Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer

Li Yun Ding; Ya Chin Hou; I. Ying Kuo; Ting Yi Hsu; Tsung Ching Tsai; Hsiu Wei Chang; Wei Yu Hsu; Chih Chieh Tsao; Chung Chen Tian; Po Shun Wang; Hao Chen Wang; Chung Ta Lee; Yi Ching Wang; Sheng Hsiang Lin; Michael W. Hughes; Woei Jer Chuang; Pei Jung Lu; Yan Shen Shan; Po Hsien Huang

doi:10.1186/s13148-020-00878-6

Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer

Li Yun Ding, Ya Chin Hou, I. Ying Kuo, Ting Yi Hsu, Tsung Ching Tsai, Hsiu Wei Chang, Wei Yu Hsu, Chih Chieh Tsao, Chung Chen Tian, Po Shun Wang, Hao Chen Wang, Chung Ta Lee, Yi Ching Wang, Sheng Hsiang Lin, Michael W. Hughes, Woei Jer Chuang, Pei Jung Lu, Yan Shen Shan, Po Hsien Huang

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Abstract

Background: Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). Results: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. Conclusion: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.

Original language	English
Article number	87
Journal	Clinical Epigenetics
Volume	12
Issue number	1
DOIs	https://doi.org/10.1186/s13148-020-00878-6
Publication status	Published - 2020 Jun 17

All Science Journal Classification (ASJC) codes

Molecular Biology
Genetics
Developmental Biology
Genetics(clinical)

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10.1186/s13148-020-00878-6

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Ding, L. Y., Hou, Y. C., Kuo, I. Y., Hsu, T. Y., Tsai, T. C., Chang, H. W., Hsu, W. Y., Tsao, C. C., Tian, C. C., Wang, P. S., Wang, H. C., Lee, C. T., Wang, Y. C., Lin, S. H., Hughes, M. W., Chuang, W. J., Lu, P. J., Shan, Y. S., & Huang, P. H. (2020). Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer. Clinical Epigenetics, 12(1), Article 87. https://doi.org/10.1186/s13148-020-00878-6

@article{369b1f7af58c4bb9975c59dc79161500,

title = "Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer",

abstract = "Background: Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). Results: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. Conclusion: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.",

author = "Ding, {Li Yun} and Hou, {Ya Chin} and Kuo, {I. Ying} and Hsu, {Ting Yi} and Tsai, {Tsung Ching} and Chang, {Hsiu Wei} and Hsu, {Wei Yu} and Tsao, {Chih Chieh} and Tian, {Chung Chen} and Wang, {Po Shun} and Wang, {Hao Chen} and Lee, {Chung Ta} and Wang, {Yi Ching} and Lin, {Sheng Hsiang} and Hughes, {Michael W.} and Chuang, {Woei Jer} and Lu, {Pei Jung} and Shan, {Yan Shen} and Huang, {Po Hsien}",

note = "Funding Information: This study was funded by a grant from the Ministry of Science and Technology (MOST 105-2320-B-006-018-MY3) awarded to PHH. This study was in part supported by Hsu-Yuan Education Foundation, Tainan, Taiwan. Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

month = jun,

day = "17",

doi = "10.1186/s13148-020-00878-6",

language = "English",

volume = "12",

journal = "Clinical Epigenetics",

issn = "1868-7075",

publisher = "Springer Verlag",

number = "1",

}

Ding, LY, Hou, YC, Kuo, IY, Hsu, TY, Tsai, TC, Chang, HW, Hsu, WY, Tsao, CC, Tian, CC, Wang, PS, Wang, HC, Lee, CT , Wang, YC , Lin, SH , Hughes, MW , Chuang, WJ , Lu, PJ , Shan, YS & Huang, PH 2020, 'Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer', Clinical Epigenetics, vol. 12, no. 1, 87. https://doi.org/10.1186/s13148-020-00878-6

TY - JOUR

T1 - Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer

AU - Ding, Li Yun

AU - Hou, Ya Chin

AU - Kuo, I. Ying

AU - Hsu, Ting Yi

AU - Tsai, Tsung Ching

AU - Chang, Hsiu Wei

AU - Hsu, Wei Yu

AU - Tsao, Chih Chieh

AU - Tian, Chung Chen

AU - Wang, Po Shun

AU - Wang, Hao Chen

AU - Lee, Chung Ta

AU - Wang, Yi Ching

AU - Lin, Sheng Hsiang

AU - Hughes, Michael W.

AU - Chuang, Woei Jer

AU - Lu, Pei Jung

AU - Shan, Yan Shen

AU - Huang, Po Hsien

N1 - Funding Information: This study was funded by a grant from the Ministry of Science and Technology (MOST 105-2320-B-006-018-MY3) awarded to PHH. This study was in part supported by Hsu-Yuan Education Foundation, Tainan, Taiwan. Publisher Copyright: © 2020 The Author(s).

PY - 2020/6/17

Y1 - 2020/6/17

N2 - Background: Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). Results: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. Conclusion: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.

AB - Background: Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). Results: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. Conclusion: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.

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UR - http://www.scopus.com/inward/citedby.url?scp=85086694585&partnerID=8YFLogxK

U2 - 10.1186/s13148-020-00878-6

DO - 10.1186/s13148-020-00878-6

M3 - Article

C2 - 32552862

AN - SCOPUS:85086694585

SN - 1868-7075

VL - 12

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

M1 - 87

ER -

Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer

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