Several subtypes of APCs are found in psoriasis patients, but their involvement in disease pathogenesis is poorly understood. Here, we investigated the contribution of Langerhans cells (LCs) and plasmacytoid DCs (pDCs) in psoriasis. In human psoriatic lesions and in a psoriasis mouse model (DKO* mice), LCs are severely reduced, whereas pDCs are increased. Depletion of pDCs in DKO* mice prior to psoriasis induction resulted in a milder phenotype, whereas depletion during active disease had no effect. In contrast, while depletion of Langerin-expressing APCs before disease onset had no effect, depletion from diseased mice aggravated psoriasis symptoms. Disease aggravation was due to the absence of LCs, but not other Langerin-expressing APCs. LCs derived from DKO* mice produced increased IL-10 levels, suggesting an immunosuppressive function. Moreover, IL-23 production was high in psoriatic mice and further increased in the absence of LCs. Conversely, pDC depletion resulted in reduced IL-23 production, and therapeutic inhibition of IL-23R signaling ameliorated disease symptoms. Therefore, LCs have an anti-inflammatory role during active psoriatic disease, while pDCs exert an instigatory function during disease initiation.

Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFβ/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFβ/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.

Osteosarcoma (OS) is a rare tumor of the bone occurring mainly in young adults accounting for 5% of all childhood cancers. Because of the limited therapeutic options, there has been no survival improvement for OS patients in the past 40 years. The epidermal growth factor receptor (EGFR) is highly expressed in OS; however, its clinical relevance is unclear. Here, we employed an autochthonous c-Fos-dependent OS mouse model (H2-c-fosLTR) and human OS tumor biopsies for preclinical studies aimed at identifying novel biomarkers and therapeutic benefits of anti-EGFR therapies. We show that EGFR deletion/inhibition results in reduced tumor formation in H2-c-fosLTR mice by directly inhibiting the proliferation of cancer-initiating osteoblastic cells by a mechanism involving RSK2/CREB-dependent c-Fos expression. Furthermore, OS patients with co-expression of EGFR and c-Fos exhibit reduced overall survival. Preclinical studies using human OS xenografts revealed that only tumors expressing both EGFR and c-Fos responded to anti-EGFR therapy demonstrating that c-Fos can be considered as a novel biomarker predicting response to anti-EGFR treatment in OS patients.

Toll-like receptor (TLR) stimulation induces innate immune responses involved in many inflammatory disorders including psoriasis. Although activation of the AP-1 transcription factor complex is common in TLR signaling, the specific involvement and induced targets remain poorly understood. Here, we investigated the role of c-Jun/AP-1 protein in skin inflammation following TLR7 activation using human psoriatic skin, dendritic cells (DC), and genetically engineered mouse models. We show that c-Jun regulates CCL2 production in DCs leading to impaired recruitment of plasmacytoid DCs to inflamed skin after treatment with the TLR7/8 agonist Imiquimod. Furthermore, deletion of c-Jun in DCs or chemical blockade of JNK/c-Jun signaling ameliorates psoriasis-like skin inflammation by reducing IL-23 production in DCs. Importantly, the control of IL-23 and CCL2 by c-Jun is most pronounced in murine type-2 DCs. CCL2 and IL-23 expression co-localize with c-Jun in type-2/inflammatory DCs in human psoriatic skin and JNK-AP-1 inhibition reduces the expression of these targets in TLR7/8-stimulated human DCs. Therefore, c-Jun/AP-1 is a central driver of TLR7-induced immune responses by DCs and JNK/c-Jun a potential therapeutic target in psoriasis.

Psoriasis is a common inflammatory skin disease involving a cross-talk between epidermal and immune cells. The role of specific epidermal stem cell populations, including hair follicle stem cells (HF-SCs) in psoriasis is not well defined. Here, we show reduced expression of c-JUN and JUNB in bulge HF-SCs in patients with scalp psoriasis. Using lineage tracing in mouse models of skin inflammation with inducible deletion of c-Jun and JunB, we found that mutant bulge HF-SCs initiate epidermal hyperplasia and skin inflammation. Mechanistically, thymic stromal lymphopoietin (TSLP) was identified in mutant cells as a paracrine factor stimulating proliferation of neighboring non-mutant epidermal cells, while mutant inter-follicular epidermal (IFE) cells are lost over time. Blocking TSLP in psoriasis-like mice reduced skin inflammation and decreased epidermal proliferation, VEGFα expression, and STAT5 activation. These findings unravel distinct roles of HF-SCs and IFE cells in inflammatory skin disease and provide novel mechanistic insights into epidermal cell interactions in inflammation.

We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.