KRAS-dependent intercellular signaling organizes the tumor microenvironment
Abstract/Contents
- Abstract
- Cancer is amongst the leading cause of death in the world, with lung cancer being the leading cause of cancer related deaths. Over half a century of cancer research has revealed many key features of cancer, yet for many cancers we are no closer to treating cancer than the 1900s. Part of this has to do with the heterogeneity of tumors, where the genomic instability induces mutations causing heterogeneous population of cancer cells within one tumor. This would not be much of a problem if this was the only source of heterogeneity in a tumor, but research into the tumor microenvironment reveal the tumor landscape adds several degrees of complexity to tumors. The tumor microenvironment has rapidly gained attention in the cancer community, quickly moving to the forefront of cancer research. The intercellular signaling between cancer cells and its surrounding cells dictate microenvironment composition and tumor progression. Over a dozen different cell types are found in the tumor microenvironment and communicate with each other to create a stable environment for cancer. Much of this communication happens through signaling proteins secreted to the extracellular space. These secreted proteins have already been implicated in various tumor related functions such as tumor growth, angiogenesis, immunosuppression, and metastasis. Despite their importance, the composition of secreted protein in the tumor microenvironment and much of the secreted protein's function remain unknown. This is partly due to the difficulty of studying this set of protein as they are dispersed outside the cell. We expanded the understanding of cancer secreted proteins by profiling the secretome of NSCLC driven by the most prolific oncogene, KRAS, using data independent acquisition on Bruker's state-of-the-art mass spectrometer timsTOF Pro. We identify over 1000 proteins secreted by 27 NSCLC, of which 76 were significantly changed in response to KRAS inhibition. We produced these proteins and applied them to cells in various functional assays to characterize their function and reveal proteins involved in key tumor functions cell including proliferation and cell migration. We then examined signaling responses in the recipient cells by measuring global kinase activity changes in the responding cells using phosphoproteomic analysis and discovered the casein kinase 2 was upregulated in metastasis in response to cancer secreted proteins. We hope to apply our research to translational research, using combinatory treatment based off various points of vulnerability found in our study as therapy for cancer with hopes that we can eradicate this disease once and for all.
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 | Cheng, Ran |
|---|---|
| Degree supervisor | Jackson, Peter |
| Thesis advisor | Jackson, Peter |
| Thesis advisor | Dixon, Scott |
| Thesis advisor | Gozani, Or |
| Thesis advisor | Winslow, Monte |
| Degree committee member | Dixon, Scott |
| Degree committee member | Gozani, Or |
| Degree committee member | Winslow, Monte |
| Associated with | Stanford University, School of Humanities and Sciences |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Ran Cheng. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/wc363fm8773 |
Access conditions
- Copyright
- © 2023 by Ran Cheng
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