Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors
Most anticancer therapies to date focus on druggable features of tumor epithelia. Despite the increasing repertoire of treatment options, patient responses remain varied. Moreover, tumor resistance and relapse remain persistent clinical challenges. These observations imply an incomplete understandin...
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| Format: | Journal Article |
| Language: | English |
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2019
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| Online Access: | https://hdl.handle.net/10356/90275 http://hdl.handle.net/10220/48495 |
| _version_ | 1826122757715263488 |
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| author | Chan, Jeremy Soon Kiat Sng, Ming Keat Teo, Zi Qiang Chong, Han Chung Twang, Jing Shun Tan, Nguan Soon |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Chan, Jeremy Soon Kiat Sng, Ming Keat Teo, Zi Qiang Chong, Han Chung Twang, Jing Shun Tan, Nguan Soon |
| author_sort | Chan, Jeremy Soon Kiat |
| collection | NTU |
| description | Most anticancer therapies to date focus on druggable features of tumor epithelia. Despite the increasing repertoire of treatment options, patient responses remain varied. Moreover, tumor resistance and relapse remain persistent clinical challenges. These observations imply an incomplete understanding of tumor heterogeneity. The tumor microenvironment is a major determinant of disease progression and therapy outcome. Cancer-associated fibroblasts (CAFs) are the dominant cell type within the reactive stroma of tumors. They orchestrate paracrine pro-tumorigenic signaling with adjacent tumor cells, thus exacerbating the hallmarks of cancer and accelerating tumor malignancy. Although CAF-derived soluble factors have been investigated for tumor stroma-directed therapy, the underlying transcriptional programs that enable the oncogenic functions of CAFs remain poorly understood. Nuclear receptors (NRs), a large family of ligand-responsive transcription factors, are pharmacologically viable targets for the suppression of CAF-facilitated oncogenesis. In this study, we defined the expression profiles of NRs in CAFs from clinical cutaneous squamous cell carcinoma (SCC) biopsies. We further identified a cluster of driver NRs in CAFs as important modifiers of CAF function with profound influence on cancer cell invasiveness, proliferation, drug resistance, energy metabolism and oxidative stress status. Importantly, guided by the NR profile of CAFs, retinoic acid receptor β and androgen receptor antagonists were identified for concurrent therapy with cisplatin, resulting in the inhibition of chemoresistance in recurred SCC:CAF xenografts. Our work demonstrates that treatments targeting both the tumor epithelia and the surrounding CAFs can extend the efficacy of conventional chemotherapy. |
| first_indexed | 2024-10-01T05:53:24Z |
| format | Journal Article |
| id | ntu-10356/90275 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:53:24Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/902752023-02-28T17:03:14Z Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors Chan, Jeremy Soon Kiat Sng, Ming Keat Teo, Zi Qiang Chong, Han Chung Twang, Jing Shun Tan, Nguan Soon School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Biological sciences Squamous Cell Carcinoma Cancer Microenvironment Most anticancer therapies to date focus on druggable features of tumor epithelia. Despite the increasing repertoire of treatment options, patient responses remain varied. Moreover, tumor resistance and relapse remain persistent clinical challenges. These observations imply an incomplete understanding of tumor heterogeneity. The tumor microenvironment is a major determinant of disease progression and therapy outcome. Cancer-associated fibroblasts (CAFs) are the dominant cell type within the reactive stroma of tumors. They orchestrate paracrine pro-tumorigenic signaling with adjacent tumor cells, thus exacerbating the hallmarks of cancer and accelerating tumor malignancy. Although CAF-derived soluble factors have been investigated for tumor stroma-directed therapy, the underlying transcriptional programs that enable the oncogenic functions of CAFs remain poorly understood. Nuclear receptors (NRs), a large family of ligand-responsive transcription factors, are pharmacologically viable targets for the suppression of CAF-facilitated oncogenesis. In this study, we defined the expression profiles of NRs in CAFs from clinical cutaneous squamous cell carcinoma (SCC) biopsies. We further identified a cluster of driver NRs in CAFs as important modifiers of CAF function with profound influence on cancer cell invasiveness, proliferation, drug resistance, energy metabolism and oxidative stress status. Importantly, guided by the NR profile of CAFs, retinoic acid receptor β and androgen receptor antagonists were identified for concurrent therapy with cisplatin, resulting in the inhibition of chemoresistance in recurred SCC:CAF xenografts. Our work demonstrates that treatments targeting both the tumor epithelia and the surrounding CAFs can extend the efficacy of conventional chemotherapy. MOE (Min. of Education, S’pore) Published version 2019-05-30T07:55:49Z 2019-12-06T17:44:34Z 2019-05-30T07:55:49Z 2019-12-06T17:44:34Z 2017 Journal Article Chan, J. S. K., Sng, M. K., Teo, Z. Q., Chong, H. C., Twang, J. S., & Tan, N. S. (2018). Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors. Oncogene, 37(2), 160-173. doi:10.1038/onc.2017.319 0950-9232 https://hdl.handle.net/10356/90275 http://hdl.handle.net/10220/48495 10.1038/onc.2017.319 en Oncogene © 2018 The Author(s) (Nature Publishing Group). This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ 14 p. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences Squamous Cell Carcinoma Cancer Microenvironment Chan, Jeremy Soon Kiat Sng, Ming Keat Teo, Zi Qiang Chong, Han Chung Twang, Jing Shun Tan, Nguan Soon Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors |
| title | Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors |
| title_full | Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors |
| title_fullStr | Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors |
| title_full_unstemmed | Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors |
| title_short | Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors |
| title_sort | targeting nuclear receptors in cancer associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors |
| topic | DRNTU::Science::Biological sciences Squamous Cell Carcinoma Cancer Microenvironment |
| url | https://hdl.handle.net/10356/90275 http://hdl.handle.net/10220/48495 |
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