Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer
Abstract In early-stage estrogen receptor-positive (ER + ) breast cancer, resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) often involve a shift away from estrogen-driven proliferation. The nature and source of compensatory growth signals driving cancer proliferation remain unkno...
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| Format: | Article |
| Language: | English |
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Springer Nature
2025-05-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/s44320-025-00104-6 |
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| author | Jason I Griffiths Feng Chi Elena Farmaki Eric F Medina Patrick A Cosgrove Kimya L Karimi Jinfeng Chen Vince K Grolmusz Frederick R Adler Qamar J Khan Aritro Nath Jeffrey T Chang Andrea H Bild |
| author_facet | Jason I Griffiths Feng Chi Elena Farmaki Eric F Medina Patrick A Cosgrove Kimya L Karimi Jinfeng Chen Vince K Grolmusz Frederick R Adler Qamar J Khan Aritro Nath Jeffrey T Chang Andrea H Bild |
| author_sort | Jason I Griffiths |
| collection | DOAJ |
| description | Abstract In early-stage estrogen receptor-positive (ER + ) breast cancer, resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) often involve a shift away from estrogen-driven proliferation. The nature and source of compensatory growth signals driving cancer proliferation remain unknown but represent direct therapeutic targets of resistant cells. By analyzing single-cell RNA-sequencing data from serial biopsies of patient tumors, we elucidated compensatory growth signaling pathways activated in ET + CDK4/6i-resistant cancer cells, along with the intercellular growth signal communications within the tumor microenvironment. In most patient tumors, resistant cancer cells increased ERBB growth pathway activity during treatment, only partially through ERBB receptor upregulation. Concurrently, fibroblasts within the tumor increased ERBB ligand communication with cancer cells, as they differentiated to a proliferative and mesenchymal phenotype in response to TGF $$\beta$$ β signals from cancer cells. In vitro model systems demonstrated molecularly how therapy induces a mutualistic cycle of crosstalk between cancer cells and fibroblasts, fostering a growth factor-rich tumor microenvironment circumventing estrogen reliance. We show that ERBB inhibition can break this cancer-fibroblasts mutualism, targeting an acquired sensitivity of resistant cancer cells. |
| format | Article |
| id | doaj-art-e37e7ccbb4cb4c7b99ec431e1fdb4440 |
| institution | DOAJ |
| issn | 1744-4292 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-e37e7ccbb4cb4c7b99ec431e1fdb44402025-08-20T03:04:21ZengSpringer NatureMolecular Systems Biology1744-42922025-05-0121782585510.1038/s44320-025-00104-6Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancerJason I Griffiths0Feng Chi1Elena Farmaki2Eric F Medina3Patrick A Cosgrove4Kimya L Karimi5Jinfeng Chen6Vince K Grolmusz7Frederick R Adler8Qamar J Khan9Aritro Nath10Jeffrey T Chang11Andrea H Bild12Department of Medical Oncology & Therapeutics, City of Hope National Medical CenterDepartment of Medical Oncology & Therapeutics, City of Hope National Medical CenterDepartment of Medical Oncology & Therapeutics, City of Hope National Medical CenterDepartment of Medical Oncology & Therapeutics, City of Hope National Medical CenterDepartment of Medical Oncology & Therapeutics, City of Hope National Medical CenterDepartment of Medical Oncology & Therapeutics, City of Hope National Medical CenterDepartment of Medical Oncology & Therapeutics, City of Hope National Medical CenterDepartment of Medical Oncology & Therapeutics, City of Hope National Medical CenterDepartment of Mathematics, University of Utah 155 South 1400 EastDivision of Medical Oncology, Department of Internal Medicine, The University of Kansas Medical CenterDepartment of Medical Oncology & Therapeutics, City of Hope National Medical CenterDepartment of Integrative Biology and Pharmacology, School of Medicine, School of Biomedical Informatics, UT Health Science Center at HoustonDepartment of Medical Oncology & Therapeutics, City of Hope National Medical CenterAbstract In early-stage estrogen receptor-positive (ER + ) breast cancer, resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) often involve a shift away from estrogen-driven proliferation. The nature and source of compensatory growth signals driving cancer proliferation remain unknown but represent direct therapeutic targets of resistant cells. By analyzing single-cell RNA-sequencing data from serial biopsies of patient tumors, we elucidated compensatory growth signaling pathways activated in ET + CDK4/6i-resistant cancer cells, along with the intercellular growth signal communications within the tumor microenvironment. In most patient tumors, resistant cancer cells increased ERBB growth pathway activity during treatment, only partially through ERBB receptor upregulation. Concurrently, fibroblasts within the tumor increased ERBB ligand communication with cancer cells, as they differentiated to a proliferative and mesenchymal phenotype in response to TGF $$\beta$$ β signals from cancer cells. In vitro model systems demonstrated molecularly how therapy induces a mutualistic cycle of crosstalk between cancer cells and fibroblasts, fostering a growth factor-rich tumor microenvironment circumventing estrogen reliance. We show that ERBB inhibition can break this cancer-fibroblasts mutualism, targeting an acquired sensitivity of resistant cancer cells.https://doi.org/10.1038/s44320-025-00104-6Endocrine ResistanceCancer-fibroblast-mutualismERBB SignalingTME-communication |
| spellingShingle | Jason I Griffiths Feng Chi Elena Farmaki Eric F Medina Patrick A Cosgrove Kimya L Karimi Jinfeng Chen Vince K Grolmusz Frederick R Adler Qamar J Khan Aritro Nath Jeffrey T Chang Andrea H Bild Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer Molecular Systems Biology Endocrine Resistance Cancer-fibroblast-mutualism ERBB Signaling TME-communication |
| title | Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer |
| title_full | Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer |
| title_fullStr | Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer |
| title_full_unstemmed | Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer |
| title_short | Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer |
| title_sort | blocking cancer fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer |
| topic | Endocrine Resistance Cancer-fibroblast-mutualism ERBB Signaling TME-communication |
| url | https://doi.org/10.1038/s44320-025-00104-6 |
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