Non-canonical hedgehog signaling mechanisms of resistance in basal cell carcinoma
Abstract/Contents
- Abstract
- Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We have identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGF-beta cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/ LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.
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 | Yao, Catherine Yao |
|---|---|
| Degree supervisor | Oro, Anthony, 1958- |
| Degree supervisor | Sage, Julien |
| Thesis advisor | Oro, Anthony, 1958- |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Jackson, Peter K. (Peter Kent) |
| Thesis advisor | Khavari, Paul A |
| Degree committee member | Jackson, Peter K. (Peter Kent) |
| Degree committee member | Khavari, Paul A |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Catherine Yao. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/sq121yh7441 |
Access conditions
- Copyright
- © 2021 by Catherine Yao Yao
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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