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Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration

ABSTRACT: Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration

PROVIDER: PRJNA1046484 | ENA |

REPOSITORIES: ENA

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Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration

Project description:Acute pancreatitis-induced acinar-to-ductal metaplasia (ADM) involves global chromatin remodeling and contributes to normal tissue regeneration. Oncogenic KRAS hijacks this process to promote PDAC formation. Here we show that regeneration and KRASG12D-driven oncogenesis can be decoupled from tissue regeneration through a chromatin remodeler, SMARCA5. We show that SMARCA5 maintains KRASG12D-dependent chromatin accessibility at regions specifically required for malignancy, without affecting chromatin opening that occurs during normal regeneration. Without SMARCA5, regeneration can be restored in the presence of KRASG12D. Mechanistically, regeneration-related or malignancy-related chromatin remodeling activities occur in a time-sensitive manner. The activity of SMARCA5 is controlled spatiotemporally by transcription factor RUNX1, which only accumulates at sufficient levels with sustained MAPK signals. We further show that inhibition of the SMARCA5-containing NoRC complex specifically inhibits the growth of PDAC organoid but not that of normal tissue derived from patients.

2025-08-23 | PXD047272 | Pride

Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (RNA-Seq)

Project description:De-differentiation or trans-differentiation is a common response to injury in many tissues, and the processes predispose cells to cancer. Acute pancreatitis-induced acinar-to-ductal metaplasia (ADM) is similar to pancreatic ductal adenocarcinoma (PDAC) at both the chromatin level and gene expression level. Mutant KRAS induces chromatin remodeling activities required for both regeneration and tumorigenesis at the peak of ADM, and it blocks regeneration. We show that chromatin remodeler SMARCA5 (SNF2H) can promotes the regeneration defects caused by mutant KRAS by maintaining chromatin accessibility at regions specifically required for malignancy. Mechanistically, regeneration-related chromatin remodeling activities are shared between wild-type and mutant KRAS and they occur very early upon pancreatitis, while the malignancy-related chromatin regions become accessible much later. The activity of SMARCA5 is controlled spatiotemporally by transcription factor RUNX1, which is only accumulated at sufficient levels at late ADM lock-in stage. Finally, we show that the malignancy regulation activity of SMARCA5 is different from its general function in CTCF recruitment. In summary, we have identified a specific function of a general chromatin remodeler that is precisely controlled during acinar cell trans-differentiation to separate malignancy from tissue regeneration.

2025-07-01 | GSE248947 | GEO

Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (CUT&Tag)

2025-07-01 | GSE248945 | GEO

Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (CUT&RUN)

2025-07-01 | GSE248944 | GEO

Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (ChIP-Seq)

2025-07-01 | GSE248943 | GEO

Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (ATAC-Seq)

2025-07-01 | GSE248942 | GEO

Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (ChIP-Seq)

Project description:Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (ChIP-Seq)

| PRJNA1046492 | ENA

Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (CUT&Tag)

Project description:Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (CUT&Tag)

| PRJNA1046490 | ENA

Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (RNA-Seq)

Project description:Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (RNA-Seq)

| PRJNA1046497 | ENA

Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (ATAC-Seq)

Project description:Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration (ATAC-Seq)

| PRJNA1046488 | ENA

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