Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression
Background: Cancer-associated fibroblasts (CAFs) promote tumor progression through extracellular matrix (ECM) remodeling and extensive communication with other cells in tumor microenvironment. However, most CAF-targeting strategies failed in clinical trials due to the heterogeneity of CAFs. Hence, w...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1121586/full |
| _version_ | 1797947051866062848 |
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| author | Jiayu Zhang Shiqi Lu Tong Lu Donghui Han Keying Zhang Lunbiao Gan Xinjie Wu Yu Li Xiaolong Zhao Zhengxuan Li Yajie Shen Sijun Hu Fa Yang Weihong Wen Weijun Qin |
| author_facet | Jiayu Zhang Shiqi Lu Tong Lu Donghui Han Keying Zhang Lunbiao Gan Xinjie Wu Yu Li Xiaolong Zhao Zhengxuan Li Yajie Shen Sijun Hu Fa Yang Weihong Wen Weijun Qin |
| author_sort | Jiayu Zhang |
| collection | DOAJ |
| description | Background: Cancer-associated fibroblasts (CAFs) promote tumor progression through extracellular matrix (ECM) remodeling and extensive communication with other cells in tumor microenvironment. However, most CAF-targeting strategies failed in clinical trials due to the heterogeneity of CAFs. Hence, we aimed to identify the cluster of tumor-promoting CAFs, elucidate their function and determine their specific membrane markers to ensure precise targeting.Methods: We integrated multiple single-cell RNA sequencing (scRNA-seq) datasets across different tumors and adjacent normal tissues to identify the tumor-promoting CAF cluster. We analyzed the origin of these CAFs by pseudotime analysis, and tried to elucidate the function of these CAFs by gene regulatory network analysis and cell-cell communication analysis. We also performed cell-type deconvolution analysis to examine the association between the proportion of these CAFs and patients’ prognosis in TCGA cancer cohorts, and validated that through IHC staining in clinical tumor tissues. In addition, we analyzed the membrane molecules in different fibroblast clusters, trying to identify the membrane molecules that were specifically expressed on these CAFs.Results: We found that COL11A1+ fibroblasts specifically exist in tumor tissues but not in normal tissues and named them cancer-specific fibroblasts (CSFs). We revealed that these CSFs were transformed from normal fibroblasts. CSFs represented a more activated CAF cluster and may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. High CSF proportion was associated with poor prognosis in bladder cancer (BCa) and lung adenocarcinoma (LUAD), and IHC staining of COL11A1 confirmed their specific expression in tumor stroma in clinical BCa samples. We also identified that CSFs specifically express the membrane molecules LRRC15, ITGA11, SPHK1 and FAP, which could distinguish CSFs from other fibroblasts.Conclusion: We identified that CSFs is a tumor specific cluster of fibroblasts, which are in active state, may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. Membrane molecules LRRC15, ITGA11, SPHK1 and FAP could be used as therapeutic targets for CSF-targeting cancer treatment. |
| first_indexed | 2024-04-10T21:20:39Z |
| format | Article |
| id | doaj.art-65ad3fe4fa73461e8e50cf74046d79e8 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T21:20:39Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-65ad3fe4fa73461e8e50cf74046d79e82023-01-20T04:58:08ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-01-011410.3389/fphar.2023.11215861121586Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progressionJiayu Zhang0Shiqi Lu1Tong Lu2Donghui Han3Keying Zhang4Lunbiao Gan5Xinjie Wu6Yu Li7Xiaolong Zhao8Zhengxuan Li9Yajie Shen10Sijun Hu11Fa Yang12Weihong Wen13Weijun Qin14Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaInstitute of Medical Research, Northwestern Polytechnical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaInstitute of Medical Research, Northwestern Polytechnical University, Xi’an, ChinaInstitute of Medical Research, Northwestern Polytechnical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaInstitute of Medical Research, Northwestern Polytechnical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaInstitute of Medical Research, Northwestern Polytechnical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaBackground: Cancer-associated fibroblasts (CAFs) promote tumor progression through extracellular matrix (ECM) remodeling and extensive communication with other cells in tumor microenvironment. However, most CAF-targeting strategies failed in clinical trials due to the heterogeneity of CAFs. Hence, we aimed to identify the cluster of tumor-promoting CAFs, elucidate their function and determine their specific membrane markers to ensure precise targeting.Methods: We integrated multiple single-cell RNA sequencing (scRNA-seq) datasets across different tumors and adjacent normal tissues to identify the tumor-promoting CAF cluster. We analyzed the origin of these CAFs by pseudotime analysis, and tried to elucidate the function of these CAFs by gene regulatory network analysis and cell-cell communication analysis. We also performed cell-type deconvolution analysis to examine the association between the proportion of these CAFs and patients’ prognosis in TCGA cancer cohorts, and validated that through IHC staining in clinical tumor tissues. In addition, we analyzed the membrane molecules in different fibroblast clusters, trying to identify the membrane molecules that were specifically expressed on these CAFs.Results: We found that COL11A1+ fibroblasts specifically exist in tumor tissues but not in normal tissues and named them cancer-specific fibroblasts (CSFs). We revealed that these CSFs were transformed from normal fibroblasts. CSFs represented a more activated CAF cluster and may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. High CSF proportion was associated with poor prognosis in bladder cancer (BCa) and lung adenocarcinoma (LUAD), and IHC staining of COL11A1 confirmed their specific expression in tumor stroma in clinical BCa samples. We also identified that CSFs specifically express the membrane molecules LRRC15, ITGA11, SPHK1 and FAP, which could distinguish CSFs from other fibroblasts.Conclusion: We identified that CSFs is a tumor specific cluster of fibroblasts, which are in active state, may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. Membrane molecules LRRC15, ITGA11, SPHK1 and FAP could be used as therapeutic targets for CSF-targeting cancer treatment.https://www.frontiersin.org/articles/10.3389/fphar.2023.1121586/fullcancer-associated fibroblastssingle-cell RNA sequencingtumor microenvironmentECM remodelingimmune response |
| spellingShingle | Jiayu Zhang Shiqi Lu Tong Lu Donghui Han Keying Zhang Lunbiao Gan Xinjie Wu Yu Li Xiaolong Zhao Zhengxuan Li Yajie Shen Sijun Hu Fa Yang Weihong Wen Weijun Qin Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression Frontiers in Pharmacology cancer-associated fibroblasts single-cell RNA sequencing tumor microenvironment ECM remodeling immune response |
| title | Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression |
| title_full | Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression |
| title_fullStr | Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression |
| title_full_unstemmed | Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression |
| title_short | Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression |
| title_sort | single cell analysis reveals the col11a1 fibroblasts are cancer specific fibroblasts that promote tumor progression |
| topic | cancer-associated fibroblasts single-cell RNA sequencing tumor microenvironment ECM remodeling immune response |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1121586/full |
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