Evolution of esophageal adenocarcinoma from precursor lesion stem cells

Wa Xian; Shan Wang; Jingzhong Xie; Yusuke Yamamoto; Melina Khorrami; Yanting Zhang; Raul Caballero Montes; Caycel Desales; Melika Khorrami; Zaal Mory; Ashley Hoffman; Amber Su; Crystal Nguyen; Peter J. A. Davies; Clifford Stephan; Shuang Pan; Wengen Wu; Yuxin Liu; Jeremy Siegelman; Rebecca E. Waters; William A. Ross; Shumei Song; Mark Metersky; David G. Beer; Christopher P. Crum; Alexander J. Stewart; Matthew Vincent; Richard Russell; Robert A. Izard; Khek Yu Ho; Jack Hung-Sen Lai; William W. Bachovchin; Jaffer A. Ajani; Frank D. McKeon

doi:10.1053/j.gastro.2025.02.032

Evolution of esophageal adenocarcinoma from precursor lesion stem cells

Wa Xian
, Shan Wang
, Jingzhong Xie
, Yusuke Yamamoto
, Melina Khorrami
, Yanting Zhang
, Raul Caballero Montes
, Caycel Desales
, Melika Khorrami
, Zaal Mory
, Ashley Hoffman
, Amber Su
, Crystal Nguyen
, Peter J. A. Davies
, Clifford Stephan
, Shuang Pan
, Wengen Wu
, Yuxin Liu
, Jeremy Siegelman
, Rebecca E. Waters

William A. Ross, Shumei Song, Mark Metersky, David G. Beer, Christopher P. Crum, Alexander J. Stewart, Matthew Vincent, Richard Russell, Robert A. Izard, Khek Yu Ho, Jack Hung-Sen Lai, William W. Bachovchin, Jaffer A. Ajani, Frank D. McKeon^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background & Aims

Metastatic cancers arise from a decades-long succession of increasingly virulent precursor lesions, each of which represents prospective targets for therapeutic intervention. This evolutionary process has been particularly vivid in esophageal adenocarcinoma (EAC), as this cancer and associated precursor lesions, including Barrett's esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), coexist in an accessible, 2-dimensional pattern in esophageal mucosa. Given the durability of these precursor lesions, it is likely that they, like EAC, rely on stem cells for their regenerative growth. To assess the role of stem cells in the evolution of EAC, we apply technology that selectively clones stem cells from the gastrointestinal tract to patient-matched endoscopic biopsies from each of the precursor lesions implicated in EAC.

Methods
Histologically validated, endoscopic biopsy series including EAC, HGD, LGD, BE, and normal esophageal mucosa were obtained from patients presenting with EAC. Rare (1:1000) cells from each of these lesions proved clonogenic and were assessed by in vitro differentiation, tumorigenicity in mice, and by molecular genetics.

Results
Each of the lesions in the evolution of EAC possesses a discrete set of clonogenic cells marked by immaturity, enormous proliferative potential, and lesion-specific differentiation fate. DNA sequencing of these clones reveals intralesional heterogeneity and clonal resolution of the mutation progression within a given patient from BE, LGD, HGD, and EAC. High-throughput chemical screens against BE stem cells reveal drug combinations that are similarly effective against stem cells of LGD, HGD, and EAC.

Conclusions
All lesions in the evolution of EAC possess discrete populations of stem cells that are potential therapeutic targets.

Original language	English
Pages (from-to)	277-293
Number of pages	17
Journal	Gastroenterology
Volume	169
Issue number	2
Early online date	14 Mar 2025
DOIs	https://doi.org/10.1053/j.gastro.2025.02.032
Publication status	Published - 1 Aug 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Barrett's esophagus
Cancer stem cells
Precursor lesions
Cancer evolution
Intratumor heterogeneity

Access to Document

10.1053/j.gastro.2025.02.032Licence: CC BY

Xian_2025_Gastroenterology_Evolution-esophageal-adenocarcinoma_CC
© 2025 The Author(s). This is an open access article distributed under the terms of the Creative Commons CC-BY license (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Final published version, 7.43 MBLicence: CC BY

Handle.net

Persistent link to portal record

Cite this

Xian, W., Wang, S., Xie, J., Yamamoto, Y., Khorrami, M., Zhang, Y., Montes, R. C., Desales, C., Khorrami, M., Mory, Z., Hoffman, A., Su, A., Nguyen, C., Davies, P. J. A., Stephan, C., Pan, S., Wu, W., Liu, Y., Siegelman, J., ... McKeon, F. D. (2025). Evolution of esophageal adenocarcinoma from precursor lesion stem cells. Gastroenterology, 169(2), 277-293. https://doi.org/10.1053/j.gastro.2025.02.032

@article{62aeed73e655487185b1e53100890494,

title = "Evolution of esophageal adenocarcinoma from precursor lesion stem cells",

abstract = "Background \& Aims Metastatic cancers arise from a decades-long succession of increasingly virulent precursor lesions, each of which represents prospective targets for therapeutic intervention. This evolutionary process has been particularly vivid in esophageal adenocarcinoma (EAC), as this cancer and associated precursor lesions, including Barrett's esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), coexist in an accessible, 2-dimensional pattern in esophageal mucosa. Given the durability of these precursor lesions, it is likely that they, like EAC, rely on stem cells for their regenerative growth. To assess the role of stem cells in the evolution of EAC, we apply technology that selectively clones stem cells from the gastrointestinal tract to patient-matched endoscopic biopsies from each of the precursor lesions implicated in EAC. Methods Histologically validated, endoscopic biopsy series including EAC, HGD, LGD, BE, and normal esophageal mucosa were obtained from patients presenting with EAC. Rare (1:1000) cells from each of these lesions proved clonogenic and were assessed by in vitro differentiation, tumorigenicity in mice, and by molecular genetics. Results Each of the lesions in the evolution of EAC possesses a discrete set of clonogenic cells marked by immaturity, enormous proliferative potential, and lesion-specific differentiation fate. DNA sequencing of these clones reveals intralesional heterogeneity and clonal resolution of the mutation progression within a given patient from BE, LGD, HGD, and EAC. High-throughput chemical screens against BE stem cells reveal drug combinations that are similarly effective against stem cells of LGD, HGD, and EAC. Conclusions All lesions in the evolution of EAC possess discrete populations of stem cells that are potential therapeutic targets.",

keywords = "Barrett's esophagus, Cancer stem cells, Precursor lesions, Cancer evolution, Intratumor heterogeneity",

author = "Wa Xian and Shan Wang and Jingzhong Xie and Yusuke Yamamoto and Melina Khorrami and Yanting Zhang and Montes, \{Raul Caballero\} and Caycel Desales and Melika Khorrami and Zaal Mory and Ashley Hoffman and Amber Su and Crystal Nguyen and Davies, \{Peter J. A.\} and Clifford Stephan and Shuang Pan and Wengen Wu and Yuxin Liu and Jeremy Siegelman and Waters, \{Rebecca E.\} and Ross, \{William A.\} and Shumei Song and Mark Metersky and Beer, \{David G.\} and Crum, \{Christopher P.\} and Stewart, \{Alexander J.\} and Matthew Vincent and Richard Russell and Izard, \{Robert A.\} and Ho, \{Khek Yu\} and Lai, \{Jack Hung-Sen\} and Bachovchin, \{William W.\} and Ajani, \{Jaffer A.\} and McKeon, \{Frank D.\}",

note = "Funding: This work was supported by grants from the Cancer Prevention Research Institute of Texas (CPRIT; RR150104 to Wa Xian and RR150088 to Frank D. McKeon), the National Institutes of Health (1RO1CA272906 to Wa Xian, Jaffer A. Ajani, and Frank D. McKeon; 1R01CA241600–01, U24CA228550, 1R01DK115445–01A, and 1RO1-HL149678 to Frank D. McKeon and Wa Xian), the US Department of Defense (DOD) (WA81XWH2010755 and W81XWH-17-1-0123 to Wa Xian; W81XWH-19-1-0127 to Christopher P. Crum), the American Gastroenterological Association Research and Development Pilot Award in Technology (to Wa Xian), and a sponsored research grant from TractBio (000182799). Jaffer A. Ajani has received generous donations from the Caporella, Hyland, Sultan, Smith, Myers, Kevin, and Park families, as well as from the Stupid Strong Foundation and Gastric Cancer Foundation (V Foundation), John Armstrong Fund, Golfers Against Cancer, Zeus Immunology Research Fund, Anonymous Donor, and The University of Texas MD Anderson Cancer Center (Houston, Texas) multidisciplinary grant programs. Wa Xian and Frank D. McKeon are CPRIT Scholars for Cancer Research.",

year = "2025",

month = aug,

day = "1",

doi = "10.1053/j.gastro.2025.02.032",

language = "English",

volume = "169",

pages = "277--293",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "2",

}

Xian, W, Wang, S, Xie, J, Yamamoto, Y, Khorrami, M, Zhang, Y, Montes, RC, Desales, C, Khorrami, M, Mory, Z, Hoffman, A, Su, A, Nguyen, C, Davies, PJA, Stephan, C, Pan, S, Wu, W, Liu, Y, Siegelman, J, Waters, RE, Ross, WA, Song, S, Metersky, M, Beer, DG, Crum, CP, Stewart, AJ, Vincent, M, Russell, R, Izard, RA, Ho, KY, Lai, JH-S, Bachovchin, WW, Ajani, JA & McKeon, FD 2025, 'Evolution of esophageal adenocarcinoma from precursor lesion stem cells', Gastroenterology, vol. 169, no. 2, pp. 277-293. https://doi.org/10.1053/j.gastro.2025.02.032

TY - JOUR

T1 - Evolution of esophageal adenocarcinoma from precursor lesion stem cells

AU - Xian, Wa

AU - Wang, Shan

AU - Xie, Jingzhong

AU - Yamamoto, Yusuke

AU - Khorrami, Melina

AU - Zhang, Yanting

AU - Montes, Raul Caballero

AU - Desales, Caycel

AU - Khorrami, Melika

AU - Mory, Zaal

AU - Hoffman, Ashley

AU - Su, Amber

AU - Nguyen, Crystal

AU - Davies, Peter J. A.

AU - Stephan, Clifford

AU - Pan, Shuang

AU - Wu, Wengen

AU - Liu, Yuxin

AU - Siegelman, Jeremy

AU - Waters, Rebecca E.

AU - Ross, William A.

AU - Song, Shumei

AU - Metersky, Mark

AU - Beer, David G.

AU - Crum, Christopher P.

AU - Stewart, Alexander J.

AU - Vincent, Matthew

AU - Russell, Richard

AU - Izard, Robert A.

AU - Ho, Khek Yu

AU - Lai, Jack Hung-Sen

AU - Bachovchin, William W.

AU - Ajani, Jaffer A.

AU - McKeon, Frank D.

N1 - Funding: This work was supported by grants from the Cancer Prevention Research Institute of Texas (CPRIT; RR150104 to Wa Xian and RR150088 to Frank D. McKeon), the National Institutes of Health (1RO1CA272906 to Wa Xian, Jaffer A. Ajani, and Frank D. McKeon; 1R01CA241600–01, U24CA228550, 1R01DK115445–01A, and 1RO1-HL149678 to Frank D. McKeon and Wa Xian), the US Department of Defense (DOD) (WA81XWH2010755 and W81XWH-17-1-0123 to Wa Xian; W81XWH-19-1-0127 to Christopher P. Crum), the American Gastroenterological Association Research and Development Pilot Award in Technology (to Wa Xian), and a sponsored research grant from TractBio (000182799). Jaffer A. Ajani has received generous donations from the Caporella, Hyland, Sultan, Smith, Myers, Kevin, and Park families, as well as from the Stupid Strong Foundation and Gastric Cancer Foundation (V Foundation), John Armstrong Fund, Golfers Against Cancer, Zeus Immunology Research Fund, Anonymous Donor, and The University of Texas MD Anderson Cancer Center (Houston, Texas) multidisciplinary grant programs. Wa Xian and Frank D. McKeon are CPRIT Scholars for Cancer Research.

PY - 2025/8/1

Y1 - 2025/8/1

N2 - Background & Aims Metastatic cancers arise from a decades-long succession of increasingly virulent precursor lesions, each of which represents prospective targets for therapeutic intervention. This evolutionary process has been particularly vivid in esophageal adenocarcinoma (EAC), as this cancer and associated precursor lesions, including Barrett's esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), coexist in an accessible, 2-dimensional pattern in esophageal mucosa. Given the durability of these precursor lesions, it is likely that they, like EAC, rely on stem cells for their regenerative growth. To assess the role of stem cells in the evolution of EAC, we apply technology that selectively clones stem cells from the gastrointestinal tract to patient-matched endoscopic biopsies from each of the precursor lesions implicated in EAC. Methods Histologically validated, endoscopic biopsy series including EAC, HGD, LGD, BE, and normal esophageal mucosa were obtained from patients presenting with EAC. Rare (1:1000) cells from each of these lesions proved clonogenic and were assessed by in vitro differentiation, tumorigenicity in mice, and by molecular genetics. Results Each of the lesions in the evolution of EAC possesses a discrete set of clonogenic cells marked by immaturity, enormous proliferative potential, and lesion-specific differentiation fate. DNA sequencing of these clones reveals intralesional heterogeneity and clonal resolution of the mutation progression within a given patient from BE, LGD, HGD, and EAC. High-throughput chemical screens against BE stem cells reveal drug combinations that are similarly effective against stem cells of LGD, HGD, and EAC. Conclusions All lesions in the evolution of EAC possess discrete populations of stem cells that are potential therapeutic targets.

AB - Background & Aims Metastatic cancers arise from a decades-long succession of increasingly virulent precursor lesions, each of which represents prospective targets for therapeutic intervention. This evolutionary process has been particularly vivid in esophageal adenocarcinoma (EAC), as this cancer and associated precursor lesions, including Barrett's esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), coexist in an accessible, 2-dimensional pattern in esophageal mucosa. Given the durability of these precursor lesions, it is likely that they, like EAC, rely on stem cells for their regenerative growth. To assess the role of stem cells in the evolution of EAC, we apply technology that selectively clones stem cells from the gastrointestinal tract to patient-matched endoscopic biopsies from each of the precursor lesions implicated in EAC. Methods Histologically validated, endoscopic biopsy series including EAC, HGD, LGD, BE, and normal esophageal mucosa were obtained from patients presenting with EAC. Rare (1:1000) cells from each of these lesions proved clonogenic and were assessed by in vitro differentiation, tumorigenicity in mice, and by molecular genetics. Results Each of the lesions in the evolution of EAC possesses a discrete set of clonogenic cells marked by immaturity, enormous proliferative potential, and lesion-specific differentiation fate. DNA sequencing of these clones reveals intralesional heterogeneity and clonal resolution of the mutation progression within a given patient from BE, LGD, HGD, and EAC. High-throughput chemical screens against BE stem cells reveal drug combinations that are similarly effective against stem cells of LGD, HGD, and EAC. Conclusions All lesions in the evolution of EAC possess discrete populations of stem cells that are potential therapeutic targets.

KW - Barrett's esophagus

KW - Cancer stem cells

KW - Precursor lesions

KW - Cancer evolution

KW - Intratumor heterogeneity

U2 - 10.1053/j.gastro.2025.02.032

DO - 10.1053/j.gastro.2025.02.032

M3 - Article

C2 - 40090599

SN - 0016-5085

VL - 169

SP - 277

EP - 293

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -

Evolution of esophageal adenocarcinoma from precursor lesion stem cells

Abstract

UN SDGs

Keywords

Access to Document

Handle.net

Fingerprint

Cite this