Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

ASCL1 promotes tumor progression through cell-autonomous signaling and immune modulation in a subset of lung adenocarcinoma

Miyashita, Naoya ; Horie, Masafumi ; Mikami, Yu ; Urushiyama, Hirokazu ; Fukuda, Kensuke ; Miyakawa, Kazuko ; Matsuzaki, Hirotaka ; Makita, Kosuke ; Morishita, Yasuyuki and Harada, Hiroaki , et al. (2020) In Cancer Letters 489. p.121-132
Abstract

The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8+, CD4+, CD20+,... (More)

The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ lymphocytes and CD163+ macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells. In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ASCL1, Chemokine, Immunotherapy, Lung adenocarcinoma, Neuroendocrine
in
Cancer Letters
volume
489
pages
12 pages
publisher
Elsevier
external identifiers
  • pmid:32534174
  • scopus:85087033543
ISSN
0304-3835
DOI
10.1016/j.canlet.2020.06.002
language
English
LU publication?
yes
id
10846bd8-290f-4165-9bd9-aef25f62ae84
date added to LUP
2020-07-07 09:40:30
date last changed
2024-03-04 22:41:54
@article{10846bd8-290f-4165-9bd9-aef25f62ae84,
  abstract     = {{<p>The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8<sup>+</sup>, CD4<sup>+</sup>, CD20<sup>+</sup>, and FOXP3<sup>+</sup> lymphocytes and CD163<sup>+</sup> macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells. In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity.</p>}},
  author       = {{Miyashita, Naoya and Horie, Masafumi and Mikami, Yu and Urushiyama, Hirokazu and Fukuda, Kensuke and Miyakawa, Kazuko and Matsuzaki, Hirotaka and Makita, Kosuke and Morishita, Yasuyuki and Harada, Hiroaki and Backman, Max and Lindskog, Cecilia and Brunnström, Hans and Micke, Patrick and Nagase, Takahide and Saito, Akira}},
  issn         = {{0304-3835}},
  keywords     = {{ASCL1; Chemokine; Immunotherapy; Lung adenocarcinoma; Neuroendocrine}},
  language     = {{eng}},
  pages        = {{121--132}},
  publisher    = {{Elsevier}},
  series       = {{Cancer Letters}},
  title        = {{ASCL1 promotes tumor progression through cell-autonomous signaling and immune modulation in a subset of lung adenocarcinoma}},
  url          = {{http://dx.doi.org/10.1016/j.canlet.2020.06.002}},
  doi          = {{10.1016/j.canlet.2020.06.002}},
  volume       = {{489}},
  year         = {{2020}},
}