Loss of lkb1 and pten leads to lung squamous cell carcinoma with elevated pd-l1 expression

Chunxiao Xu; Christine M. Fillmore; Shohei Koyama; Hongbo Wu; Yanqiu Zhao; Zhao Chen; Grit S. Herter-Sprie; Esra A. Akbay; Jeremy H. Tchaicha; Abigail Altabef; Jacob B. Reibel; Zandra Walton; Hongbin Ji; Hideo Watanabe; Pasi A. Jänne; Diego H. Castrillon; Anil K. Rustgi; Adam J. Bass; Gordon J. Freeman; Robert F. Padera; Glenn Dranoff; Peter S. Hammerman; Carla F. Kim; Kwok Kin Wong

doi:10.1016/j.ccr.2014.03.033

Loss of lkb1 and pten leads to lung squamous cell carcinoma with elevated pd-l1 expression

Chunxiao Xu, Christine M. Fillmore, Shohei Koyama, Hongbo Wu, Yanqiu Zhao, Zhao Chen, Grit S. Herter-Sprie, Esra A. Akbay, Jeremy H. Tchaicha, Abigail Altabef, Jacob B. Reibel, Zandra Walton, Hongbin Ji, Hideo Watanabe, Pasi A. Jänne, Diego H. Castrillon, Anil K. Rustgi, Adam J. Bass, Gordon J. Freeman, Robert F. PaderaGlenn Dranoff, Peter S. Hammerman, Carla F. Kim, Kwok Kin Wong

Toxicology and Cancer Biology

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

303 Citations (SciVal)

Abstract

Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1⁺NGFR⁺ fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR⁺ cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.

Original language	English
Pages (from-to)	590-604
Number of pages	15
Journal	Cancer Cell
Volume	25
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2014.03.033
State	Published - May 12 2014

Bibliographical note

Funding Information:
We thank the Boston Children’s Hospital flow cytometry facility and members of the C.F.K. and Zon Labs for helpful discussions. This work was supported in part by the United Against Lung Cancer and the Susan Spooner Research Fund (to K.-K.W.); American Cancer Society Post-Doctoral Fellowship PF-12-151-01-DMC (to C.M.F.); a Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award (to S.K.); American Cancer Society Research Scholar grant RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O’Conner March of Dimes Starter Award, the Harvard Stem Cell Institute, and the Lung Cancer Research Foundation (to C.F.K.); the Cancer Prevention Research Institute of Texas (RP100550); and grants HL090136, HL100402, CA122794, CA140594, CA163896, CA166480, P0CA154303, CA098101, CA141576, CA137181, P0CA120964, CA143083, and CA163677 from the NIH.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

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

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10.1016/j.ccr.2014.03.033

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Xu, C., Fillmore, C. M., Koyama, S., Wu, H., Zhao, Y., Chen, Z., Herter-Sprie, G. S., Akbay, E. A., Tchaicha, J. H., Altabef, A., Reibel, J. B., Walton, Z., Ji, H., Watanabe, H., Jänne, P. A., Castrillon, D. H., Rustgi, A. K., Bass, A. J., Freeman, G. J., ... Wong, K. K. (2014). Loss of lkb1 and pten leads to lung squamous cell carcinoma with elevated pd-l1 expression. Cancer Cell, 25(5), 590-604. https://doi.org/10.1016/j.ccr.2014.03.033

@article{b2fb9d1677614007b4ac4c88ebf92459,

title = "Loss of lkb1 and pten leads to lung squamous cell carcinoma with elevated pd-l1 expression",

abstract = "Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1+NGFR+ fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR+ cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.",

author = "Chunxiao Xu and Fillmore, {Christine M.} and Shohei Koyama and Hongbo Wu and Yanqiu Zhao and Zhao Chen and Herter-Sprie, {Grit S.} and Akbay, {Esra A.} and Tchaicha, {Jeremy H.} and Abigail Altabef and Reibel, {Jacob B.} and Zandra Walton and Hongbin Ji and Hideo Watanabe and J{\"a}nne, {Pasi A.} and Castrillon, {Diego H.} and Rustgi, {Anil K.} and Bass, {Adam J.} and Freeman, {Gordon J.} and Padera, {Robert F.} and Glenn Dranoff and Hammerman, {Peter S.} and Kim, {Carla F.} and Wong, {Kwok Kin}",

note = "Funding Information: We thank the Boston Children{\textquoteright}s Hospital flow cytometry facility and members of the C.F.K. and Zon Labs for helpful discussions. This work was supported in part by the United Against Lung Cancer and the Susan Spooner Research Fund (to K.-K.W.); American Cancer Society Post-Doctoral Fellowship PF-12-151-01-DMC (to C.M.F.); a Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award (to S.K.); American Cancer Society Research Scholar grant RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O{\textquoteright}Conner March of Dimes Starter Award, the Harvard Stem Cell Institute, and the Lung Cancer Research Foundation (to C.F.K.); the Cancer Prevention Research Institute of Texas (RP100550); and grants HL090136, HL100402, CA122794, CA140594, CA163896, CA166480, P0CA154303, CA098101, CA141576, CA137181, P0CA120964, CA143083, and CA163677 from the NIH. ",

year = "2014",

month = may,

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doi = "10.1016/j.ccr.2014.03.033",

language = "English",

volume = "25",

pages = "590--604",

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Xu, C, Fillmore, CM, Koyama, S, Wu, H, Zhao, Y, Chen, Z, Herter-Sprie, GS, Akbay, EA, Tchaicha, JH, Altabef, A, Reibel, JB, Walton, Z, Ji, H, Watanabe, H, Jänne, PA, Castrillon, DH, Rustgi, AK, Bass, AJ, Freeman, GJ, Padera, RF, Dranoff, G, Hammerman, PS, Kim, CF & Wong, KK 2014, 'Loss of lkb1 and pten leads to lung squamous cell carcinoma with elevated pd-l1 expression', Cancer Cell, vol. 25, no. 5, pp. 590-604. https://doi.org/10.1016/j.ccr.2014.03.033

TY - JOUR

T1 - Loss of lkb1 and pten leads to lung squamous cell carcinoma with elevated pd-l1 expression

AU - Xu, Chunxiao

AU - Fillmore, Christine M.

AU - Koyama, Shohei

AU - Wu, Hongbo

AU - Zhao, Yanqiu

AU - Chen, Zhao

AU - Herter-Sprie, Grit S.

AU - Akbay, Esra A.

AU - Tchaicha, Jeremy H.

AU - Altabef, Abigail

AU - Reibel, Jacob B.

AU - Walton, Zandra

AU - Ji, Hongbin

AU - Watanabe, Hideo

AU - Jänne, Pasi A.

AU - Castrillon, Diego H.

AU - Rustgi, Anil K.

AU - Bass, Adam J.

AU - Freeman, Gordon J.

AU - Padera, Robert F.

AU - Dranoff, Glenn

AU - Hammerman, Peter S.

AU - Kim, Carla F.

AU - Wong, Kwok Kin

N1 - Funding Information: We thank the Boston Children’s Hospital flow cytometry facility and members of the C.F.K. and Zon Labs for helpful discussions. This work was supported in part by the United Against Lung Cancer and the Susan Spooner Research Fund (to K.-K.W.); American Cancer Society Post-Doctoral Fellowship PF-12-151-01-DMC (to C.M.F.); a Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award (to S.K.); American Cancer Society Research Scholar grant RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O’Conner March of Dimes Starter Award, the Harvard Stem Cell Institute, and the Lung Cancer Research Foundation (to C.F.K.); the Cancer Prevention Research Institute of Texas (RP100550); and grants HL090136, HL100402, CA122794, CA140594, CA163896, CA166480, P0CA154303, CA098101, CA141576, CA137181, P0CA120964, CA143083, and CA163677 from the NIH.

PY - 2014/5/12

Y1 - 2014/5/12

N2 - Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1+NGFR+ fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR+ cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.

AB - Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1+NGFR+ fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR+ cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.

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DO - 10.1016/j.ccr.2014.03.033

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AN - SCOPUS:84900393562

VL - 25

SP - 590

EP - 604

IS - 5

ER -

Loss of lkb1 and pten leads to lung squamous cell carcinoma with elevated pd-l1 expression

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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