TGFβ Signaling in the Pancreatic Tumor Microenvironment

Principe, Daniel R.; Timbers, Kaytlin E.; Atia, Luke G.; Koch, R.; Rana, Ajay

doi:10.3390/cancers13205086

Cited by 46 publications

(38 citation statements)

References 173 publications

(208 reference statements)

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“…Accordingly, TGFb pathway inhibition is showing early promise in clinical trial for PDAC patients, particularly when combined with chemo- (32) or immunotherapy (33). While related trials are ongoing (34), to our knowledge, no studies have examined whether patients with genetic defects in the TGFb/SMAD4 signaling pathway will have alterations in local immune function.…”

Section: Discussionmentioning

confidence: 99%

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

et al. 2022

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Transforming Growth Factor β (TGFβ) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFβ inhibitors in select immunotherapy regimens shows early promise. Though the TGFβ target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFβ modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFβ. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

et al. 2022

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“…For instance, our KEGG enrichment analysis showed that the TGF-β signaling pathway was only activated in HPNE cells in response to ROS stress, while the mRNA transcripts associated with the Jak/STAT signaling pathway were mainly seen in PANC-1 cells after H 2 O 2 treatment. As a double-edged sword, the TGF-β signaling pathway can suppress tumor development by inhibiting cell proliferation and inducing apoptosis, but it can also promote cancer cell invasion and metastasis [31][32][33]. The Jak/STAT pathway is activated in many solid tumor cells and contributes to the malignant properties of cancer cells [34].…”

Section: Discussionmentioning

confidence: 99%

Characterization of H2O2-Induced Alterations in Global Transcription of mRNA and lncRNA

et al. 2022

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Hydrogen peroxide (H2O2) is an important reactive oxygen species that plays a major role in redox signaling. Although H2O2 is known to regulate gene expression and affect multiple cellular processes, the characteristics and mechanisms of such transcriptional regulation remain to be defined. In this study, we utilized transcriptome sequencing to determine the global changes of mRNA and lncRNA transcripts induced by H2O2 in human pancreatic normal epithelial (HPNE) and pancreatic cancer (PANC-1) cells. Promoter analysis using PROMO and TRRUST revealed that mRNAs and lncRNAs largely shared the same sets of transcription factors in response to ROS stress. Interestingly, promoters of the upregulated genes were similar to those of the downregulated transcripts, suggesting that the H2O2-responding promoters are conserved but they alone do not determine the levels of transcriptional outputs. We also found that H2O2 induced significant changes in molecules involved in the pathways of RNA metabolism, processing, and transport. Detailed analyses further revealed a significant difference between pancreatic cancer and noncancer cells in their response to H2O2 stress, especially in the transcription of genes involved in cell-cycle regulation and DNA repair. Our study provides new insights into RNA transcriptional regulation upon ROS stress in cancer and normal cells.

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“…Finally, selective inhibitors of the TGF-β signaling pathway are now under evaluation, showing early promise. However, the paradoxical role this growth factor may play in the tumor microenvironment, for example in the case of pancreatic adenocarcinoma, has led to questions regarding the potential biological consequences of inactivating selected components from this pathway, to identify the most effective combination therapy (Principe et al, 2021).…”

Section: Tgf-βmentioning

confidence: 99%

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

et al. 2022

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Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.

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TGFβ Signaling in the Pancreatic Tumor Microenvironment

Cited by 46 publications

References 173 publications

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

Characterization of H2O2-Induced Alterations in Global Transcription of mRNA and lncRNA

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

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