The investigation of mechanisms governing small cell lung cancer metastasis
Abstract/Contents
- Abstract
- Small cell lung cancer (SCLC) is a prevalent and almost uniformly lethal malignancy. One of the major factors that lead to the poor outcome of SCLC patients is the ability of cancer cells to leave the primary tumors and establish inoperable metastases. Thus, the molecular mechanism of metastasis is one of the major unanswered problems in tumor biology and an area of investigation highly pertinent to patient survival. Using genetically engineered mouse model of SCLC, we identified a global increase in chromatin accessibility in SCLC metastases compared to primary tumors. This striking chromatin opening is linked to the activity of the Nfib transcription factor, which controls the expression of metastatic gene programs likely via its action at gene distal regulatory elements. Nfib expression is necessary and sufficient for multiple steps of the metastatic cascade. This identification of widespread chromatin changes during SCLC metastasis reveals an unexpected global reprogramming of cancer cells and the resulting activated neuronal differentiation gene program can facilitate invasion and migration during metastatic progression. Unexpectedly, when we used an approach to specifically initiate SCLC in pulmonary neuroendocrine cells (which is thought to be the cell of origin of SCLC), we found that while the mice still developed metastatic SCLC, the metastases almost never expressed Nfib. Unbiased analyses of gene expression programs (RNA-seq) and chromatin structure (ATAC-seq) of cancer cells isolated from primary tumors and liver metastases from the two mouse models conclusively showed that metastatic progression of each subtype is molecularly distinct. Furthermore, our work investigates inter-tumoral heterogeneity at a new level and shows that tumors with identical histology but distinct molecular profiles evolve entirely different. Our data showed for the first time that the inter-tumoral heterogeneity is attributed to the identity of the cells-of-origin from which SCLC is initiated and this can further determine the evolution of primary tumors towards specific metastatic states.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2017 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Yang, Dian |
|---|---|
| Associated with | Stanford University, Cancer Biology Program. |
| Primary advisor | Sage, Julien |
| Primary advisor | Winslow, Monte |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Winslow, Monte |
| Thesis advisor | Giaccia, Amato J |
| Thesis advisor | Krasnow, Mark, 1956- |
| Advisor | Giaccia, Amato J |
| Advisor | Krasnow, Mark, 1956- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Dian Yang. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2017. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2017 by Dian Yang
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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