Li, Liu, Guo, and Zhang et al. employed a dual CRISPR-inhibitor and -activator functional Perturb-seq single-cell screening, coupled with in silico genomic analysis of patient-derived tumor and tumor-adjacent fibroblasts. An antagonistic relationship was identified between a pro-tumoral TGFβ-dependent myofibroblast program and an antitumoral IFN-I responsive program, which was mediated by ADAM12. Loss of fibroblast-specific ADAM12 enhanced IFN-I signaling and restricted TGFβ signaling, resulting in TME remodeling, enhanced CD8+ T cell numbers and function, and decreased tumor burden in multiple models, boostable by ICB.
Contributed by Katherine Turner
ABSTRACT: Clinical trials targeting cancer-associated fibroblasts (CAFs)-crucial pro-tumoral factors in cancer-have almost all failed. This may be ascribed to their intrinsic functional plasticity and the opaque regulatory circuits underlying their heterogeneous phenotypes within tumors. We address these by developing a systematic screening approach for patient-derived fibroblasts using complementary CRISPR interference (CRISPRi) and activation (CRISPRa)-based Perturb-seq. An anti-tumoral interferon (IFN)-I response-associated program is identified as the primary antagonism axis counteracting TGF-β-driven pro-tumoral myofibroblast activation. ADAM12 emerges as a molecular checkpoint mediating this relationship. Its ablation elicits IFN-I-responsive programs, reconfigures myofibroblast population structures into progenitor-like states, revitalizes T cell-based immune responses, and induces tumor rejection across various murine models. Further combined with human genomics data analysis, our findings position ADAM12 as a potential target for fibroblasts, paving the way for actionable therapeutic interventions.
Author Info: (1) Changping Laboratory, Beijing 102206, China; Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National
Author Info: (1) Changping Laboratory, Beijing 102206, China; Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China; Peking University Beijing-Tianjin-Hebei Biomedical Pioneering Innovation Center, Tianjin 300405, China. Electronic address: lijianan@pku.edu.cn. (2) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (3) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China; Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. (4) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (5) State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China. (6) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (7) Analytical Biosciences Limited, Beijing 100084, China. (8) Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China. (9) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China; Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing 400016, China. (10) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (11) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (12) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (13) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (14) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (15) Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China. (16) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (17) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (18) GeneX Health Co, Led, Beijing 100195, China. (19) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (20) Analytical Biosciences Limited, Beijing 100084, China; Peking University Beijing-Tianjin-Hebei Biomedical Pioneering Innovation Center, Tianjin 300405, China. (21) Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; Ninth School of Clinical Medicine, Peking University, Beijing 100038, China. (22) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. (23) State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China. Electronic address: jzx@pku.edu.cn. (24) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China. Electronic address: wangdf19@pku.edu.cn. (25) Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, National Key Laboratory of Metabolic Disorders and Esophageal Cancer Prevention and Treatment, Peking University, Beijing 100871, China; Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing 400016, China. Electronic address: zemin@pku.edu.cn.
