Workshop 4: Tumor Heterogeneity and the Microenvironment

(February 2,2015 - February 6,2015 )

Organizers


Alexander Anderson
Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute
Trevor Graham
Tumour Biology, Barts Cancer Institute, QMUL
Michael Ostrowski
Department of Molecular and Cellular Biochemistry, The Ohio State University
Charlie Swanton
London Research Institute

Heterogeneity in cancer is an observed fact, both genetically and phenotypically. Cell-cell variation is seen in almost all aspects of cancer from early development through to invasion and subsequent metastasis. Our current understanding of this heterogeneity has mainly focused at the genetic scale with little information on how this variation translates to actual changes in cell phenotypic behavior. Given that many genotypes can lead to the same cellular phenotype, we must also understand the range and scope of this heterogeneity at the phenotypic scale as ultimately this variability will dictate the aggressiveness of the tumor and its treatability. Central to our understanding of this heterogeneity is how the tumor cells interact with each other and with their microenvironment.

The tumor microenvironment is not simply the extra cellular matrix, but a complex milieu consisting of growth promoting and inhibiting factors, nutrients (including oxygen and glucose), chemokines, and importantly other cell types including (but not limited to) fibroblasts, immune cells, endothelial cells and normal epithelial cells. These microenvironmental factors and different cell types interact with one another and the tumor as it grows. The role of endothelial cells and the immune system in cancer development are fairly well established, but less is known about the function of host fibroblasts in this process. Most solid tumors present as dense fibrotic masses, which suggests that fibroblasts contribute to tumor growth by infiltrating and depositing extracellular matrix proteins. In addition, the phenotype of fibroblasts found within and around tumors (activated fibroblasts or cancer associated fibroblasts: CAFs) is different to normal fibroblasts, and closely resembles myofibroblasts. Fibroblasts act in wound healing, angiogenesis and tissue remodeling by releasing growth factors and proteases such as matrix metalloproteinases. They also deposit matrix proteins such as laminin, tenascin and fibronectin. Therefore, if the growing tumor can co-opt such fibroblasts it has an unlimited source of many of the fundamental elements required for growth and invasion.

The two central themes of this workshop are:

  • Heterogeneity (be it phenotypic, signaling or genotypic), and
  • Microenvironment (ECM, nutrients, fibroblasts and immune cells).

Since a highly heterogeneous tumor has the potential to adapt to any microenvironment, understanding how interactions between the growing tumor and its microenvironment modulate tumor heterogeneity is critical to unraveling the mechanisms of cancer initiation.

Accepted Speakers

Alexander Anderson
Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute
Fran Balkwill
Centre for Cancer and Inflammation, Queen Mary University of London
Mary Helen Barcellos-Hoff
Robert Clarke
Joseph Costello
Christina Curtis
Medicine and Genetics, Stanford University
Elza De Bruin
Jude Fitzgibbon
Robert Gatenby
H. Lee Moffitt Cancer Center & Research Institute
Philip Gerlee
Mathematical Sciences, Chalmers University of Technology
Trevor Graham
Tumour Biology, Barts Cancer Institute, QMUL
Simon Hayward
Medical Center, Vanderbilt University
Sui Huang
Cell and Molecular Biology, Northwestern University Medical School
Shelley Hwang
Simon Leedham
Wellcome Trust Centre for Human Genetics, University of Oxford
Gustavo Leone
Molecular Virology, Immunology, and Medical Genetics, The Ohio State University
Parag Mallick
Morag Park
Biochemistry and Oncology, McGill University
Vito Quaranta
Department of Cancer Biology, Vanderbilt University
Sergio Quezada
Erik Sahai
Tumor Cell Biology Lab, London Research Institute
Owen Sansom
Colorectal Cancer and Wnt Signalling, Cancer Research UK Beatson Insititue
Richard Sole
Andrea Sottoriva
Centre for Evolution and Cancer, The Institute of Cancer Research
Zoltan Szallasi
Thea Tlsty
Valerie Weaver
Richard White
Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center
Daniel Worthley
Medicine, University of Adelaide
Yinyin Yuan
Centre for Evolution and Cancer, The Institute of Cancer Research
Monday, February 2, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:30 AM

Greetings and info from MBI - Marty Golubitsky

09:30 AM
10:15 AM
Mary Helen Barcellos-Hoff
10:15 AM
11:00 AM
Christina Curtis
11:00 AM
11:30 AM

Break

11:30 AM
12:15 PM
Jude Fitzgibbon
12:15 PM
01:00 PM
Sui Huang
01:00 PM
02:15 PM

Lunch Break

02:15 PM
03:00 PM
Joseph Costello
03:00 PM
03:45 PM
Morag Park
03:45 PM
04:00 PM

Break

04:00 PM
04:45 PM
Robert Gatenby
04:45 PM
05:00 PM

Discussion

05:00 PM
07:00 PM

Reception and Poster Session

07:00 PM

Shuttle pick-up from MBI

Tuesday, February 3, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:45 AM
Richard White - Identifying mechanisms of diversity using zebrafish melanoma models

Abstract not submitted.

09:45 AM
10:30 AM
Alexander Anderson
10:30 AM
11:00 AM

Break

11:00 AM
11:45 AM
Simon Leedham
11:45 AM
12:30 PM
Daniel Worthley
12:30 PM
01:45 PM

Lunch Break

01:45 PM
02:30 PM
Owen Sansom
02:30 PM
04:15 PM

Breakout Session

04:15 PM
05:00 PM
Philip Gerlee
05:00 PM

Shuttle pick-up from MBI

Wednesday, February 4, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:45 AM
Vito Quaranta
09:45 AM
10:30 AM
Andrea Sottoriva
10:30 AM
11:00 AM

Break

11:00 AM
11:45 AM
Zoltan Szallasi
11:45 AM
12:30 PM
Parag Mallick
12:30 PM
01:45 PM

Lunch Break

01:45 PM
02:30 PM
Erik Sahai
02:30 PM
04:15 PM

Breakout Discussion

04:15 PM
05:00 PM
Robert Clarke
05:00 PM

Shuttle pick-up from MBI

Thursday, February 5, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:45 AM
Sergio Quezada
09:45 AM
10:30 AM
Fran Balkwill
10:30 AM
11:00 AM

Break

11:00 AM
11:45 AM
Yinyin Yuan - The Ecosystem Diversity Landscape of Breast Cancer

It is increasingly recognised that the tumor microenvironment is an important determinant in cancer progression and evolution, where tumors act as complex ecosytems involving interactions between cancer cells, stromal cells and their physical environment. To study this we developed a statistical model to systematically quantify the spatial heterogeneity of the tumor ecosystem based on automated image analysis of 1,026 Hematoxylin & Eosin (H&E) stained primary breast tumors. I will discuss the clinical implication of heterogeneous tumour ecosystem, how ecosystem diversity was capable of predicting prognosis independent to known clinical and cancer heterogeneity parameters, before moving on to the bioinformatics integration of this measurement with whole-genome genomic profiling data for all of these tumours. This helped us reveal enrichment of specific copy number alterations for certain genes in this subtype, for which an RNAi screen showed an overall pattern of increased cell invasion, suggesting that tumour ecosystem heterogeneity may aid cancer progression through its interplay with specific genomic alterations. Taken together, these results support the use of statistical modelling of spatial pathological data for a quantitative understanding of ecosystem heterogeneity and provide initial evidences of the clinical implication of tumour ecosystem diversity.

11:45 AM
12:30 PM
Thea Tlsty
12:30 PM
01:45 PM

Lunch Break

01:45 PM
02:30 PM
Trevor Graham
02:30 PM
04:15 PM

Breakout Discussion

04:15 PM
05:00 PM
Simon Hayward
05:00 PM

Shuttle pick-up from MBI

Friday, February 6, 2015
Time Session
08:00 AM

Shuttle to MBI

08:15 AM
09:00 AM

Breakfast

09:00 AM
09:45 AM

TBD

09:45 AM
10:30 AM
Valerie Weaver
10:30 AM
11:00 AM

Break

11:00 AM
11:45 AM
Shelley Hwang
11:45 AM
12:30 PM
Richard Sole
12:30 PM
01:15 PM
Gustavo Leone
01:15 PM

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

Name Email Affiliation
Altrock, Philipp paltrock@jimmy.harvard.edu Program for Evolutionary Dynamics, Harvard University
Anderson, Alexander alexander.Anderson@moffitt.org Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute
Baker, Ann-Marie a.m.c.baker@qmul.ac.uk Tumour Biology, Barts Cancer Institute, Queen Mary University of London
Balkwill, Fran f.balkwill@qmul.ac.uk Centre for Cancer and Inflammation, Queen Mary University of London
Barcellos-Hoff, Mary Helen MHBarcellos-Hoff@nyumc.org
Basanta, David david@cancerevo.org Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center
Botesteanu, Dana dboteste@math.umd.edu Center for Scientific Computation and Mathematical Modeling, University of Maryland
Clarke, Robert clarker@georgetown.edu
Costello, Joseph jcostello@cc.ucsf.edu
Curtis, Christina ccurtis2@stanford.edu Medicine and Genetics, Stanford University
de Bruin, Elza e.debruin@ucl.ac.uk
Domogauer, Jason jdomogauer@gmail.com Radiology, Rutgers New Jersey Medical School
Durrett, Rick rtd@math.duke.edu Department of Mathematics, Duke University
Fitzgibbon, Jude j.fitzgibbon@qmul.ac.uk
Gallaher, Jill jill.gallaher@moffitt.org Integrated Mathematical Oncology, Moffitt Cancer Center
Gatenby, Robert robert.gatenby@moffitt.org H. Lee Moffitt Cancer Center & Research Institute
Gerlee, Philip philipgerlee@gmail.com Mathematical Sciences, Chalmers University of Technology
Graham, Trevor t.graham@qmul.ac.uk Tumour Biology, Barts Cancer Institute, QMUL
Hayward, Simon simon.hayward@vanderbilt.edu Medical Center, Vanderbilt University
Huang, Sui sui.huang@systemsbiology.org Cell and Molecular Biology, Northwestern University Medical School
Hwang, Shelley shelley.hwang@duke.edu
Irshad, Shazia shazia.irshad@well.ox.ac.uk
Jacobsen, Karly jacobsen.50@mbi.osu.edu Mathematical Biosciences Institute, The Ohio State University
Jiang, Yi yijianglanl@gmail.com Mathematics and Statistics, Georgia State University
Kan, Rebecca Pei Qi kanrebecca@gmail.com Clinical Oncology, University of Hong Kong
Kianercy, Ardeshir akianer1@jhmi.edu Urology, Johns Hopkins Hospital
Klimov, Sergey sklimov3@gmail.com Interdisciplinarity Biology and Mathematics, Georgia State University
Leedham, Simon simon.leedham@cancer.org.uk Wellcome Trust Centre for Human Genetics, University of Oxford
Leone, Gustavo gustavo.leone@osumc.edu Molecular Virology, Immunology, and Medical Genetics, The Ohio State University
Lowengrub, John lowengrb@math.uci.edu Mathematics, University of California, Irvine
Mallick, Parag paragm@stanford.edu
Martinez, Pierre p.martinez@qmul.ac.uk Tumour Biology, Evolution and Cancer laboratory, Queen Mary University of London
Ostrowski, Michael michael.ostrowski@osumc.edu Department of Molecular and Cellular Biochemistry, The Ohio State University
Park, Morag morag.park@mcgill.ca Biochemistry and Oncology, McGill University
Quaranta, Vito vito.quaranta@vanderbilt.edu Department of Cancer Biology, Vanderbilt University
Quezada, Sergio s.quezada@ucl.ac.uk
Robertson Tessi, Mark Mark.Robertsontessi@moffitt.org Integrated Mathematical Oncology, Moffitt Cancer Center
Sahai, Erik erik.sahai@cancer.org.uk Tumor Cell Biology Lab, London Research Institute
Sansom, Owen o.sansom@beatson.gla.ac.uk Colorectal Cancer and Wnt Signalling, Cancer Research UK Beatson Insititue
Scherz-Shouval, Ruth ruthsh@wi.mit.edu Lindquist lab, Whitehead Institute for Biomedical Research
Shibata, Darryl dshibata@usc.edu Department of Pathology, University of Southern California
Sole, Richard ricard.sole@upf.edu
Sottoriva, Andrea andrea.sottoriva@icr.ac.uk Centre for Evolution and Cancer, The Institute of Cancer Research
Szallasi, Zoltan zszallasi@chip.org
Tlsty, Thea thea.tlsty@ucsf.edu
Weaver, Valerie valerie.weaver@ucsfmedctr.org
White, Richard whiter@mskcc.org Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center
Worthley, Daniel daniel.worthley@adelaide.edu.au Medicine, University of Adelaide
Yuan, Yinyin yinyin.yuan@icr.ac.uk Centre for Evolution and Cancer, The Institute of Cancer Research
Identifying mechanisms of diversity using zebrafish melanoma models

Abstract not submitted.

The Ecosystem Diversity Landscape of Breast Cancer

It is increasingly recognised that the tumor microenvironment is an important determinant in cancer progression and evolution, where tumors act as complex ecosytems involving interactions between cancer cells, stromal cells and their physical environment. To study this we developed a statistical model to systematically quantify the spatial heterogeneity of the tumor ecosystem based on automated image analysis of 1,026 Hematoxylin & Eosin (H&E) stained primary breast tumors. I will discuss the clinical implication of heterogeneous tumour ecosystem, how ecosystem diversity was capable of predicting prognosis independent to known clinical and cancer heterogeneity parameters, before moving on to the bioinformatics integration of this measurement with whole-genome genomic profiling data for all of these tumours. This helped us reveal enrichment of specific copy number alterations for certain genes in this subtype, for which an RNAi screen showed an overall pattern of increased cell invasion, suggesting that tumour ecosystem heterogeneity may aid cancer progression through its interplay with specific genomic alterations. Taken together, these results support the use of statistical modelling of spatial pathological data for a quantitative understanding of ecosystem heterogeneity and provide initial evidences of the clinical implication of tumour ecosystem diversity.