MYC Synergizes with Activated BRAFV600E in Mouse Lung Tumor Development by Suppressing Senescence.
Tabor, Vedrana ; Bocci, Matteo LU
; Alikhani, Nyosha
; Kuiper, Raoul
and Larsson, Lars-Gunnar
(2014)
In Cancer Research
74(16).
p.4222-4229
- Abstract
- The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence - a major barrier imposed to tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether Myc has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen (TAM)-regulatable MycER, we show that TAM-induced activation of MYC accelerated the onset and increased the number and size of BRAFV600E-driven adenomas in a dose dependent manner, resulting in reduced survival. Further, MYC activation lead to reduced expression of the senescence markers p16INK4A, p21CIP1... (More)
- The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence - a major barrier imposed to tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether Myc has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen (TAM)-regulatable MycER, we show that TAM-induced activation of MYC accelerated the onset and increased the number and size of BRAFV600E-driven adenomas in a dose dependent manner, resulting in reduced survival. Further, MYC activation lead to reduced expression of the senescence markers p16INK4A, p21CIP1 and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki-67+ tumor cells. This suggests that MYC already early during tumor formation suppresses a BRAFV600E-induced senescence-like state. Initial activation of MYC followed by TAM withdrawal still resulted in an increased number of tumors and reduced survival. However, these tumors were of smaller size, showed increased expression of p16INK4A and p21CIP1 and reduced number of Ki-67+ cells, indicating that MYC inactivation restores BRAFV600E-induced senescence. Surprisingly, MYC activation did not promote adenoma to carcinoma progression. This suggests that senescence suppression by MYC is a discrete step in tumor development important for sustained tumor growth but preceding malignant transformation, and that additional oncogenic events are required for carcinoma development and metastasis. These findings contribute to our understanding of the neoplastic transformation process with implications for future treatment strategies. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4528387
- author
- Tabor, Vedrana
; Bocci, Matteo
LU
; Alikhani, Nyosha
; Kuiper, Raoul
and Larsson, Lars-Gunnar
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cancer Research
- volume
- 74
- issue
- 16
- pages
- 4222 - 4229
- publisher
- American Association for Cancer Research Inc.
- external identifiers
-
- pmid:24934810
- wos:000341186700003
- scopus:84905968843
- pmid:24934810
- ISSN
- 1538-7445
- DOI
- 10.1158/0008-5472.CAN-13-3234
- language
- English
- LU publication?
- yes
- id
- d30f06fd-df97-45eb-a490-c71a7044591f (old id 4528387)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/24934810?dopt=Abstract
- date added to LUP
- 2016-04-01 11:02:49
- date last changed
- 2023-04-18 21:44:27
@article{d30f06fd-df97-45eb-a490-c71a7044591f,
abstract = {{The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence - a major barrier imposed to tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether Myc has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen (TAM)-regulatable MycER, we show that TAM-induced activation of MYC accelerated the onset and increased the number and size of BRAFV600E-driven adenomas in a dose dependent manner, resulting in reduced survival. Further, MYC activation lead to reduced expression of the senescence markers p16INK4A, p21CIP1 and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki-67+ tumor cells. This suggests that MYC already early during tumor formation suppresses a BRAFV600E-induced senescence-like state. Initial activation of MYC followed by TAM withdrawal still resulted in an increased number of tumors and reduced survival. However, these tumors were of smaller size, showed increased expression of p16INK4A and p21CIP1 and reduced number of Ki-67+ cells, indicating that MYC inactivation restores BRAFV600E-induced senescence. Surprisingly, MYC activation did not promote adenoma to carcinoma progression. This suggests that senescence suppression by MYC is a discrete step in tumor development important for sustained tumor growth but preceding malignant transformation, and that additional oncogenic events are required for carcinoma development and metastasis. These findings contribute to our understanding of the neoplastic transformation process with implications for future treatment strategies.}},
author = {{Tabor, Vedrana and Bocci, Matteo and Alikhani, Nyosha and Kuiper, Raoul and Larsson, Lars-Gunnar}},
issn = {{1538-7445}},
language = {{eng}},
number = {{16}},
pages = {{4222--4229}},
publisher = {{American Association for Cancer Research Inc.}},
series = {{Cancer Research}},
title = {{MYC Synergizes with Activated BRAFV600E in Mouse Lung Tumor Development by Suppressing Senescence.}},
url = {{http://dx.doi.org/10.1158/0008-5472.CAN-13-3234}},
doi = {{10.1158/0008-5472.CAN-13-3234}},
volume = {{74}},
year = {{2014}},
}