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Grant Details

Grant Number: 5R01CA140657-10 Interpret this number
Primary Investigator: Maley, Carlo
Organization: Arizona State University-Tempe Campus
Project Title: Modeling Neoplastic Progression in Barrett's Esophagus
Fiscal Year: 2018
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Abstract

DESCRIPTION (provided by applicant): One of the main clinical problems in Barrett's esophagus (BE), like most pre-malignant neoplasms, is predicting which patients are likely to progress to cancer (i.e., risk stratification). Once we identify high risk patients, we can justify interventions to prevent development of cancer. However, neoplasms progress to cancer through a fundamentally stochastic process of somatic evolution leading to clonal heterogeneity in both space and time. Recent cancer genome sequencing results show that many different combinations of mutations can generate a cancer. All of this makes it difficult to develop reliable and accurate panels of mutations for risk stratification. As leaders in the evolutionary biology of cancer and agent-based modeling of neoplastic progression, with access to tissue samples and data from the world's best prospective cohorts of BE, we are in a unique position to study the evolutionary dynamics of neoplastic progression in BE and translate our results to the clinic. Our preliminary results show that by measuring the parameters of somatic evolution, rather than its products, we can develop robust biomarkers for risk stratification that may be universally applicable to most, if not all neoplasms. Specifically, we have shown that measures of genetic diversity, which is the fuel of natural selection, predict progression in BE. We also demonstrated that we can measure the somatic mutation rate, in vivo, and that non-steroidal anti-inflammatory drugs, which appear to prevent cancer in BE, were associated with an order of magnitude decrease in that mutation rate in most patients. This novel initial view of the dynamics of progression revealed 3 surprises that are important for risk stratification and cancer prevention in BE: (1) The mutation rate at the biopsy level is apparently very low: ~1 chromosomal lesion per year, per cell lineage. Aim 1 will test if the mutation rate within crypts is higher than can b observed in biopsies, both in patients that progressed to cancer, and those that did not. (2) The vast majority of lesions occur prior to the first endoscopy, which is often concomitant with the start of powerful acid suppressive medications such as proton-pump inhibitors (PPIs). Aim 2 will use an observational cross-over study design to test the effects of PPIs on mutation rate at the biopsy and crypt levels. This would be the first time that PPIs would be tested for a cancer prevention mechanism. (3) Current theory posits that neoplastic progression proceeds through a series of (e.g., ~20) clonal expansions. Yet, we only observed one such expansion in 156 patient years of surveillance based on biopsy sampling. Aim 3 will develop methods to detect clonal expansions in the much finer resolution available in single cells from cytology brushings of BE from two large, independent cohorts, and test if the detection of a clonal expansion predicts progression. We will also use these cohorts as an independent validation study to test if cell level genetic diversity predicts progression. For each aim, we use computational models to generate the expected data under alternative hypotheses and to identify the most sensitive aspects of the somatic evolutionary process for cancer prevention.

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Publications

Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms.
Authors: Alcock J. , Maley C.C. , Aktipis C.A. .
Source: Bioessays : News And Reviews In Molecular, Cellular And Developmental Biology, 2014 Oct; 36(10), p. 940-9.
PMID: 25103109
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Temporal and spatial evolution of somatic chromosomal alterations: a case-cohort study of Barrett's esophagus.
Authors: Li X. , Galipeau P.C. , Paulson T.G. , Sanchez C.A. , Arnaudo J. , Liu K. , Sather C.L. , Kostadinov R.L. , Odze R.D. , Kuhner M.K. , et al. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2014 Jan; 7(1), p. 114-27.
PMID: 24253313
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Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution.
Authors: Humphries A. , Cereser B. , Gay L.J. , Miller D.S. , Das B. , Gutteridge A. , Elia G. , Nye E. , Jeffery R. , Poulsom R. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2013-07-02 00:00:00.0; 110(27), p. E2490-9.
EPub date: 2013-07-02 00:00:00.0.
PMID: 23766371
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NSAIDs modulate clonal evolution in Barrett's esophagus.
Authors: Kostadinov R.L. , Kuhner M.K. , Li X. , Sanchez C.A. , Galipeau P.C. , Paulson T.G. , Sather C.L. , Srivastava A. , Odze R.D. , Blount P.L. , et al. .
Source: Plos Genetics, 2013 Jun; 9(6), p. e1003553.
PMID: 23785299
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An Evolutionary Explanation For The Presence Of Cancer Nonstem Cells In Neoplasms
Authors: Sprouffske K. , Athena Aktipis C. , Radich J.P. , Carroll M. , Nedelcu A.M. , Maley C.C. .
Source: Evolutionary Applications, 2013 Jan; 6(1), p. 92-101.
PMID: 23397439
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Cancer in light of experimental evolution.
Authors: Sprouffske K. , Merlo L.M. , Gerrish P.J. , Maley C.C. , Sniegowski P.D. .
Source: Current Biology : Cb, 2012-09-11 00:00:00.0; 22(17), p. R762-71.
PMID: 22975007
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Development and characterization of an organotypic model of Barrett's esophagus.
Authors: Kosoff R.E. , Gardiner K.L. , Merlo L.M. , Pavlov K. , Rustgi A.K. , Maley C.C. .
Source: Journal Of Cellular Physiology, 2012 Jun; 227(6), p. 2654-9.
PMID: 21882191
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Dispersal evolution in neoplasms: the role of disregulated metabolism in the evolution of cell motility.
Authors: Aktipis C.A. , Maley C.C. , Pepper J.W. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2012 Feb; 5(2), p. 266-75.
PMID: 21930797
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Clonal evolution in cancer.
Authors: Greaves M. , Maley C.C. .
Source: Nature, 2012-01-18 00:00:00.0; 481(7381), p. 306-13.
EPub date: 2012-01-18 00:00:00.0.
PMID: 22258609
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Spatial structure increases the waiting time for cancer.
Authors: Martens E.A. , Kostadinov R. , Maley C.C. , Hallatschek O. .
Source: New Journal Of Physics, 2011-11-01 00:00:00.0; 13, .
EPub date: 2011-11-01 00:00:00.0.
PMID: 22707911
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An in vitro co-culture model of esophageal cells identifies ascorbic acid as a modulator of cell competition.
Authors: Merlo L.M. , Kosoff R.E. , Gardiner K.L. , Maley C.C. .
Source: Bmc Cancer, 2011-10-25 00:00:00.0; 11, p. 461.
EPub date: 2011-10-25 00:00:00.0.
PMID: 22026449
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Accurate reconstruction of the temporal order of mutations in neoplastic progression.
Authors: Sprouffske K. , Pepper J.W. , Maley C.C. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2011 Jul; 4(7), p. 1135-44.
PMID: 21490131
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Is Cooperation Viable In Mobile Organisms? Simple Walk Away Rule Favors The Evolution Of Cooperation In Groups
Authors: Aktipis C.A. .
Source: Evolution And Human Behavior : Official Journal Of The Human Behavior And Evolution Society, 2011 Jul; 32(4), p. 263-276.
PMID: 21666771
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New strategies in Barrett's esophagus: integrating clonal evolutionary theory with clinical management.
Authors: Reid B.J. , Kostadinov R. , Maley C.C. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2011-06-01 00:00:00.0; 17(11), p. 3512-9.
EPub date: 2011-06-01 00:00:00.0.
PMID: 21498395
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Solving the puzzle of metastasis: the evolution of cell migration in neoplasms.
Authors: Chen J. , Sprouffske K. , Huang Q. , Maley C.C. .
Source: Plos One, 2011-04-27 00:00:00.0; 6(4), p. e17933.
EPub date: 2011-04-27 00:00:00.0.
PMID: 21556134
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Peto's Paradox: evolution's prescription for cancer prevention.
Authors: Caulin A.F. , Maley C.C. .
Source: Trends In Ecology & Evolution, 2011 Apr; 26(4), p. 175-82.
PMID: 21296451
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Overlooking evolution: a systematic analysis of cancer relapse and therapeutic resistance research.
Authors: Aktipis C.A. , Kwan V.S. , Johnson K.A. , Neuberg S.L. , Maley C.C. .
Source: Plos One, 2011; 6(11), p. e26100.
PMID: 22125594
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Parental Investment Without Kin Recognition: Simple Conditional Rules For Parent-offspring Behavior
Authors: Aktipis C.A. , Fernandez-Duque E. .
Source: Behavioral Ecology And Sociobiology, 2010-12-22 00:00:00.0; 65(5), p. 1079-1091.
PMID: 21552348
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A comprehensive survey of clonal diversity measures in Barrett's esophagus as biomarkers of progression to esophageal adenocarcinoma.
Authors: Merlo L.M. , Shah N.A. , Li X. , Blount P.L. , Vaughan T.L. , Reid B.J. , Maley C.C. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2010 Nov; 3(11), p. 1388-97.
PMID: 20947487
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Theory for the evolution of diffusible external goods.
Authors: Driscoll W.W. , Pepper J.W. .
Source: Evolution; International Journal Of Organic Evolution, 2010 Sep; 64(9), p. 2682-7.
PMID: 20394658
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New models of neoplastic progression in Barrett's oesophagus.
Authors: Pavlov K. , Maley C.C. .
Source: Biochemical Society Transactions, 2010 Apr; 38(2), p. 331-6.
PMID: 20298178
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The role of genetic diversity in cancer.
Authors: Merlo L.M. , Maley C.C. .
Source: The Journal Of Clinical Investigation, 2010 Feb; 120(2), p. 401-3.
PMID: 20101092
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Life history trade-offs in cancer evolution.
Authors: Aktipis C.A. , Boddy A.M. , Gatenby R.A. , Brown J.S. , Maley C.C. .
Source: Nature Reviews. Cancer, 2013 12; 13(12), p. 883-92.
PMID: 24213474
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The spatio-temporal evolution of lymph node spread in early breast cancer.
Authors: Barry P. , Vatsiou A. , Spiteri I. , Nichol D. , Cresswell G.D. , Acar A. , Trahearn N.A. , Hrebien S. , Garcia-Murillas I. , Chkhaidze K. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2018-06-11 00:00:00.0; , .
EPub date: 2018-06-11 00:00:00.0.
PMID: 29891724
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Prediction of Occult Invasive Disease in Ductal Carcinoma in Situ Using Deep Learning Features.
Authors: Shi B. , Grimm L.J. , Mazurowski M.A. , Baker J.A. , Marks J.R. , King L.M. , Maley C.C. , Hwang E.S. , Lo J.Y. .
Source: Journal Of The American College Of Radiology : Jacr, 2018 Mar; 15(3 Pt B), p. 527-534.
EPub date: 2018-02-02 00:00:00.0.
PMID: 29398498
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Evolution of Barrett's esophagus through space and time at single-crypt and whole-biopsy levels.
Authors: Martinez P. , Mallo D. , Paulson T.G. , Li X. , Sanchez C.A. , Reid B.J. , Graham T.A. , Kuhner M.K. , Maley C.C. .
Source: Nature Communications, 2018-02-23 00:00:00.0; 9(1), p. 794.
EPub date: 2018-02-23 00:00:00.0.
PMID: 29476056
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Modeling the Subclonal Evolution of Cancer Cell Populations.
Authors: Chowell D. , Napier J. , Gupta R. , Anderson K.S. , Maley C.C. , Sayres M.A.W. .
Source: Cancer Research, 2018-02-01 00:00:00.0; 78(3), p. 830-839.
EPub date: 2017-11-29 00:00:00.0.
PMID: 29187407
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Cooperation and cheating as innovation: insights from cellular societies.
Authors: Aktipis A. , Maley C.C. .
Source: Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences, 2017-12-05 00:00:00.0; 372(1735), .
PMID: 29061894
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Peto's Paradox: how has evolution solved the problem of cancer prevention?
Authors: Tollis M. , Boddy A.M. , Maley C.C. .
Source: Bmc Biology, 2017-07-13 00:00:00.0; 15(1), p. 60.
EPub date: 2017-07-13 00:00:00.0.
PMID: 28705195
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Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer.
Authors: Lote H. , Spiteri I. , Ermini L. , Vatsiou A. , Roy A. , McDonald A. , Maka N. , Balsitis M. , Bose N. , Simbolo M. , et al. .
Source: Annals Of Oncology : Official Journal Of The European Society For Medical Oncology, 2017-06-01 00:00:00.0; 28(6), p. 1243-1249.
PMID: 28327965
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Genomic Instability in Cancer: Teetering on the Limit of Tolerance.
Authors: Andor N. , Maley C.C. , Ji H.P. .
Source: Cancer Research, 2017-05-01 00:00:00.0; 77(9), p. 2179-2185.
EPub date: 2017-05-01 00:00:00.0.
PMID: 28432052
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Natural Selection in Cancer Biology: From Molecular Snowflakes to Trait Hallmarks.
Authors: Fortunato A. , Boddy A. , Mallo D. , Aktipis A. , Maley C.C. , Pepper J.W. .
Source: Cold Spring Harbor Perspectives In Medicine, 2017-02-01 00:00:00.0; 7(2), .
EPub date: 2017-02-01 00:00:00.0.
PMID: 28148564
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Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study.
Authors: Timmer M.R. , Martinez P. , Lau C.T. , Westra W.M. , Calpe S. , Rygiel A.M. , Rosmolen W.D. , Meijer S.L. , Ten Kate F.J. , Dijkgraaf M.G. , et al. .
Source: Gut, 2016 Oct; 65(10), p. 1602-10.
PMID: 26104750
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Dynamic Clonal Equilibrium And Predetermined Cancer Risk In Barrett's Oesophagus
Authors: Martinez P. , Timmer M.R. , Lau C.T. , Calpe S. , Sancho-Serra M.C. , Straub D. , Baker A.M. , Meijer S.L. , Kate F.J. , Mallant-Hent R.C. , et al. .
Source: Nature Communications, 2016-08-19 00:00:00.0; 7, p. 12158.
PMID: 27538785
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Bulk Genotyping of Biopsies Can Create Spurious Evidence for Hetereogeneity in Mutation Content.
Authors: Kostadinov R. , Maley C.C. , Kuhner M.K. .
Source: Plos Computational Biology, 2016 Apr; 12(4), p. e1004413.
PMID: 27105344
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When (distant) relatives stay too long: implications for cancer medicine.
Authors: Chowell D. , Boddy A.M. , Mallo D. , Tollis M. , Maley C.C. .
Source: Genome Biology, 2016-02-24 00:00:00.0; 17, p. 34.
EPub date: 2016-02-24 00:00:00.0.
PMID: 26912072
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Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.
Authors: Andor N. , Graham T.A. , Jansen M. , Xia L.C. , Aktipis C.A. , Petritsch C. , Ji H.P. , Maley C.C. .
Source: Nature Medicine, 2016 Jan; 22(1), p. 105-13.
PMID: 26618723
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Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.
Authors: Abegglen L.M. , Caulin A.F. , Chan A. , Lee K. , Robinson R. , Campbell M.S. , Kiso W.K. , Schmitt D.L. , Waddell P.J. , Bhaskara S. , et al. .
Source: Jama, 2015-11-03 00:00:00.0; 314(17), p. 1850-60.
PMID: 26447779
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An ecological measure of immune-cancer colocalization as a prognostic factor for breast cancer.
Authors: Maley C.C. , Koelble K. , Natrajan R. , Aktipis A. , Yuan Y. .
Source: Breast Cancer Research : Bcr, 2015-09-22 00:00:00.0; 17(1), p. 131.
EPub date: 2015-09-22 00:00:00.0.
PMID: 26395345
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Assessment of Esophageal Adenocarcinoma Risk Using Somatic Chromosome Alterations in Longitudinal Samples in Barrett's Esophagus.
Authors: Li X. , Paulson T.G. , Galipeau P.C. , Sanchez C.A. , Liu K. , Kuhner M.K. , Maley C.C. , Self S.G. , Vaughan T.L. , Reid B.J. , et al. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2015 Sep; 8(9), p. 845-56.
PMID: 26130253
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Peto's paradox and the promise of comparative oncology.
Authors: Nunney L. , Maley C.C. , Breen M. , Hochberg M.E. , Schiffman J.D. .
Source: Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences, 2015-07-19 00:00:00.0; 370(1673), .
PMID: 26056361
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Cancer across the tree of life: cooperation and cheating in multicellularity.
Authors: Aktipis C.A. , Boddy A.M. , Jansen G. , Hibner U. , Hochberg M.E. , Maley C.C. , Wilkinson G.S. .
Source: Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences, 2015-07-19 00:00:00.0; 370(1673), .
PMID: 26056363
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Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis.
Authors: Caulin A.F. , Graham T.A. , Wang L.S. , Maley C.C. .
Source: Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences, 2015-07-19 00:00:00.0; 370(1673), .
PMID: 26056366
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Can oncology recapitulate paleontology? Lessons from species extinctions.
Authors: Walther V. , Hiley C.T. , Shibata D. , Swanton C. , Turner P.E. , Maley C.C. .
Source: Nature Reviews. Clinical Oncology, 2015 May; 12(5), p. 273-85.
PMID: 25687908
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Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia.
Authors: Paguirigan A.L. , Smith J. , Meshinchi S. , Carroll M. , Maley C. , Radich J.P. .
Source: Science Translational Medicine, 2015-04-01 00:00:00.0; 7(281), p. 281re2.
PMID: 25834112
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Classifying the evolutionary and ecological features of neoplasms.
Authors: Maley C.C. , Aktipis A. , Graham T.A. , Sottoriva A. , Boddy A.M. , Janiszewska M. , Silva A.S. , Gerlinger M. , Yuan Y. , Pienta K.J. , et al. .
Source: Nature Reviews. Cancer, 2017 10; 17(10), p. 605-619.
EPub date: 2017-09-15 00:00:00.0.
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