Asset Details
Do you wish to reserve the book?
LKB1 inactivation modulates chromatin accessibility to drive metastatic progression
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
LKB1 inactivation modulates chromatin accessibility to drive metastatic progression
Do you wish to request the book?
LKB1 inactivation modulates chromatin accessibility to drive metastatic progression
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
LKB1 inactivation modulates chromatin accessibility to drive metastatic progression
2021
Overview
Metastasis is the leading cause of cancer-related deaths and enables cancer cells to compromise organ function by expanding in secondary sites. Since primary tumours and metastases often share the same constellation of driver mutations, the mechanisms that drive their distinct phenotypes are unclear. Here we show that inactivation of the frequently mutated tumour suppressor gene
LKB1
(encoding liver kinase B1) has evolving effects throughout the progression of lung cancer, which leads to the differential epigenetic re-programming of early-stage primary tumours compared with late-stage metastases. By integrating genome-scale CRISPR–Cas9 screening with bulk and single-cell multi-omic analyses, we unexpectedly identify LKB1 as a master regulator of chromatin accessibility in lung adenocarcinoma primary tumours. Using an in vivo model of metastatic progression, we further show that loss of LKB1 activates the early endoderm transcription factor SOX17 in metastases and a metastatic-like sub-population of cancer cells within primary tumours. The expression of SOX17 is necessary and sufficient to drive a second wave of epigenetic changes in LKB1-deficient cells that enhances metastatic ability. Overall, our study demonstrates how the downstream effects of an individual driver mutation can change throughout cancer development, with implications for stage-specific therapeutic resistance mechanisms and the gene regulatory underpinnings of metastatic evolution.
Pierce et al perform genome-wide CRISPR screening and identify LKB1 as a regulator of chromatin accessibility and metastatic progression in lung cancer through a mechanism of SOX17-mediated epigenetic changes.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/106
/ 38
/ 38/91
/ 45/44
/ 64/60
/ 82/51
/ Adenocarcinoma - physiopathology
/ AMP-Activated Protein Kinases
/ Animals
/ Biomedical and Life Sciences
/ CRISPR
/ Endoderm
/ Female
/ Genomes
/ Humans
/ Kinases
/ Lung Neoplasms - physiopathology
/ Male
/ Mice
/ Mutation
/ Neoplasm Metastasis - genetics
/ Protein Serine-Threonine Kinases - genetics
/ Protein Serine-Threonine Kinases - physiology
/ SOXF Transcription Factors - metabolism
/ Tumors
