scholarly journals Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models

2021 ◽  
Vol 13 (599) ◽  
pp. eaba9772
Author(s):  
Yao-Xin Lin ◽  
Yi Wang ◽  
Jianxun Ding ◽  
Aiping Jiang ◽  
Jie Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Interleukin 12 ◽  
Orthotopic Model ◽  
Pten Mrna

Increasing clinical evidence has demonstrated that the deletion or mutation of tumor suppressor genes such as the gene-encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in cancer cells may correlate with an immunosuppressive tumor microenvironment (TME) and poor response or resistance to immune checkpoint blockade (ICB) therapy. It is largely unknown whether the restoration of functional PTEN may modulate the TME and improve the tumor’s sensitivity to ICB therapy. Here, we demonstrate that mRNA delivery by polymeric nanoparticles can effectively induce expression of PTEN in Pten-mutated melanoma cells and Pten-null prostate cancer cells, which in turn induces autophagy and triggers cell death–associated immune activation via release of damage-associated molecular patterns. In vivo results illustrated that PTEN mRNA nanoparticles can reverse the immunosuppressive TME by promoting CD8+ T cell infiltration of the tumor tissue, enhancing the expression of proinflammatory cytokines, such as interleukin-12, tumor necrosis factor–α, and interferon-γ, and reducing regulatory T cells and myeloid-derived suppressor cells. The combination of PTEN mRNA nanoparticles with an immune checkpoint inhibitor, anti–programmed death–1 antibody, results in a highly potent antitumor effect in a subcutaneous model of Pten-mutated melanoma and an orthotopic model of Pten-null prostate cancer. Moreover, the combinatorial treatment elicits immunological memory in the Pten-null prostate cancer model.

scholarly journals Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Chengguo Li ◽  
Qian Shen ◽  
Peng Zhang ◽  
Tao Wang ◽  
Weizhen Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Combination Therapy ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Anticancer Effect ◽  
Gastric Cancer Cells ◽  
Therapeutic Value

Abstract Background Identification of genomic biomarkers to predict the anticancer effects of indicated drugs is considered a promising strategy for the development of precision medicine. DNA endonuclease MUS81 plays a pivotal role in various biological processes during malignant diseases, mainly in DNA damage repair and replication fork stability. Our previous study reported that MUS81 was highly expressed and linked to tumor metastasis in gastric cancer; however, its therapeutic value has not been fully elucidated. Methods Bioinformatics analysis was used to define MUS81-related differential genes, which were further validated in clinical tissue samples. Gain or loss of function MUS81 cell models were constructed to elucidate the effect and mechanism of MUS81 on WEE1 expression. Moreover, the antitumor effect of targeting MUS81 combined with WEE1 inhibitors was verified using in vivo and in vitro assays. Thereafter, the cGAS/STING pathway was evaluated, and the therapeutic value of MUS81 for immunotherapy of gastric cancer was determined. Results In this study, MUS81 negatively correlated with the expression of cell cycle checkpoint kinase WEE1. Furthermore, we identified that MUS81 regulated the ubiquitination of WEE1 via E-3 ligase β-TRCP in an enzymatic manner. In addition, MUS81 inhibition could sensitize the anticancer effect of the WEE1 inhibitor MK1775 in gastric cancer in vitro and in vivo. Interestingly, when MUS81 was targeted, it increased the accumulation of cytosolic DNA induced by MK1775 treatment and activated the DNA sensor STING-mediated innate immunity in the gastric cancer cells. Thus, the WEE1 inhibitor MK1775 specifically enhanced the anticancer effect of immune checkpoint blockade therapy in MUS81 deficient gastric cancer cells. Conclusions Our data provide rational evidence that targeting MUS81 could elevate the expression of WEE1 by regulating its ubiquitination and could activate the innate immune response, thereby enhancing the anticancer efficacy of WEE1 inhibitor and immune checkpoint blockade combination therapy in gastric cancer cells.

Restoration of tumor suppression in vivo by systemic delivery of chemically-modified PTEN mRNA nanoparticles.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11582-11582 ◽  
Author(s):  
Mohammad Ariful Islam ◽  
Yingjie Xu ◽  
Harshal Zope ◽  
Wuji Cao ◽  
Morteza Mahmoudi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppression ◽  
Pten Expression ◽  
Akt Pathway ◽  
Castration Resistant Prostate Cancer ◽  
Systemic Delivery ◽  
Pten Mrna

11582 Background: The onset and maintenance of cancer frequently involves gain of oncogenic function along with loss of tumor suppression. PTEN is a well-characterized tumor suppressor gene that is lost or mutated in many human cancers including ~50% of metastatic castration-resistant prostate cancer (mCRPC). Reintroduction of functional PTEN for mCRPC treatment has proven difficult. Methods: PTEN mRNA was synthesized by in vitro transcription method and modified with ARCA capping and enzymatic polyadenylation, and then substituted with Pseudo-UTP, 5’-Methyl-CTP. A robust self-assembly approach was employed to prepare PTEN mRNA nanoparticles (NPs) using cationic lipid-like compound G0-C14 and PLGA polymer coated with lipid-PEG shell. PTEN expression in tumors and PI3K-AKT pathway were confirmed by IHC and western blot, respectively. Apoptosis was checked by flow cytometry and Tunel assays. In vivo toxicity was studied by hematologic and histologic tests, and immune response. Results: We successfully restored PTEN mRNA to PTEN-null prostate cancer (PCa) cells via systemic delivery of mRNA NPs. These mRNA NPs are stable in serum, demonstrate minimal toxicity, and provide highly effective transfection in PCa cells (substantially higher HA-PTEN expression than plasmid PTEN transfection) and PCa xenograft tumors, leading to ~85% inhibition of tumor cell growth in vitro and in vivo. We also confirm mRNA NP-mediated systemic restoration of PTEN function in PTEN-null PCa and delineate its tumor suppression through inhibition of the PI3K-AKT pathway and enhancement of apoptosis. Conclusions: The work provides proof of principle for the systemic reintroduction of mRNA-based tumor suppressor genes to tumors in vivo. Because PTEN loss is frequent in late-stage PCa, this approach may have feasibility in this patient population. Considering the strong potential of mRNA therapy and the lack of systemic studies of in vivo mRNA transfection of tumors, this study sheds light on the useful application of NP-mediated mRNA delivery for validating tumor suppressors (e.g., PTEN) as a therapeutic target in cancer treatment where loss of a tumor suppressor contributes to the underlying genetic mechanism of cancer.

scholarly journals Differential Targeting of Gr-MDSCs, T Cells and Prostate Cancer Cells by Dactolisib and Dasatinib

2020 ◽  
Vol 21 (7) ◽  
pp. 2337 ◽  
Author(s):  
Guoqiang Liu ◽  
Zhijian Jin ◽  
Xin Lu
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Cancer Cells ◽  
Kinase Inhibitor ◽  
Expression Patterns ◽  
Suppressor Cells ◽  
Specific Protein ◽  
Immune Checkpoint Blockade ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells

Granulocytic myeloid-derived suppressor cells (Gr-MDSCs) promote immune evasion and resistance to immunotherapeutics in a variety of malignancies. Our previous study showed that dual PI3K/mTOR inhibitor Dactolisib impaired the viability and immunosuppressive function of Gr-MDSCs, and significantly synergized with immune checkpoint blockade (ICB) antibodies targeting PD1 and CTLA4 to eradicate metastatic castration-resistant prostate cancer (CRPC) in a preclinical transgenic mouse model. On the contrary, tyrosine kinase inhibitor Dasatinib diminished tumor-infiltrating T lymphocytes and showed no synergic activity with ICB. The understanding of the distinct effects of Dactolisib and Dasatinib on Gr-MDSCs, T cells and prostate neoplastic cells is inadequate, limiting the clinical translation of the combination immunotherapy. To address this question, we applied Reverse Phase Protein Array (RPPA) to profile 297 proteins and protein phosphorylation sites of Gr-MDSCs, T cells and prostate cancer cells isolated from the CRPC model. We found cell type-specific protein expression patterns and highly selective targets by the two drugs, including preferential inhibition of phospho-4E-BP1 in Gr-MDSCs by Dactolisib and preferential suppression of phospho-Src and phospho-p38 MAPK in T cells. Furthermore, transcriptomic profiling of Gr-MDSCs treated with the two inhibitors revealed downregulation of mitochondrial respiration pathways by Dactolisib but not Dasatinib. Overall, these results provide important mechanistic insight into the efficacious combination of Dactolisib and ICB as well as the detrimental effect of Dasatinib on anti-tumor immunity.

scholarly journals DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mTORC1/2 signals

Oncogene ◽  
2019 ◽  
Vol 39 (7) ◽  
pp. 1557-1571 ◽  
Author(s):  
Xiaoyu Chen ◽  
Xiufang Xiong ◽  
Danrui Cui ◽  
Fei Yang ◽  
Dongping Wei ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Human Prostate ◽  
Migration And Invasion ◽  
Human Prostate Cancer ◽  
Prostate Tumorigenesis ◽  
Mesenchymal Transition

Abstract The DEPTOR-mTORC1/2 axis has been shown to play an important, but a context dependent role in the regulation of proliferation and the survival of various cancer cells in cell culture settings. The in vivo role of DEPTOR in tumorigenesis remains elusive. Here we showed that the levels of both DEPTOR protein and mRNA were substantially decreased in human prostate cancer tissues, which positively correlated with disease progression. DEPTOR depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, DEPTOR depletion not only activated both mTORC1 and mTORC2 signals to promote cell proliferation and survival, but also induced an AKT-dependent epithelial–mesenchymal transition (EMT) and β-catenin nuclear translocation to promote cell migration and invasion. Abrogation of mTOR or AKT activation rescued the biological consequences of DEPTOR depletion. Importantly, in a Deptor-KO mouse model, Deptor knockout accelerated prostate tumorigenesis triggered by Pten loss via the activation of mTOR signaling. Collectively, our study demonstrates that DEPTOR is a tumor suppressor in the prostate, and its depletion promotes tumorigenesis via the activation of mTORC1 and mTORC2 signals. Thus, DEPTOR reactivation via a variety of means would have therapeutic potential for the treatment of prostate cancer.

scholarly journals Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer

Nature Cancer ◽  
2021 ◽  
Author(s):  
Yuanyuan Qiao ◽  
Jae Eun Choi ◽  
Jean C. Tien ◽  
Stephanie A. Simko ◽  
Thekkelnaycke Rajendiran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Autophagy Inhibition

scholarly journals Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Navatha Shree Polavaram ◽  
Samikshan Dutta ◽  
Ridwan Islam ◽  
Arup K. Bag ◽  
Sohini Roy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Potential Effect ◽  
Tumor Burden ◽  
Bone Lesions ◽  
Prostate Cancer Cells

AbstractUnderstanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

scholarly journals Inhibition of mutant KRAS-driven overexpression of ARF6 and MYC by an eIF4A inhibitor drug improves the effects of anti-PD-1 immunotherapy for pancreatic cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ari Hashimoto ◽  
Haruka Handa ◽  
Soichiro Hata ◽  
Akio Tsutaho ◽  
Takao Yoshida ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Mrna Translation ◽  
Immune Checkpoint Blockade ◽  
Small Gtpase ◽  
Initiation Factor ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Intact Cells ◽  
Cell Functions

AbstractMany clinical trials are being conducted to clarify effective combinations of various drugs for immune checkpoint blockade (ICB) therapy. However, although extensive studies from multiple aspects have been conducted regarding treatments for pancreatic ductal adenocarcinoma (PDAC), there are still no effective ICB-based therapies or biomarkers for this cancer type. A series of our studies have identified that the small GTPase ARF6 and its downstream effector AMAP1 (also called ASAP1/DDEF1) are often overexpressed in different cancers, including PDAC, and closely correlate with poor patient survival. Mechanistically, the ARF6-AMAP1 pathway drives cancer cell invasion and immune evasion, via upregulating β1-integrins and PD-L1, and downregulating E-cadherin, upon ARF6 activation by external ligands. Moreover, the ARF6-AMAP1 pathway enhances the fibrosis caused by PDAC, which is another barrier for ICB therapies. KRAS mutations are prevalent in PDACs. We have shown previously that oncogenic KRAS mutations are the major cause of the aberrant overexpression of ARF6 and AMAP1, in which KRAS signaling enhances eukaryotic initiation factor 4A (eIF4A)-dependent ARF6 mRNA translation and eIF4E-dependent AMAP1 mRNA translation. MYC overexpression is also a key pathway in driving cancer malignancy. MYC mRNA is also known to be under the control of eIF4A, and the eIF4A inhibitor silvestrol suppresses MYC and ARF6 expression. Using a KPC mouse model of human PDAC (LSL-Kras(G12D/+); LSL-Trp53(R172H/+)); Pdx-1-Cre), we here demonstrate that inhibition of the ARF6-AMAP1 pathway by shRNAs in cancer cells results in therapeutic synergy with an anti-PD-1 antibody in vivo; and furthermore, that silvestrol improves the efficacy of anti-PD-1 therapy, whereas silvestrol on its own promotes tumor growth in vivo. ARF6 and MYC are both essential for normal cell functions. We demonstrate that silvestrol substantially mitigates the overexpression of ARF6 and MYC in KRAS-mutated cells, whereas the suppression is moderate in KRAS-intact cells. We propose that targeting eIF4A, as well as mutant KRAS, provides novel methods to improve the efficacy of anti-PD-1 and associated ICB therapies against PDACs, in which ARF6 and AMAP1 overexpression, as well as KRAS mutations of cancer cells are biomarkers to identify patients with drug-susceptible disease. The same may be applicable to other cancers with KRAS mutations.

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