Toward understanding and exploiting tumor heterogeneity

doi:10.1038/nm.3915

. 2015 Aug;21(8):846-53.

doi: 10.1038/nm.3915.

Toward understanding and exploiting tumor heterogeneity

Ash A Alizadeh¹, Victoria Aranda², Alberto Bardelli³, Cedric Blanpain⁴, Christoph Bock⁵, Christine Borowski², Carlos Caldas⁶, Andrea Califano⁷, Michael Doherty⁸, Markus Elsner⁹, Manel Esteller¹⁰, Rebecca Fitzgerald¹¹, Jan O Korbel¹², Peter Lichter¹³, Christopher E Mason¹⁴, Nicholas Navin¹⁵, Dana Pe'er¹⁶, Kornelia Polyak¹⁷, Charles W M Roberts¹⁸, Lillian Siu¹⁹, Alexandra Snyder²⁰, Hannah Stower², Charles Swanton²¹, Roel G W Verhaak²², Jean C Zenklusen²³, Johannes Zuber²⁴, Jessica Zucman-Rossi²⁵

Affiliations

¹ 1] Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. [2] Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. [3] Cancer Institute, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
² Nature Medicine, New York, New York, USA.
³ 1] Department of Oncology, University of Torino, Candiolo, Torino, Italy. [2] Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Candiolo, Torino, Italy.
⁴ Université Libre de Bruxelles (ULB), Brussels, Belgium.
⁵ 1] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [2] Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
⁶ Department of Oncology, University of Cambridge, Cambridge, UK.
⁷ 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. [3] Department of Biomedical Informatics, Columbia University, New York, New York, USA.
⁸ Genentech Inc., South San Francisco, California, USA.
⁹ Nature Biotechnology, New York, New York, USA.
¹⁰ Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.
¹¹ MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK.
¹² Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
¹³ German Cancer Research Center, DKFZ, Heidelberg, Germany.
¹⁴ Weill Cornell Medical College, New York, New York, USA.
¹⁵ 1] Department of Genetics, MD Anderson Cancer Center, Houston, Texas, USA. [2] Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, Texas, USA.
¹⁶ 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Biological Sciences, Columbia University, New York, New York, USA.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
¹⁸ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
¹⁹ Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
²⁰ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
²¹ 1] University College London Cancer Institute, London, UK. [2] University College London Hospitals NHS Foundation Trust, London, UK. [3] The Francis Crick Institute, London, UK.
²² 1] Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, Texas, USA. [2] Department of Genomic Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
²³ The Cancer Genome Atlas, Center for Cancer Genomics, National Cancer Institute, Bethesda, Maryland, USA.
²⁴ Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
²⁵ Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Institut Universitaire d'Hématologie (IUH), Paris, France.

PMID: 26248267
PMCID: PMC4785013
DOI: 10.1038/nm.3915

Toward understanding and exploiting tumor heterogeneity

Ash A Alizadeh et al. Nat Med. 2015 Aug.

. 2015 Aug;21(8):846-53.

doi: 10.1038/nm.3915.

Authors

Affiliations

¹ 1] Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. [2] Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. [3] Cancer Institute, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
² Nature Medicine, New York, New York, USA.
³ 1] Department of Oncology, University of Torino, Candiolo, Torino, Italy. [2] Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Candiolo, Torino, Italy.
⁴ Université Libre de Bruxelles (ULB), Brussels, Belgium.
⁵ 1] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [2] Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
⁶ Department of Oncology, University of Cambridge, Cambridge, UK.
⁷ 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. [3] Department of Biomedical Informatics, Columbia University, New York, New York, USA.
⁸ Genentech Inc., South San Francisco, California, USA.
⁹ Nature Biotechnology, New York, New York, USA.
¹⁰ Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.
¹¹ MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK.
¹² Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
¹³ German Cancer Research Center, DKFZ, Heidelberg, Germany.
¹⁴ Weill Cornell Medical College, New York, New York, USA.
¹⁵ 1] Department of Genetics, MD Anderson Cancer Center, Houston, Texas, USA. [2] Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, Texas, USA.
¹⁶ 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Biological Sciences, Columbia University, New York, New York, USA.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
¹⁸ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
¹⁹ Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
²⁰ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
²¹ 1] University College London Cancer Institute, London, UK. [2] University College London Hospitals NHS Foundation Trust, London, UK. [3] The Francis Crick Institute, London, UK.
²² 1] Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, Texas, USA. [2] Department of Genomic Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
²³ The Cancer Genome Atlas, Center for Cancer Genomics, National Cancer Institute, Bethesda, Maryland, USA.
²⁴ Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
²⁵ Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Institut Universitaire d'Hématologie (IUH), Paris, France.

PMID: 26248267
PMCID: PMC4785013
DOI: 10.1038/nm.3915

Abstract

The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity. Once these key questions were established, the attendees devised potential solutions. Their ideas are presented here.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare competing financial interests: details are available in the online version of the paper.

Figures

**Figure 1**
Herrenhausen Palace. Image credit: Eberhard Franke for Volkswagen Foundation.

**Figure 2**
The clonality of tumor evolution. In tumor evolution, driver alterations may result in the formation of the initial tumor clone. As further driver alterations occur, these clones then branch off to form subclones. Founder mutations that occur in the original tumor clone are hard to identify, however, as a mutation at point (1) may be considered to be a founder mutation, but further mutations at point (2) would have been considered to be in the initial clone had the sample at point 1 not been taken.

**Figure 3**
Influences on cancer cell state. The cancer cell state is representative of the genetic and epigenetic components as well as the signaling environment, which collectively determine which genes are expressed by the cell. These properties may be altered by subclonal evolution and can influence the initiation, progression and drug response of the tumor, affecting both the bulk tumor and the single-cell state. The gray arrows show the timescales of these processes and the factors that might influence cell state on each timescale are indicated.

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References

1. Zardavas D, et al. Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol. 2015;12:381–394. - PubMed
1. Marusyk A, et al. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer. 2012;12:323–334. - PubMed
1. McGranahan N, Charles Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27:15–26. - PubMed
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1. Gould SE, Junttila MR, de Sauvage FJ. Translational value of mouse models in oncology drug development. Nat Med. 2015;21:431–439. - PubMed

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[1] Zardavas D, et al. Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol. 2015;12:381–394. - PubMed

[2] Zardavas D, et al. Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol. 2015;12:381–394. - PubMed

[3] Marusyk A, et al. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer. 2012;12:323–334. - PubMed

[4] Marusyk A, et al. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer. 2012;12:323–334. - PubMed

[5] McGranahan N, Charles Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27:15–26. - PubMed

[6] McGranahan N, Charles Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27:15–26. - PubMed

[7] Chen JC, et al. Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. Cell. 2014;159:402–414. - PMC - PubMed

[8] Chen JC, et al. Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. Cell. 2014;159:402–414. - PMC - PubMed

[9] Gould SE, Junttila MR, de Sauvage FJ. Translational value of mouse models in oncology drug development. Nat Med. 2015;21:431–439. - PubMed

[10] Gould SE, Junttila MR, de Sauvage FJ. Translational value of mouse models in oncology drug development. Nat Med. 2015;21:431–439. - PubMed

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Toward understanding and exploiting tumor heterogeneity

Affiliations

Toward understanding and exploiting tumor heterogeneity

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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MeSH terms

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