Dual tumor suppressive and pro-oncogenic roles for the Notch signaling pathway in small cell lung cancer
Abstract/Contents
- Abstract
- Developmental pathways are frequently re-activated and implicated during tumorigenesis. During lung development, Notch signaling inhibits the formation of pulmonary neuroendocrine cells, which are the adult epithelial cells of origin for small cell lung cancer (SCLC), the most aggressive and lethal subtype of lung cancer. This inhibitory role of Notch in neuroendocrine differentiation suggested that Notch activity might be tumor suppressive in SCLC. Consistent with this, genomic studies revealed inactivating mutations in the NOTCH receptors in ~15-25% of SCLC tumors. Ectopic Notch activation also inhibited tumor initiation in a mouse model for SCLC, suppressed the proliferation of neuroendocrine SCLC cells in culture and induced a differentiation switch to a non-neuroendocrine cell fate. Surprisingly, however, we identified a subset (~25%) of cells (Notch+ cells) in SCLC tumors that activate endogenous Notch signaling. These cells are non-neuroendocrine, proliferate slower than the Notch-, neuroendocrine tumor cells and are generated from the neuroendocrine cells, thus establishing a level of intratumoral heterogeneity generated by the bulk tumor cells themselves. Notch+ cells promote the proliferation of neuroendocrine cells, and Notch inhibition cooperates with chemotherapy to inhibit SCLC growth. These data show that the Notch pathway can be both tumor suppressive and oncogenic in SCLC; Notch inhibits the proliferation and differentiation of neuroendocrine cells but also promotes their growth in a paracrine manner. Downstream of Notch, we identified Rest/Nrsf, a transcriptional repressor that typically acts to restrict the expression of neuronal genes, as a target of Notch that mediates its inhibition of neuroendocrine cell fate. Thus, the Notch pathway has complex roles in SCLC and is able to modulate both tumor growth as well as its neuroendocrine differentiation.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Lim, Jing Shan |
|---|---|
| Associated with | Stanford University, Cancer Biology Program. |
| Primary advisor | Sage, Julien |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Krasnow, Mark, 1956- |
| Thesis advisor | Rando, Thomas A |
| Thesis advisor | Sweet-Cordero, Eric |
| Advisor | Krasnow, Mark, 1956- |
| Advisor | Rando, Thomas A |
| Advisor | Sweet-Cordero, Eric |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Jing Shan Lim. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Jing Shan Lim
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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