Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer

• Published in: Molecular systems biology Vol. 21; no. 7; pp. 825 - 855
• Main Authors: Griffiths, Jason I, Chi, Feng, Farmaki, Elena, Medina, Eric F, Cosgrove, Patrick A, Karimi, Kimya L, Chen, Jinfeng, Grolmusz, Vince K, Adler, Frederick R, Khan, Qamar J, Nath, Aritro, Chang, Jeffrey T, Bild, Andrea H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.07.2025; Springer Nature
• Subjects: Antineoplastic Agents, Hormonal - pharmacology; Biomedical and Life Sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer-Associated Fibroblasts - drug effects; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cancer-fibroblast-mutualism; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Drug Resistance, Neoplasm - drug effects; EMBO03; EMBO09; Endocrine Resistance; ErbB Receptors - metabolism; ERBB Signaling; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Life Sciences; Protein Kinase Inhibitors - pharmacology; Signal Transduction - drug effects; Systems Biology; TME-communication; Tumor Microenvironment - drug effects; Cancer-fibroblast-mutualism; TME-communication; ERBB Signaling; Endocrine Resistance
• ISSN: 1744-4292; 1744-4292
• DOI: 10.1038/s44320-025-00104-6

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 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. Synopsis Serial single-cell RNA sequencing of estrogen receptor-positive (ER + ) breast tumors from multiple patient cohorts, combined with experimental analyses, uncovers molecular mechanisms of compensatory growth signaling that drive proliferation in endocrine +/- CDK4/6 inhibitor-resistant cancer cells. A shift to ERBB growth factor mediated proliferation away from estrogen signaling is observed in resistant cancer cells in most tumors during treatment, partially facilitated by ERBB receptor upregulation. Fibroblasts are stimulated by cancer cells exposed to endocrine therapy to differentiate and secrete ERBB ligands, which in turn crosstalk with ERBB receptors on cancer cells to drive growth. Mutualistic cancer-fibroblast crosstalk mechanisms, identified from patient samples, were verified across in vitro model systems, showing that ERBB growth factor-enrichment bypasses estrogen dependence. This cancer-fibroblast communication is blocked by pan-ERBB inhibitors, targeting an acquired sensitivity to overcome endocrine resistance. Serial single-cell RNA sequencing of estrogen receptor-positive (ER + ) breast tumors from multiple patient cohorts, combined with experimental analyses, uncovers molecular mechanisms of compensatory growth signaling that drives proliferation in endocrine +/- CDK4/6 inhibitor-resistant cancer cells.