Tissue engineered 3D in vitro bone cancer models for elucidating drivers of cancer progression and drug discovery
Abstract/Contents
- Abstract
- Malignant bone tumors are aggressive neoplasms which can arise from bone tissue or as a result of metastasis. The most prevalent types of cancer, such as breast cancer and prostate cancer, preferentially metastasize to bone, yet the role of the bone niche in promoting cancer progression is poorly understood. Tissue engineering tools have the potential to bridge this knowledge gap by providing 3D in vitro platforms that can be specifically designed to mimic key properties of the bone niche. However, most 3D models to date have been designed to mimic soft tissue tumors, which lack the unique matrix and cellular compositions of the bone niche. Here, we present our work on engineering 3D models of osteosarcoma (OS), an aggressive pediatric bone cancer for which treatments have seen little progress in over 30 years. Using microribbon (µRB) scaffolds with bone-mimicking compositions, we evaluated the role of 3D culture and hydroxyapatite in OS signaling and drug response. Our findings reveal hydroxyapatite in 3D was critical to support retention of OS signaling and drug resistance similar to patient tissues and mouse orthotopic tumors. Integrating 3D PDX OS models with RNA sequencing, we identified a 3D-specific druggable target for OS which predicted in vivo drug response. Together, our results demonstrate the potential of 3D µRB models to serve as novel experimental tools to enable discovery of new therapies for OS which would otherwise be missed in 2D screens. Bone is the most frequent site of metastasis in breast and prostate cancer, yet why cancer cells preferentially metastasize to the bones remains unknown. Furthermore, there are currently no effective treatments for bone metastases, highlighting a critical need to elucidate the mechanisms underlying bone metastasis development and establish tools to facilitate the discovery of new therapies. To address this unmet need, we developed 3D in vitro models of breast cancer and prostate cancer metastasis to bone using spatially patterned biomaterials that mimic the in vivo cancer cell interface with bone tissues. Our data demonstrate that spatially patterned, 3D models recapitulate the preferential migration of cancer cells into bone, cancer aggressiveness, and drug response consistent with in vivo models. Importantly, we show that such 3D models can recapitulate cancer-induced dysregulation of bone remodeling, a key pathological outcome in patients which leads to significant morbidity and mortality. Lastly, we demonstrate the potential of integrating spatially patterned 3D models with single-cell RNA sequencing to identify key signaling drivers of cancer metastasis to bone. Taken together, our findings establish spatially patterned 3D in vitro bone metastasis models as a promising platform to elucidate bone metastasis biology and expedite drug discovery.
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 | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Gonzalez Diaz, Eva Carolina |
|---|---|
| Degree supervisor | Yang, Fan, (Bioengineering researcher and teacher) |
| Thesis advisor | Yang, Fan, (Bioengineering researcher and teacher) |
| Thesis advisor | Bhutani, Nidhi |
| Thesis advisor | Yang, Yunzhi Peter |
| Degree committee member | Bhutani, Nidhi |
| Degree committee member | Yang, Yunzhi Peter |
| Associated with | Stanford University, Department of Bioengineering |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Eva C. González Díaz. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/hm863cp6612 |
Access conditions
- Copyright
- © 2022 by Eva Carolina Gonzalez Diaz
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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