KDM6A epigenetically regulates subtype plasticity in small cell lung cancer

Leslie Duplaquet; Yixiang Li; Matthew A. Booker; Yingtian Xie; Sarah Naomi Olsen; Radhika A. Patel; Deli Hong; Charlie Hatton; Thomas Denize; Emily Walton; Yasmin N. Laimon; Rong Li; Yijia Jiang; Roderick T. Bronson; Jackson Southard; Shuqiang Li; Sabina Signoretti; Xintao Qiu; Paloma Cejas; Scott A. Armstrong; Henry W. Long; Michael Y. Tolstorukov; Michael C. Haffner; Matthew G. Oser

doi:10.1038/s41556-023-01210-z

KDM6A epigenetically regulates subtype plasticity in small cell lung cancer

Leslie Duplaquet, Yixiang Li, Matthew A. Booker, Yingtian Xie, Sarah Naomi Olsen, Radhika A. Patel, Deli Hong, Charlie Hatton, Thomas Denize, Emily Walton, Yasmin N. Laimon, Rong Li, Yijia Jiang, Roderick T. Bronson, Jackson Southard, Shuqiang Li, Sabina Signoretti, Xintao Qiu, Paloma Cejas, Scott A. ArmstrongHenry W. Long, Michael Y. Tolstorukov, Michael C. Haffner, Matthew G. Oser

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

19 Scopus citations

Abstract

Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35–40% of human SCLCs.

Original language	English
Pages (from-to)	1346-1358
Number of pages	13
Journal	Nature Cell Biology
Volume	25
Issue number	9
DOIs	https://doi.org/10.1038/s41556-023-01210-z
State	Published - Sep 2023
Externally published	Yes

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Duplaquet, L., Li, Y., Booker, M. A., Xie, Y., Olsen, S. N., Patel, R. A., Hong, D., Hatton, C., Denize, T., Walton, E., Laimon, Y. N., Li, R., Jiang, Y., Bronson, R. T., Southard, J., Li, S., Signoretti, S., Qiu, X., Cejas, P., ... Oser, M. G. (2023). KDM6A epigenetically regulates subtype plasticity in small cell lung cancer. Nature Cell Biology, 25(9), 1346-1358. https://doi.org/10.1038/s41556-023-01210-z

@article{4365b9ae2efc49c0a4ab45cdc935575d,

title = "KDM6A epigenetically regulates subtype plasticity in small cell lung cancer",

abstract = "Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35–40% of human SCLCs.",

author = "Leslie Duplaquet and Yixiang Li and Booker, {Matthew A.} and Yingtian Xie and Olsen, {Sarah Naomi} and Patel, {Radhika A.} and Deli Hong and Charlie Hatton and Thomas Denize and Emily Walton and Laimon, {Yasmin N.} and Rong Li and Yijia Jiang and Bronson, {Roderick T.} and Jackson Southard and Shuqiang Li and Sabina Signoretti and Xintao Qiu and Paloma Cejas and Armstrong, {Scott A.} and Long, {Henry W.} and Tolstorukov, {Michael Y.} and Haffner, {Michael C.} and Oser, {Matthew G.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = sep,

doi = "10.1038/s41556-023-01210-z",

language = "English",

volume = "25",

pages = "1346--1358",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Research",

number = "9",

}

Duplaquet, L, Li, Y, Booker, MA, Xie, Y, Olsen, SN, Patel, RA, Hong, D, Hatton, C, Denize, T, Walton, E, Laimon, YN, Li, R, Jiang, Y, Bronson, RT, Southard, J, Li, S, Signoretti, S, Qiu, X, Cejas, P, Armstrong, SA, Long, HW, Tolstorukov, MY, Haffner, MC & Oser, MG 2023, 'KDM6A epigenetically regulates subtype plasticity in small cell lung cancer', Nature Cell Biology, vol. 25, no. 9, pp. 1346-1358. https://doi.org/10.1038/s41556-023-01210-z

TY - JOUR

T1 - KDM6A epigenetically regulates subtype plasticity in small cell lung cancer

AU - Duplaquet, Leslie

AU - Li, Yixiang

AU - Booker, Matthew A.

AU - Xie, Yingtian

AU - Olsen, Sarah Naomi

AU - Patel, Radhika A.

AU - Hong, Deli

AU - Hatton, Charlie

AU - Denize, Thomas

AU - Walton, Emily

AU - Laimon, Yasmin N.

AU - Li, Rong

AU - Jiang, Yijia

AU - Bronson, Roderick T.

AU - Southard, Jackson

AU - Li, Shuqiang

AU - Signoretti, Sabina

AU - Qiu, Xintao

AU - Cejas, Paloma

AU - Armstrong, Scott A.

AU - Long, Henry W.

AU - Tolstorukov, Michael Y.

AU - Haffner, Michael C.

AU - Oser, Matthew G.

PY - 2023/9

Y1 - 2023/9

N2 - Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35–40% of human SCLCs.

AB - Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35–40% of human SCLCs.

UR - http://www.scopus.com/inward/record.url?scp=85168083804&partnerID=8YFLogxK

U2 - 10.1038/s41556-023-01210-z

DO - 10.1038/s41556-023-01210-z

M3 - Article

C2 - 37591951

AN - SCOPUS:85168083804

SN - 1465-7392

VL - 25

SP - 1346

EP - 1358

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 9

ER -

KDM6A epigenetically regulates subtype plasticity in small cell lung cancer

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