Investigating genetic and cellular determinants of small cell lung cancer initiation and progression
Abstract/Contents
- Abstract
- Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer with poor response to therapy. While the recent approval of immunotherapy as a first-line treatment for extensive-stage SCLC patients has improved patient survival, there still exists a dearth of targeted therapy options for SCLC patients. To better address SCLC progression and resistance to therapy, a greater molecular understanding of the disease is needed. To this end, we developed a higher-throughput method to screen for drivers of SCLC initiation and progression in in vivo settings. Using this method, we identified TSC1 as a strong tumor suppressor of SCLC and demonstrated potential therapeutic benefit of mTOR inhibition in patients with TSC1 alteration and/or patients that present with mixed SCLC/giant cell carcinoma histology. Among other drivers, we also identified ARID1A and ARID1B as oncogenes in SCLC, suggesting an important role for the SWI/SNF complex in modulating SCLC disease state. While cGRP+ pulmonary neuroendocrine cells have traditionally been thought to be the cell-of-origin for SCLC, recent experiments using mice with various genetic backgrounds and findings that non-neuroendocrine subtypes of SCLC exist have challenged that assumption. Because cell-of-origin has been shown influence the genetic mechanisms SCLC co-opts for progression and metastasis, we tested several cell-of-origin candidates such as PCSK1+ neuroendocrine cells, K5+ basal cells, TERT+ progenitor cells, and endothelial cells. We demonstrate that PCSK1+ neuroendocrine cells can serve as cell-of-origin for SCLC, while the other cell types provide potential models for several other histopathology, such as pancreatic islet hyperplasia, adrenal medullary hyperplasia, and angiosarcoma.
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 | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Lee, Myung Chang |
|---|---|
| Degree supervisor | Sage, Julien |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Khavari, Paul A |
| Thesis advisor | Rankin, Erinn |
| Thesis advisor | Winslow, Monte |
| Degree committee member | Khavari, Paul A |
| Degree committee member | Rankin, Erinn |
| Degree committee member | Winslow, Monte |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Myung Chang Lee. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/yb394jn6710 |
Access conditions
- Copyright
- © 2023 by Myung Chang Lee
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...