Mechanisms of LKB1-mediated tumor suppression in vivo
Abstract/Contents
- Abstract
- Tumor suppressor genes govern critical barriers to tumor initiation and progression. Elucidating tumor suppressor pathways can aid in understanding how their inactivation derails normal cellular processes and identifying strategies to either counteract or exploit the molecular consequences. While cancer genomics can be leveraged to identify putative tumor suppressors, predicting upstream activators and downstream effectors on the basis of these datasets is oftentimes not straightforward. Molecular profiling and biochemical studies can uncover the spectrum of interactions that a tumor suppressor undergoes, some or all of which may be critical for tumor suppression. Ultimately, functional genomics studies provide an indispensable complementary function in that they enable the interrogation of the importance of various interactors within tumor suppressor networks. LKB1 is frequently inactivated in multiple human cancer types, and germline loss of LKB1 underlies the familial cancer susceptibility disorder Peutz--Jeghers syndrome. In lung adenocarcinoma, LKB1 has emerged as a critical tumor suppressor that is lost in 15% to 30% of cases. The inactivation of Lkb1 in vivo accelerates the growth and progression of oncogenic KRAS-driven lung tumors as well as expands the spectrum of histological subtypes that emerge. After nearly 15 years following this discovery, many consequences of LKB1 loss in lung tumors have been uncovered, but our understanding of the mechanism by which LKB1 constrains tumorigenesis remains incomplete. To identify factors engaged by LKB1 that are critical for tumor suppression in vivo, I employed complementary targeted and unbiased approaches using advanced genetic engineering techniques in vivo. First, using a CRISPR/Cas9-enabled mouse model of lung cancer, I uncovered members of the salt-inducible kinase (SIK) family as key tumor suppressors among the AMPK-related kinases, which are the canonical substrates of LKB1 kinase activity. Multiple parallels between Lkb1-deficient and Sik-targeted tumors were identified at the histological and transcriptional levels. Further, the expression of SIK-dependent genes changed accordingly within LKB1 mutant human lung adenocarcinomas as compared to wild-type, and SIK-dependent genes were regulated by LKB1 activity in vitro, thus underscoring the existence of an LKB1-SIK axis of tumor suppression. To capture the processes engaged by LKB1 in an unbiased manner in vivo, we generated an Lkb1XTR allele to allow for reversible inactivation of Lkb1. Restoration of Lkb1 in established lung tumors induced stable tumor stasis, activated of a series of putative C/EBP target genes, and reinforced alveolar type II epithelial cell (ATII) differentiation, which is lost as a consequence of Lkb1 inactivation. I show that the inactivation of C/ebp transcription factors elicits transcriptional changes that significantly yet incompletely overlap with Lkb1 loss, suggesting that LKB1 indirectly regulates C/EBP activity. Furthermore, I demonstrate that a defining factor of the ATII lineage, C/EBPα, is a tumor suppressor, suggesting that C/EBPα operates indirectly downstream of LKB1 to maintain ATII differentiation and constrain tumor growth.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Murray, Christopher William |
|---|---|
| Degree supervisor | Winslow, Monte |
| Thesis advisor | Winslow, Monte |
| Thesis advisor | Axelrod, Jeffrey (Jeffrey David) |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Oro, Anthony, 1958- |
| Degree committee member | Axelrod, Jeffrey (Jeffrey David) |
| Degree committee member | Brunet, Anne, 1972- |
| Degree committee member | Oro, Anthony, 1958- |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Christopher William Murray. |
|---|---|
| Note | Submitted to the Department of Cancer Biology. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/nj176md3672 |
Access conditions
- Copyright
- © 2021 by Christopher William Murray
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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