing for so many years on the majority cell populations in tumors, and not on the rarer cancer stem cells (cancer initiating cells), scientists and clinicians may have missed out on opportunities to understand, diagnose and treat the processes in cancer that matter most. Further, there is increasing evidence that cell stemness may be a function of the local environment rather than being a predetermined property of a cell. What are the consequences of this plasticity in cell behavior? Other important open questions in the field include: What cell types within the normal tissues are capable of being the cells of origin for tumors? What is the relationship between normal tissue stem cells and tumor-initiating cells (e.g., cancer stem cells)? Which signaling and other regulatory networks are altered in tumors relative to the normal tissues, and how do they function within the tumor? Finally, there is growing evidence that therapies aimed at the major cell types in tumors may sometimes make things worse, by leading to an expansion in the fraction of cancer stem cells. How can this be avoided? This workshop will address these and other questions through discussions among mathematical and computational modelers and experimentalists. In particular, the strong connections between normal development, tumor growth and the use of novel treatment strategies will be discussed.

Accepted Speakers

Zvia Agur
Institute for Medical Biomathematics
David Axelrod
Department of Genetics, Rutgers University
Andreas Buttenschoen
Department of Mathematical and Statistical Sciences, University of Alberta
Helen Byrne
Centre for Mathematical Medicine and Biology, University of Nottingham
Vincenzo Capasso
ADAMSS, Università degli Studi di Milano and "Gregorio Millan" Institute Escuela Politecnica Superior Universidad Carlos III de Madrid
Dirk Drasdo
Bioinformatics, Physical and Mathematical Biology, Institut National de Recherche en Informatique Automatique (INRIA)
Avner Friedman
Department of Mathematics, The Ohio State University
Ryan Gao
Inria Team Dracula, Inria Center Grenoble Rhone-Alpes
Philip Hahnfeldt
Center of Cancer Systems Biology, Tufts University
Leonid Hanin
Department of Mathematics, Idaho State University
Anita Hjelmeland
Cell, Developmental and Integrative Biology, University of Alabama at Birmingham
Yangjin Kim
Department of Mathematics, Konkuk University
Marek Kimmel
Department of Statistics, Rice University
Natalia Komarova
Department of Mathematics, University of California, Irvine
Michael Lewis
Paul Macklin
Center for Applied Molecular Medicine, University of Southern California
Anna Marciniak-Czochra
Institute of Applied Mathematics, Ruprecht-Karls-Universit""at Heidelberg
Kevin Painter
Department of Mathematics, Heriot-Watt University
Alexander Pearson
Hematology and Medical Oncology, University of Michigan
Jan Poleszczuk
Lynne-Marie Postovit
Oncology, University of Alberta
Jeremy Rich
Stem Cell Biology and Regenerative Medicine, Cleveland Clinic
Ignacio Rodriguez-Brenes
Mathematics, University of California, Irvine
Andrea Sottoriva
Centre for Evolution and Cancer, The Institute of Cancer Research
Christina Surulescu
Mathematics, Felix-Klein-Zentrum für Mathematik, TU Kaiserslautern
Kristin Swanson
Neurological Surgery, Northwestern University
Jose Ignacio Tello
Department of Applied Mathematics, Universidad Complutense de Madrid
Vitaly Volpert
Mathematics and applications, CNRS
Monday, April 13, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
10:00 AM
Lynne-Marie Postovit
10:00 AM
10:30 AM

Break

10:30 AM
11:10 AM
Zvia Agur
11:15 AM
11:55 AM
Natalia Komarova
12:00 PM
02:00 PM

Lunch Break

02:00 PM
02:40 PM
Leonid Hanin
02:45 PM
03:25 PM
David Axelrod
03:25 PM
03:40 PM

Break

03:40 PM
04:20 PM
Avner Friedman
04:20 PM
05:00 PM

NN

05:00 PM
07:00 PM

Reception and Poster Session

07:15 PM

Shuttle pick-up from MBI

Tuesday, April 14, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
10:00 AM
Dirk Drasdo
10:00 AM
10:30 AM

Break

10:30 AM
11:10 AM
Jeremy Rich
11:15 AM
11:55 AM
Paul Macklin
12:00 PM
02:00 PM

Lunch Break

02:00 PM
02:40 PM
Kristin Swanson
02:45 PM
03:25 PM
Anita Hjelmeland
03:25 PM
03:40 PM

Break

03:40 PM
04:20 PM
Yangjin Kim
04:20 PM
05:00 PM

NN

05:00 PM

Shuttle pick-up from MBI

Wednesday, April 15, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
10:00 AM
Philip Hahnfeldt
10:00 AM
10:30 AM

Break

10:30 AM
11:10 AM
Kevin Painter
11:15 AM
11:55 AM
Andreas Buttenschoen
12:00 PM
02:00 PM

Lunch Break

02:00 PM
02:40 PM
Christina Surulescu
02:45 PM
03:25 PM
Ryan Gao
03:25 PM
03:40 PM

Break

03:40 PM
04:20 PM
Vincenzo Capasso
04:20 PM
05:00 PM

NN

05:00 PM

Shuttle pick-up from MBI

Thursday, April 16, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
10:00 AM
Marek Kimmel
10:00 AM
10:30 AM

Break

10:30 AM
11:10 AM
Alexander Pearson
11:15 AM
11:55 AM
Vitaly Volpert
12:00 PM
02:00 PM

Lunch Break

02:00 PM
02:40 PM
Michael Lewis
02:45 PM
03:25 PM
Anna Marciniak-Czochra
03:25 PM
03:40 PM

Break

03:40 PM
04:20 PM
Jan Poleszczuk
04:20 PM
05:00 PM
Andrea Sottoriva
05:00 PM

Shuttle pick-up from MBI

05:30 PM
06:00 PM

Cash Bar - Crowne Plaza

06:00 PM
07:30 PM

Banquet at Crowne Plaza

Friday, April 17, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
10:00 AM
Helen Byrne
10:00 AM
10:30 AM

Break

10:30 AM
11:10 AM
Jose Ignacio Tello
11:15 AM
11:55 AM
Ignacio Rodriguez-Brenes
12:00 PM

Shuttle pick-up from MBI (One to airport and one back to hotel)

Name Email Affiliation
Agur, Zvia agur@imbm.org Institute for Medical Biomathematics
Axelrod, David axelrod@biology.rutgers.edu Department of Genetics, Rutgers University
Buttenschoen, Andreas andreas.buttenschoen@ualberta.ca Department of Mathematical and Statistical Sciences, University of Alberta
Byrne, Helen byrneh@maths.ox.ac.uk Centre for Mathematical Medicine and Biology, University of Nottingham
Capasso, Vincenzo vincenzo.capasso@unimi.it ADAMSS, Università degli Studi di Milano and "Gregorio Millan" Institute Escuela Politecnica Superior Universidad Carlos III de Madrid
Drasdo, Dirk dirk.drasdo@inria.fr Bioinformatics, Physical and Mathematical Biology, Institut National de Recherche en Informatique Automatique (INRIA)
Durrett, Rick rtd@math.duke.edu Department of Mathematics, Duke University
Enderling, Heiko heiko.enderling@moffitt.org Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute
Friedman, Avner afriedman@math.ohio-state.edu Department of Mathematics, The Ohio State University
Friedman, Samuel samuelf@usc.edu
Gao, Xuefeng ryan.gaoim@gmail.com Inria Team Dracula, Inria Center Grenoble Rhone-Alpes
Hahnfeldt, Philip philip.hahnfeldt@tufts.edu Center of Cancer Systems Biology, Tufts University
Hanin, Leonid hanin@isu.edu Department of Mathematics, Idaho State University
Hillen, Thomas thillen@ualberta.ca Mathematical and Statistical Sciences, University of Alberta
Hjelmeland, Anita hjelmea@uab.edu Cell, Developmental and Integrative Biology, University of Alabama at Birmingham
Jilkine, Alexandra ajilkine@nd.edu ACMS, University of Notre Dame
Kim, Yangjin ahyouhappy@konkuk.ac.kr Department of Mathematics, Konkuk University
Kimmel, Marek kimmel@rice.edu Department of Statistics, Rice University
Komarova, Natalia komarova@uci.edu Department of Mathematics, University of California, Irvine
Lewis, Michael mtlewis@bcm.edu
Macklin, Paul Paul.Macklin@usc.edu Center for Applied Molecular Medicine, University of Southern California
Marciniak-Czochra, Anna Anna.Marciniak@iwr.uni-heidelberg.de Institute of Applied Mathematics, Ruprecht-Karls-Universit""at Heidelberg
Olobatuyi, Oluwole olobatuy@ualberta.ca Mathematical and Statistical Sciences, University of Alberta
Painter, Kevin painter@ma.hw.ac.uk Department of Mathematics, Heriot-Watt University
Pearson, Alexander pearsona@med.umich.edu Hematology and Medical Oncology, University of Michigan
Poleszczuk, Jan j.poleszczuk@mimuw.edu.pl
Postovit, Lynne-Marie postovit@ualberta.ca Oncology, University of Alberta
Rich, Jeremy richj@ccf.org Stem Cell Biology and Regenerative Medicine, Cleveland Clinic
Rodriguez-Brenes, Ignacio iarodrig@uci.edu Mathematics, University of California, Irvine
Sishc, Brock Brock.sishc@utsouthwestern.edu Radiation Oncology, UT Southwestern Medical Center
Sottoriva, Andrea sottoriv@usc.edu Centre for Evolution and Cancer, The Institute of Cancer Research
Surulescu, Christina surulescu@mathematik.uni-kl.de Mathematics, Felix-Klein-Zentrum für Mathematik, TU Kaiserslautern
Swanson, Kristin kristin.swanson@northwestern.edu Neurological Surgery, Northwestern University
Tello, Jose Ignacio jtello@eui.upm.es Department of Applied Mathematics, Universidad Complutense de Madrid
Volpert, Vitaly volpert@math.univ-lyon1.fr Mathematics and applications, CNRS
Data-Driven Mathematical Modeling of Mammary Ductal Elongation

The Terminal End Bud (TEB) at the growing tip of mammary ducts is one of the fastest growing structures in mammals. TEBs drive ductal elongation during puberty and regress once development of the ductal tree is complete. Because of similarities between TEB growth and breast cancer growth, successful modeling of this structure may yield insight into breast development as well as cancer progression. Previous mathematical models have focused on branching morphogenesis, but there are currently no models that address ductal elongation itself. Our model exploits the constrained geometry of the TEB in vivo which provided the framework for an initial mathematical model. Parameters in this model were then informed with measureable data (morphological characteristics, proliferation rate, cell cycle duration, and apoptosis). These data were then used to calculate a value representing the movement of cells from the TEB into the mature duct (termed the flux) and this calculated flux was then used to predict a linear elongation rate. The prediction was compared to an experimentally measured displacement within the mammary fat pad. Our initial measurements of proliferation, apoptosis, and cell sizes, predicted a linear elongation rate of 1.39 mm per day, which was significantly different from our experimentally measured displacement rate of 0.54mm per day. We then refined our model by incorporating changes in the direction of growth due to bifurcation, a cost function for bifurcation (which describes duplication of the TEB), as well as an additional flux term to account for a migration of cap cells into the body cell. Iteration of the revised mathematical model yielded an estimate significantly closer to the measured displacement rate, thus indicating that the most relevant biological parameters have been accounted for. In addition, our data overturned a long held belief that cap cells contribute to the body cell lineage. We are now poised for in silico experiments that may yield predictions consistent with cancer phenotypes, as well as predictions that recapitulate known mutation phenotypes.