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Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE278990 | 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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Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity - RNA-seq of C57BL/6 murine models

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

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Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity - scRNA-seq of Adam12CKO Mouse Model CD45- cells

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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Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity

Project description:Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity

| PRJNA1169870 | ENA

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

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

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

Project description:Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity - scRNA-seq of co-injection murine models

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Project description:Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity - RNA-seq of C57BL/6 murine models

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

| PRJNA1169865 | ENA

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