Genetic Subclone Architecture of Tumor Clone-initiating Cells in Colorectal Cancer

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2017 Jun 3

PMID 28572216

Citations 16

Authors

Klara M Giessler

Kortine Kleinheinz

Daniel Huebschmann

Gnana Prakash Balasubramanian

Taronish D Dubash

Sebastian M Dieter

Christine Siegl

Friederike Herbst

Sarah Weber

Christopher M Hoffmann

Raffaele Fronza

Ivo Buchhalter

Nagarajan Paramasivam

Roland Eils

Manfred Schmidt

Christof von Kalle

Martin Schneider

Alexis Ulrich

Claudia Scholl

Stefan Frohling

Wilko Weichert

Benedikt Brors

Matthias Schlesner

Claudia R Ball

Hanno Glimm

Affiliations

Soon will be listed here.

Abstract

A hierarchically organized cell compartment drives colorectal cancer (CRC) progression. Genetic barcoding allows monitoring of the clonal output of tumorigenic cells without prospective isolation. In this study, we asked whether tumor clone-initiating cells (TcICs) were genetically heterogeneous and whether differences in self-renewal and activation reflected differential kinetics among individual subclones or functional hierarchies within subclones. Monitoring genomic subclone kinetics in three patient tumors and corresponding serial xenografts and spheroids by high-coverage whole-genome sequencing, clustering of genetic aberrations, subclone combinatorics, and mutational signature analysis revealed at least two to four genetic subclones per sample. Long-term growth in serial xenografts and spheroids was driven by multiple genomic subclones with profoundly differing growth dynamics and hence different quantitative contributions over time. Strikingly, genetic barcoding demonstrated stable functional heterogeneity of CRC TcICs during serial xenografting despite near-complete changes in genomic subclone contribution. This demonstrates that functional heterogeneity is, at least frequently, present within genomic subclones and independent of mutational subclone differences.

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References

Eirew P, Steif A, Khattra J, Ha G, Yap D, Farahani H . Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature. 2014; 518(7539):422-6. PMC: 4864027. DOI: 10.1038/nature13952. View

Jones D, Hutter B, Jager N, Korshunov A, Kool M, Warnatz H . Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013; 45(8):927-32. PMC: 3951336. DOI: 10.1038/ng.2682. View

Kanehisa M, Goto S . KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 1999; 28(1):27-30. PMC: 102409. DOI: 10.1093/nar/28.1.27. View

Gehring J, Fischer B, Lawrence M, Huber W . SomaticSignatures: inferring mutational signatures from single-nucleotide variants. Bioinformatics. 2015; 31(22):3673-5. PMC: 4817139. DOI: 10.1093/bioinformatics/btv408. View

Kim T, Jung S, An C, Lee S, Baek I, Kim M . Subclonal Genomic Architectures of Primary and Metastatic Colorectal Cancer Based on Intratumoral Genetic Heterogeneity. Clin Cancer Res. 2015; 21(19):4461-72. DOI: 10.1158/1078-0432.CCR-14-2413. View

van de Wetering M, Francies H, Francis J, Bounova G, Iorio F, Pronk A . Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015; 161(4):933-45. PMC: 6428276. DOI: 10.1016/j.cell.2015.03.053. View

Sottoriva A, Kang H, Ma Z, Graham T, Salomon M, Zhao J . A Big Bang model of human colorectal tumor growth. Nat Genet. 2015; 47(3):209-16. PMC: 4575589. DOI: 10.1038/ng.3214. View

Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G . Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015; 21(7):827. DOI: 10.1038/nm0715-827b. View

Todaro M, Perez Alea M, Di Stefano A, Cammareri P, Vermeulen L, Iovino F . Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2008; 1(4):389-402. DOI: 10.1016/j.stem.2007.08.001. View

10.

Wang J, Mullighan C, Easton J, Roberts S, Heatley S, Ma J . CREST maps somatic structural variation in cancer genomes with base-pair resolution. Nat Methods. 2011; 8(8):652-4. PMC: 3527068. DOI: 10.1038/nmeth.1628. View

11.

Hermann P, Huber S, Herrler T, Aicher A, Ellwart J, Guba M . Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2008; 1(3):313-23. DOI: 10.1016/j.stem.2007.06.002. View

12.

OBrien C, Pollett A, Gallinger S, Dick J . A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2006; 445(7123):106-10. DOI: 10.1038/nature05372. View

13.

Landau D, Carter S, Stojanov P, McKenna A, Stevenson K, Lawrence M . Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013; 152(4):714-26. PMC: 3575604. DOI: 10.1016/j.cell.2013.01.019. View

14.

. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407):330-7. PMC: 3401966. DOI: 10.1038/nature11252. View

15.

Bossi D, Cicalese A, Dellino G, Luzi L, Riva L, DAlesio C . In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype. Cancer Discov. 2016; 6(6):650-63. DOI: 10.1158/2159-8290.CD-15-1200. View

16.

Jesinghaus M, Wolf T, Pfarr N, Muckenhuber A, Ahadova A, Warth A . Distinctive Spatiotemporal Stability of Somatic Mutations in Metastasized Microsatellite-stable Colorectal Cancer. Am J Surg Pathol. 2015; 39(8):1140-7. DOI: 10.1097/PAS.0000000000000423. View

17.

Schmitz M, Breithaupt P, Scheidegger N, Cario G, Bonapace L, Meissner B . Xenografts of highly resistant leukemia recapitulate the clonal composition of the leukemogenic compartment. Blood. 2011; 118(7):1854-64. DOI: 10.1182/blood-2010-11-320309. View

18.

Gerlinger M, Rowan A, Horswell S, Math M, Larkin J, Endesfelder D . Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366(10):883-892. PMC: 4878653. DOI: 10.1056/NEJMoa1113205. View

19.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

20.

Wood L, Parsons D, Jones S, Lin J, Sjoblom T, Leary R . The genomic landscapes of human breast and colorectal cancers. Science. 2007; 318(5853):1108-13. DOI: 10.1126/science.1145720. View