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P38α Orchestrates BRAFV600E-Melanoma Progression and Immunotherapy Response via Tumor Fitness and Immune Microenvironment Modulation

ABSTRACT: Understanding how tumor cells shape the tumor microenvironment (TME) and evade the host immune response is critical for developing novel therapeutic combinations. In this study, we identify tumor cell p38α as a therapeutic target that restricts antitumor immunity and contributes to resistance against immune-checkpoint inhibitors (ICIs). Genetic analyses of mouse and human melanomas reveal alterations in the MAPK-stress pathway, including upregulation of MAPK14. We demonstrate a dual role for p38α in UVB-induced BrafV600E melanoma, acting as a tumor suppressor during melanocyte transformation but promoting melanoma growth and progression. Mechanistically, p38α impairs cytotoxic immune responses, modulates immunosuppressive myeloid cells, and regulates inflammatory mediators that shape the TME. Notably, loss or inhibition of p38α enhances and restores responsiveness to PD-1 blockade, leading to complete tumor regressions and increased overall survival, while a p38α-associated gene signature correlates with favorable immunotherapy outcomes in melanoma patients, underscoring its translational relevance.

ORGANISM(S): Mus musculus

PROVIDER: GSE330846 | GEO | 2026/08/18

REPOSITORIES: GEO

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Transcriptional profiles of UVB-induced BRAFV600E mouse melanoma tumors with or without p38α (whole tumor, CD45⁺ and CD45⁻ populations)

Project description:The role of tumor-intrinsic signaling pathways in shaping the anti-tumor immune response remains poorly defined. Using a conditional UVB-induced melanoma mouse model (Tyr::CreERT2;BrafCA/CA and Tyr::CreERT2;BrafCA/CA;p38αlox/lox), we investigated how the loss of the stress kinase p38α in melanocytes affects tumor development and immune evasion. We performed transcriptional profiling on whole tumors, as well as on separated CD45⁺ (immune) and CD45⁻ (tumor/stroma) populations. Comparative transcriptomic analysis revealed that p38α deficiency reprograms both tumor and immune compartments, promoting immune-stimulatory gene expression and reducing immunosuppressive and pro-tumorigenic signals. Many of the genes modulated by p38α loss are associated with an improved response to immune checkpoint blockade in melanoma patients. These findings underscore the role of p38α in shaping an immunosuppressive and pro-tumorigenic microenvironment, suggesting p38α as a potential target to enhance the efficacy of immunotherapy. We used microarrays to profile the global gene expression landscape of UVB-induced melanoma tumors and uncovered transcriptional changes driven by the loss of p38α specifically in tumor cells, which extended to reshape gene expression in both the immune (CD45⁺) and tumor/stroma (CD45⁻) compartments.

2026-08-07 | GSE303314 | GEO

Expression and functional validation of new p38α transcriptional targets in tumorigenesis

Project description:p38α MAP kinase plays an important tumor suppressor role, which is mediated by both its negative effect on cell proliferation and its pro-apoptotic activity. Surprisingly, most tumor suppressor mechanisms coordinated by p38α have been reported to occur at the post- translational level. This contrasts with the important role of p38α in the regulation of transcription and the profound changes in gene expression that normally occur during tumorigenesis. We have analyzed whole genome expression profiles of Ras-transformed wild- type and p38α-deficient cells and have identified 202 genes that are potentially regulated by p38α in transformed cells. Expression analysis has confirmed the regulation of these genes by p38α in tumors, and functional validation has identified several of them as likely mediators of the tumor suppressor effect of p38α on Ras-induced transformation. Interestingly, about 10% of the genes that are negatively regulated by p38α in transformed cells contribute to EGF receptor signalling. Our results suggest that inhibition of EGF receptor signalling by transcriptional targets of p38α is an important function of this signalling pathway in the context of tumor suppression. We have investigated how transcriptional regulation contributes to the tumor suppressor effect of p38α, by comparing whole-genome expression profiles of wild-type (WT) and p38α- deficient (p38α-/-) mouse embryo fibroblasts (MEFs) expressing oncogenic H-RasG12V

2011-11-23 | E-GEOD-26762 | biostudies-arrayexpress

p38α Orchestrates BRAFV600E-Melanoma Progression and Immunotherapy Response via Tumor Fitness and Immune Microenvironment Modulation

Project description:p38α Orchestrates BRAFV600E-Melanoma Progression and Immunotherapy Response via Tumor Fitness and Immune Microenvironment Modulation

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p38 blockade reverses the immune suppressive microenvironment in metastatic breast cancer

Project description:The study investigated the role of p38α in regulating the outcome of the immune-tumor interaction in metastatic breast cancer. Single-cell transcriptomic analysis of the immune-TME showed that pharmacological p38 inhibition (p38i) or tumor-specific inactivation of p38α by CRISPR/Cas9 (p38KO) resulted in a less exhausted and more activated CD8+ T cell phenotype. Moreover, the myeloid cells in the TME exhibited reduced expression of immune-suppressive factors and chemotactic receptors. Overall, this study highlights a previously unrecognized p38α-driven pathway that promotes an immune suppressive TME and that therapeutic blockade of p38α has important implications for improving antitumor immunity and patient outcomes.

2025-11-23 | GSE282734 | GEO

Expression and functional validation of new p38α transcriptional targets in tumorigenesis

2011-11-23 | GSE26762 | GEO

Role of P38α in stress erythropoiesis

Project description:The P38α modulates proliferation, survival and differentiation of different kinds of celll. Here, we demonstrate that loss of P38α accelerates recovery from anemia in mice by promoting survival of erythroblasts. To identify gene expression changes in P38α+/- versus P38α-/- erythroblasts, we sorted erythroblasts from P38α+/- and P38α-/- mice during recovery from anemia and performed microarray analysis.

2018-12-21 | GSE111751 | GEO

The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules

Project description:There is considerable evidence that inhibition of p38α mitogen-activated protein kinase diminishes cardiac damage during myocardial ischemia. During myocardial ischemia p38α interacts with TAB1, a scaffold protein, which promotes p38α autoactivation; active p38α (pp38α) then trans-phosphorylates TAB1. Previously, we solved the X-ray structure of the p38α-TAB1(384-412) complex. Here we further characterize the interaction by resolving the structure of the pp38α-TAB1(1-438) complex in the active state. Based on this information we created a global knock-in mouse with substitution of four residues on TAB1 (V390A, Y392A, V408G, M409A) we show are required for docking onto p38α. Whereas ablating p38α or TAB1 results in early embryonal lethality, the TAB1 KI mice are viable, develop normally and have no appreciable alteration in their lymphocyte repertoire or myocardial transcriptional profile. Nonetheless, following in vivo regional myocardial ischemia, infarction volume is significantly reduced and the trans- phosphorylation of TAB1 is disabled. Unexpectedly, the activation of myocardial p38α during ischemia is only mildly attenuated in TAB1 KI hearts, an effect most likely due to the removal of the steric hindrance to MAP2K3 binding. We conclude that it is the phosphorylation of TAB1 by pp38α during ischemia that is associated with cardiac damage. The data reveal that it is possible to selectively inhibit signalling downstream of p38α to attenuate ischemic injury. Our findings validate the p38α-TAB1 complex as a therapeutic target that may circumvent the toxicity associated with ATP-competitive inhibitors of p38α.

2018-08-27 | E-MTAB-6460 | biostudies-arrayexpress

Regulation of tumor angiogenesis and mesenchymal–endothelial transition by p38α through TGF-β and JNK signaling

Project description:The formation of new blood vessels is essential for normal development, tissue repair and tumor growth. Here we show that inhibition of the kinase p38α enhances angiogenesis in human and mouse colon tumors. Mesenchymal cells can contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. We show that p38α negatively regulates an angiogenic program in mesenchymal stem/stromal cells (MSCs), multipotent progenitors found in perivascular locations. This program includes the acquisition of an endothelial phenotype by MSCs mediated by both TGF-β and JNK, and negatively regulated by p38α. Abrogation of p38α in mesenchymal cells increases tumorigenesis, which correlates with enhanced angiogenesis. Using genetic models, we show that p38α regulates the acquisition of an endothelial-like phenotype by mesenchymal cells in colon tumors and damage tissue. Taken together, our results indicate that p38α in mesenchymal cells restrains a TGF-β-induced angiogenesis program including their ability to transdifferentiate into endothelial cells.

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P38α Regulates Expression of DUX4 in Facioscapulohumeral Muscular Dystrophy

Project description:Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity and cell death across FSHD1 and FSHD2 patient-derived lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/β inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/β inhibitors as effective therapeutics to treat FSHD at its root cause.

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Effect of depletion of p38α and p38β on gene expression in naïve CD8+ T cells

Project description:p38 MAPK is activated during CD8+ T cell primary response. p38 activation promotes effector CD8+ T cell terminal differentiation but represses MPEC formation. p38α/β-deficient mice possess a similar number of virus-specific effector CD8+ T cells as wildtype counterparts. Meanwhile p38α/β deletion doesn’t influence the clearance of LCMV although it impairs the cytolytic activity of CD8+ T cells. Loss of p38α/β significantly enhances IL-2-producing Tcm accumulation in mouse spleen with no impact on total memory CD8+ T cell numbers yet. And in line with this, more robust proliferation of memory CD8+ T cells in the secondary response and stronger antigen-specific killing ability in rechallenged mice are resulted from p38α/β deficiency. These results establish a pivotal role for p38α/β in skewing MPEC formation toward SLEC differentiation, as well as in suppressing Tcm formation, and thus affecting the recall response. p38α was reported to be essential in CD8+ T cell maturation, and our mice were observed to be at loss of p38α/β expression in thymic T cells during development. So it's important to see the influence of p38α/β deletion on peripheral naive CD8+ T cells and its potential inborn impact on later events. This would help determining the exact role of p38 signaling in CD8+ T cell immune responses.

2026-06-02 | GSE298331 | GEO

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