Biology subjects

Elmer, D. P.

Publications and source records attributed to Elmer, D. P..

5 recordsLinked to original sources

bioRxiv2024

Hedgehog-Hippo pathway interactions promote T cell exclusion from the tumor microenvironment in basal cell carcinoma

Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer driven primarily by genetic activation of the Hedgehog/GLI (HH/GLI) signaling pathway. BCC also displays a high mutational burden, with frequent co-occurrence of mutations in the TP53, NOTCH, N- MYC, and Hippo/YAP pathways, though the impact of these mutations on HH/GLI-driven tumorigenesis remains poorly understood. This study examines the interaction between the HH/GLI and Hippo/YAP signaling pathways in the pathogenesis of BCC and the establishment of an immunosuppressive tumor microenvironment (TME). The study used 3D human organotypic skin models and humanized mouse models to demonstrate that co-activation of HH/GLI and Hippo/YAP in epidermal cells suppresses T cell chemotaxis. Transcriptome analysis revealed a significant downregulation of chemotactic and inflammatory genes, particularly under combined GLI-YAP activation. Analysis of primary human BCC biopsies confirmed these findings and demonstrated a marked suppression of T cell chemo-attractants, including CCL22 and CCL27. Spatial profiling of immune cells in BCC tissues revealed preferential exclusion of CD8+ T cells from the TME, which correlated with high HH/GLI and Hippo/YAP activity. Further, functional assays in humanized mice showed that the GLI-YAP interaction controls immune cell distribution by inhibiting T cell recruitment and migration into the skin. These findings suggest that cooperation between oncogenic HH/GLI and Hippo/YAP signaling contributes to the development of an immunosuppressive TME in BCC by disrupting local chemokine signaling. Understanding these mechanisms provides a basis for the development of targeted combination therapies to enhance the efficacy of existing treatments, such as Smoothened (SMO) inhibitors and immune checkpoint blockers, by promoting T cell infiltration and activation within the TME.

cancer biology↗

bioRxiv2021

The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia

Aberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediates numerous inflammatory diseases. Oncogenes can activate the NLRP3 inflammasome and thereby promote myeloproliferative neoplasia, suggesting a crucial role of NLRP3 in the malignant transformation of hematopoietic cells. Here, we show that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, IL-1{beta} and IL-18 and that high-level expression of NLRP3 is linked to poor survival of AML patients. Pharmacological and genetic inhibition of NLRP3 inflammasome activation attenuated cell proliferation of MOLM-13 AML cells in vitro. In vivo, genetic inhibition of NLRP3 in MOLM-13 AML cells resulted in reduced engraftment potential in xenografts, along with reduced splenomegaly and organ infiltration. Differential proteomic analysis revealed the eIF2 pathway as potential target of NLRP3 in AML, with a significant increase of eIF2 phosphorylation upon NLRP3 inhibition. NLRP3 inhibition also caused a strong decrease in cyclin - dependent kinases CDK4 and CDK6, accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A) and a marked arrest of cell cycle progression in the G0/G1 phase, consistent with the role of eIF2 phosphorylation as negative cell cycle regulator. Taken together, we show that inhibition of the NLRP3 inflammasome reduces AML cell proliferation by promoting eIF2 phosphorylation, which in turn enhances the expression of cell cycle arrest genes such as p21. Thus, the study uncovers the NLRP3/eIF2 axis as new driver of AML proliferation and proposes a novel therapeutic treatment of AML by targeted inhibition of NLRP3 activation.

immunology↗

bioRxiv2021

Casein kinase 1D encodes a novel drug target in Hedgehog-GLI driven cancers and tumor-initiating cells resistant to SMO inhibition

(1) BackgroundAberrant activation of the Hedgehog (HH)/GLI pathway in stem-like tumor initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector Smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH/GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH/GLI driven malignancies. (2) MethodsWe genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity and monitored oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models. (3) ResultsWe show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO-inhibitor sensitive and resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent tumor-initiating cancer cells in vitro and in vivo. (4) ConclusionsPharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor sensitive and resistant tumors.

cancer biology↗

bioRxiv2020

Oncogenic GLI1 and STAT1/3 activation drives immunosuppressive tryptophan/kynurenine metabolism via synergistic induction of IDO1 in skin cancer cells

Pharmacological targeting of Hedgehog (HH)/GLI has proven effective for certain blood, brain and skin cancers including basal cell carcinoma (BCC). However, limited response rates and the development of drug resistance call for improved anti-HH therapies that take into account synergistic crosstalk mechanisms and immune evasion strategies. In previous work, we demonstrated that crosstalk of HH/GLI with pro-inflammatory Interleukin-6 (IL6) signaling drives BCC by promoting tumor cell proliferation [1]. In the present study, we screened for possible mechanisms of cancer immune evasion regulated by synergistic HH-IL6 signaling and identified the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) as a novel transcriptional target co-regulated by HH-IL6 signaling. Analysis of the cis-regulatory region of IDO1 by chromatin-immunoprecipitation revealed co-occupancy of this region by HH- IL6 induced GLI1 and STAT3 transcription factors along with active chromatin marks at the histone level. Elevated expression of IDO1 in human BCC with high-level HH and IL6 signatures supports the clinical relevance of our mechanistic data. Genetic inhibition of GLI1 expression prevented the induction of IDO1 expression in response to IL6/STAT3 and IFN{gamma}/STAT1 signaling in human melanoma cells. Pharmacological targeting of HH signaling at the level of GLI proteins interfered with IDO1 expression and consequently prevented the production of the immunosuppressive metabolite kynurenine generated by active IDO1 from tryptophan. Further, inhibition of GLI1 enhanced the efficacy of the selective IDO1 inhibitor epacadostat. Of note, inhibition of HH/GLI signaling in melanoma cells not only reduced IDO1 expression but also interfered with the repression of T cell activation by attenuating IDO1/kynurenine-mediated immunosuppression. These data identify the immunosuppressive IDO1-kynurenine pathway as a novel pro-tumorigenic effector of oncogenic HH-IL6 and GLI-STAT cooperation. Our data suggest simultaneous pharmacological targeting of the HH/GLI, JAK/STAT and IDO1- kynurenine axis as rational combination therapy in skin cancers.

cancer biology↗

bioRxiv2018

Opioids trigger breast cancer metastasis through E-Cadherin downregulation and STAT3 activation promoting epithelial mesenchymal transition

The opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental facts exist. Expression of {delta}-opioid receptors (DORs) correlates with poor prognosis for breast cancer (BCa) patients, but mechanism and genetic/pharmacologic proof of key changes in opioid-triggered cancer biology are lacking. We show that oncogenic STAT3 signaling and E-Cadherin downregulation are triggered by opioid-ligated DORs, promoting metastasis. Human and murine transplanted BCa cells (MDA-MB-231, 4T1) displayed enhanced metastasis upon opioid-induced DOR stimulation, and DOR-antagonist blocked metastasis. Opioid-exposed BCa cells showed enhanced migration, STAT3 activation, down-regulation of E-Cadherin and expression of epithelial-mesenchymal transition (EMT) markers. STAT3 knockdown or upstream inhibition through the JAK1/2 kinase inhibitor ruxolitinib prevented opioid-induced BCa cell metastasis and migration. We conclude that opioids trigger metastasis through oncogenic JAK1/2-STAT3 signaling.

cancer biology↗