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Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity - RNA-seq of B16F10 lung melanoma murine models

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 TGFβ-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE278974 | GEO | 2025/12/16

REPOSITORIES: GEO

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Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity - scRNA-seq of murine KPC models

Project description: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 TGFβ-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.

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Molecular profiling of ADAM12+ MSCs in B16-OVA melanomas

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Adam12 and lnc015192 act as ceRNAs in breast cancer by regulating miR-34a

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