Pericytes Modulate Third‐Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR‐Mutated Lung Cancer Cells Through IL32‐β5‐Integrin Paracrine Signaling
Abstract EGFR‐mutated lung cancer patients sometimes display restricted responses to third‐generation tyrosine kinase inhibitors (TKIs), potentially attributable to undervalued input from stromal cells, notably pericytes (PCs). The study shows that PCs isolated from EGFR‐mutated patients have a uniq...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202405130 |
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| author | Cheng Huang Xi Huang Xiaoyi Qiu Xiangzhan Kong Chunmiao Wu Xue Jiang Mingkang Yao Minghui Wang Liangping Su Cui Lv Ping‐Pui Wong |
| author_facet | Cheng Huang Xi Huang Xiaoyi Qiu Xiangzhan Kong Chunmiao Wu Xue Jiang Mingkang Yao Minghui Wang Liangping Su Cui Lv Ping‐Pui Wong |
| author_sort | Cheng Huang |
| collection | DOAJ |
| description | Abstract EGFR‐mutated lung cancer patients sometimes display restricted responses to third‐generation tyrosine kinase inhibitors (TKIs), potentially attributable to undervalued input from stromal cells, notably pericytes (PCs). The study shows that PCs isolated from EGFR‐mutated patients have a unique secretome profile, notably secreting IL32 and affecting signaling pathways and biological processes linked to TKI sensitivity. Clinical evidence, supported by single‐cell RNA sequencing and multiplex immunostaining of tumor tissues, confirms the presence of IL32‐expressing pericytes closely interacting with β5‐integrin‐expressing cancer cells in EGFR‐mutated patients, impacting therapeutic response and prognosis. Co‐culture and conditioned medium experiments demonstrate that PCs reduce TKI effectiveness in EGFR‐mutated cancer cells, a reversible phenomenon through silencing IL32 expression in PCs or depleting the IL32 receptor β5‐integrin on cancer cells, thereby restoring cancer cell sensitivity. Mechanistically, it is shown that YY1 signaling upregulates IL32 secretion in PCs, subsequently activating the β5‐integrin‐Src‐Akt pathway in EGFR‐mutated cancer cells, contributing to their TKI sensitivity. In animal studies, co‐injection of cancer cells with PCs compromises TKI effectiveness, independently of blood vessel functions, while inhibition of β5‐integrin restores tumor cell sensitivity. Overall, the findings highlight direct crosstalk between cancer cells and pericytes, impacting TKI sensitivity via IL32‐β5‐integrin paracrine signaling, proposing an enhanced therapeutic approach for EGFR‐mutated patients. |
| format | Article |
| id | doaj-art-124624bfeca340da8bf40159faa1c269 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-124624bfeca340da8bf40159faa1c2692025-08-20T01:59:00ZengWileyAdvanced Science2198-38442024-12-011146n/an/a10.1002/advs.202405130Pericytes Modulate Third‐Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR‐Mutated Lung Cancer Cells Through IL32‐β5‐Integrin Paracrine SignalingCheng Huang0Xi Huang1Xiaoyi Qiu2Xiangzhan Kong3Chunmiao Wu4Xue Jiang5Mingkang Yao6Minghui Wang7Liangping Su8Cui Lv9Ping‐Pui Wong10Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaClinical Biobank Center Zhujiang Hospital Southern Medical University Guangzhou 510280 ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 ChinaAbstract EGFR‐mutated lung cancer patients sometimes display restricted responses to third‐generation tyrosine kinase inhibitors (TKIs), potentially attributable to undervalued input from stromal cells, notably pericytes (PCs). The study shows that PCs isolated from EGFR‐mutated patients have a unique secretome profile, notably secreting IL32 and affecting signaling pathways and biological processes linked to TKI sensitivity. Clinical evidence, supported by single‐cell RNA sequencing and multiplex immunostaining of tumor tissues, confirms the presence of IL32‐expressing pericytes closely interacting with β5‐integrin‐expressing cancer cells in EGFR‐mutated patients, impacting therapeutic response and prognosis. Co‐culture and conditioned medium experiments demonstrate that PCs reduce TKI effectiveness in EGFR‐mutated cancer cells, a reversible phenomenon through silencing IL32 expression in PCs or depleting the IL32 receptor β5‐integrin on cancer cells, thereby restoring cancer cell sensitivity. Mechanistically, it is shown that YY1 signaling upregulates IL32 secretion in PCs, subsequently activating the β5‐integrin‐Src‐Akt pathway in EGFR‐mutated cancer cells, contributing to their TKI sensitivity. In animal studies, co‐injection of cancer cells with PCs compromises TKI effectiveness, independently of blood vessel functions, while inhibition of β5‐integrin restores tumor cell sensitivity. Overall, the findings highlight direct crosstalk between cancer cells and pericytes, impacting TKI sensitivity via IL32‐β5‐integrin paracrine signaling, proposing an enhanced therapeutic approach for EGFR‐mutated patients.https://doi.org/10.1002/advs.202405130β5‐integrinnon‐small cell lung cancerpericytestyrosine kinase inhibitor sensitivity |
| spellingShingle | Cheng Huang Xi Huang Xiaoyi Qiu Xiangzhan Kong Chunmiao Wu Xue Jiang Mingkang Yao Minghui Wang Liangping Su Cui Lv Ping‐Pui Wong Pericytes Modulate Third‐Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR‐Mutated Lung Cancer Cells Through IL32‐β5‐Integrin Paracrine Signaling Advanced Science β5‐integrin non‐small cell lung cancer pericytes tyrosine kinase inhibitor sensitivity |
| title | Pericytes Modulate Third‐Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR‐Mutated Lung Cancer Cells Through IL32‐β5‐Integrin Paracrine Signaling |
| title_full | Pericytes Modulate Third‐Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR‐Mutated Lung Cancer Cells Through IL32‐β5‐Integrin Paracrine Signaling |
| title_fullStr | Pericytes Modulate Third‐Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR‐Mutated Lung Cancer Cells Through IL32‐β5‐Integrin Paracrine Signaling |
| title_full_unstemmed | Pericytes Modulate Third‐Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR‐Mutated Lung Cancer Cells Through IL32‐β5‐Integrin Paracrine Signaling |
| title_short | Pericytes Modulate Third‐Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR‐Mutated Lung Cancer Cells Through IL32‐β5‐Integrin Paracrine Signaling |
| title_sort | pericytes modulate third generation tyrosine kinase inhibitor sensitivity in egfr mutated lung cancer cells through il32 β5 integrin paracrine signaling |
| topic | β5‐integrin non‐small cell lung cancer pericytes tyrosine kinase inhibitor sensitivity |
| url | https://doi.org/10.1002/advs.202405130 |
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