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.
|Monday, February 2, 2015|
|Tuesday, February 3, 2015|
|Wednesday, February 4, 2015|
|Thursday, February 5, 2015|
|Friday, February 6, 2015|
|Anderson, Alexander||alexander.Anderson@moffitt.org||Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute|
|Balkwill, Franemail@example.com||Centre for Cancer and Inflammation, Queen Mary University of London|
|Barcellos-Hoff, Mary Helen||MHBarcellos-Hoff@nyumc.org|
|Basanta, Davidfirstname.lastname@example.org||Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center|
|Curtis, Christinaemail@example.com||Medicine and Genetics, Stanford University|
|Durrett, Rickfirstname.lastname@example.org||Department of Mathematics, Duke University|
|Gallaher, Jillemail@example.com||Integrated Mathematical Oncology, Moffitt Cancer Center|
|Gatenby, Robertfirstname.lastname@example.org||H. Lee Moffitt Cancer Center & Research Institute|
|Gerlee, Philipemail@example.com||Integrated Mathematical Oncology, Moffitt Cancer Center|
|Graham, Trevorfirstname.lastname@example.org||Tumour Biology, Barts Cancer Institute, QMUL|
|Hayward, Simonemail@example.com||Medical Center, Vanderbilt University|
|Huang, Suifirstname.lastname@example.org||Cell and Molecular Biology, Northwestern University Medical School|
|Leedham, Simonemail@example.com||Wellcome Trust Centre for Human Genetics, University of Oxford|
|Leone, Gustavofirstname.lastname@example.org||Molecular Virology, Immunology, and Medical Genetics, The Ohio State University|
|Lowengrub, Johnemail@example.com||Mathematics, University of California, Irvine|
|Ostrowski, Michaelfirstname.lastname@example.org||Department of Molecular and Cellular Biochemistry, The Ohio State University|
|Park, Moragemail@example.com||Biochemistry and Oncology, McGill University|
|Quaranta, Vitofirstname.lastname@example.org||Department of Cancer Biology, Vanderbilt University|
|Robertson Tessi, Mark||Mark.Robertsontessi@moffitt.org||Integrated Mathematical Oncology, Moffitt Cancer Center|
|Sahai, Erikemail@example.com||Tumor Cell Biology Lab, London Research Institute|
|Sansom, Owenfirstname.lastname@example.org||Colorectal Cancer and Wnt Signalling, Cancer Research UK Beatson Insititue|
|Shibata, Darrylemail@example.com||Department of Pathology, University of Southern California|
|Sottoriva, Andreafirstname.lastname@example.org||Centre for Evolution and Cancer, The Institute of Cancer Research|
|Swanton, Charlieemail@example.com||London Research Institute|
|White, Richardfirstname.lastname@example.org||Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center|
|Worthley, Danielemail@example.com||Medicine, University of Adelaide|
|Yuan, Yinyinfirstname.lastname@example.org||Centre for Evolution and Cancer, The Institute of Cancer Research|
Increasing evidence supports complex sub clonal relationships in solid tumours, manifested as intratumour heterogeneity. Our group and others are finding evidence for spatial heterogeneity within individual tumours and the temporal dynamics of tumour evolution. Parallel evolution of sub clones, with distinct somatic events occurring in the same gene, signal transduction pathway or protein complex, suggests constraints to tumour evolution that might be therapeutically exploitable. Drivers of tumour heterogeneity appear to change during the disease course that contribute to the temporally distinct origins of cancer driver events. Genome doubling, occurring early or late in tumour evolution, exacerbates chromosomal instability contributing to intercellular heterogeneity and poor outcome. The finding of sub clonal driver events is likely to limit the efficacy of targeted mono therapies, suggesting the need for new approaches to drug development and clinical trial design. TRACERx, a longitudinal lung cancer evolution study and DARWIN clinical trials aimed at deciphering the relevance of sub clonal driver events to therapeutic outcome, will be discussed.
Abstract not submitted.
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.