bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022–07–10
fiveteen papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis.
  2. To Sleep, Perchance to Metastasize.
  3. Sustained oncogenic signaling in the cytostatic state enables targeting of non-proliferating persistent cancer cells.
  4. MARK2 regulates chemotherapeutic responses through class IIa HDAC-YAP axis in pancreatic cancer.
  5. Cell-matrix interface regulates dormancy in human colon cancer stem cells.
  6. DNMT1-mediated epigenetic silencing of TRAF6 promotes prostate cancer tumorigenesis and metastasis by enhancing EZH2 stability.
  7. Retinoic acid receptor activation reduces metastatic prostate cancer bone lesions by blocking the endothelial-to-osteoblast transition.
  8. Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models.
  9. TTC22 promotes m6A-mediated WTAP expression and colon cancer metastasis in an RPL4 binding-dependent pattern.
  10. Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
  11. GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair.
  12. PRMT5 activates AKT via methylation to promote tumor metastasis.
  13. STING activation promotes robust immune response and NK cell-mediated tumor regression in glioblastoma models.
  14. A synthetic lethal strategy using PARP and ATM inhibition for overcoming trastuzumab resistance in HER2-positive cancers.
  15. PRC2 Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1 Targeted Therapy via Enhanced Viral Mimicry.
  1. Oncogene. 2022 Jul 07.
    Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis.
    Qi Meng, Yun-Xin Lu, Chen Wei, Zi-Xian Wang, Jin-Fei Lin, Kun Liao, Xiao-Jing Luo, Kai Yu, Yi Han, Jia-Jun Li, Yue-Tao Tan, Hao Li, Zhao-Lei Zeng, Bo Li, Rui-Hua Xu, Huai-Qiang Ju.
      Metastasis accounts for the major cause of cancer-related mortality. How disseminated tumor cells survive under suspension conditions and avoid anoikis is largely unknown. Here, using a metabolic enzyme-centered CRISPR-Cas9 genetic screen, we identified methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1) as a novel suppressor of anoikis. MTHFD1 depletion obviously restrained the capacity of cellular antioxidant defense and inhibited tumor distant metastasis. Mechanistically, MTHFD1 was found to bind the protein arginine methyltransferase 5 (PRMT5) and then undergo symmetric dimethylation on R173 by PRMT5. Under suspension conditions, the interaction between MTHFD1 and PRMT5 was strengthened, which increased the symmetric dimethylation of MTHFD1. The elevated methylation of MTHFD1 largely augmented its metabolic activity to generate NADPH, therefore leading to anoikis resistance and distant organ metastasis. Therapeutically, genetic depletion or pharmacological inhibition of PRMT5 declined tumor distant metastasis. And R173 symmetric dimethylation status was associated with metastasis and prognosis of ESCC patients. In conclusion, our study uncovered a novel regulatory role and therapeutic implications of PRMT5/MTHFD1 axis in facilitating anoikis resistance and cancer metastasis.
    DOI:  https://doi.org/10.1038/s41388-022-02387-7
  2. Cancer Discov. 2022 Jul 04. OF1
    To Sleep, Perchance to Metastasize.
      Circulating tumor cells are more likely to enter the bloodstream and spread as patients sleep, according to breast cancer research. The findings could change how doctors elect to monitor and treat metastasis-prone tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2022-0049
  3. Cancer Res. 2022 Jul 06. pii: can.21.2908. [Epub ahead of print]
    Sustained oncogenic signaling in the cytostatic state enables targeting of non-proliferating persistent cancer cells.
    Lisa M Kim, Paul Y Kim, Yemarshet K Gebreyohannes, Cheuk T Leung.
      Many advanced therapeutics possess cytostatic properties that suppress cancer cell growth without directly inducing death. Treatment-induced cytostatic cancer cells can persist and constitute a reservoir from which recurrent growth and resistant clones can develop. Current management approaches primarily comprise maintenance and monitoring because strategies for targeting non-proliferating cancer cells have been elusive. Here, we utilized targeted therapy paradigms and engineered cytostatic states to explore therapeutic opportunities for depleting treatment-mediated cytostatic cancer cells. Sustained oncogenic AKT signaling was common, while non-essential, in treatment-mediated cytostatic cancer cells harboring PI3K-pathway mutations, which are associated with cancer recurrence. Engineering oncogenic signals in quiescent mammary organotypic models showed that sustained, aberrant activation of AKT sensitized cytostatic epithelial cells to proteasome inhibition. Mechanistically, sustained AKT signaling altered cytostatic state homeostasis and promoted an oxidative and proteotoxic environment, which imposed an increased proteasome dependency for maintaining cell viability. Under cytostatic conditions, inhibition of the proteasome selectively induced apoptosis in the population with aberrant AKT activation compared to normal cells. Therapeutically exploiting this AKT-driven proteasome vulnerability was effective in depleting treatment-mediated cytostatic cancer cells independent of breast cancer subtype, epithelial origin, and cytostatic agent. Moreover, transient targeting during cytostatic treatment conditions was sufficient to reduce recurrent tumor growth in spheroid and mouse models. This work identified an AKT-driven proteasome-vulnerability that enables depletion of persistent cytostatic cancer cells harboring PTEN/PI3K pathway mutations, revealing a viable strategy for targeting non-proliferating persistent cancer cell populations before drug resistance emerges.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2908
  4. Oncogene. 2022 Jul 02.
    MARK2 regulates chemotherapeutic responses through class IIa HDAC-YAP axis in pancreatic cancer.
    Yongji Zeng, Ling Yin, Jiuli Zhou, Renya Zeng, Yi Xiao, Adrian R Black, Tuo Hu, Pankaj K Singh, Feng Yin, Surinder K Batra, Fang Yu, Yuanhong Chen, Jixin Dong.
      Despite paclitaxel's wide use in cancer treatment, patient response rate is still low and drug resistance is a major clinical obstacle. Through a Phos-tag-based kinome-wide screen, we identified MARK2 as a critical regulator for paclitaxel chemosensitivity in PDAC. We show that MARK2 is phosphorylated by CDK1 in response to antitubulin chemotherapeutics and in unperturbed mitosis. Phosphorylation is essential for MARK2 in regulating mitotic progression and paclitaxel cytotoxicity in PDAC cells. Mechanistically, our findings also suggest that MARK2 controls paclitaxel chemosensitivity by regulating class IIa HDACs. MARK2 directly phosphorylates HDAC4 specifically during antitubulin treatment. Phosphorylated HDAC4 promotes YAP activation and controls expression of YAP target genes induced by paclitaxel. Importantly, combination of HDAC inhibition and paclitaxel overcomes chemoresistance in organoid culture and preclinical PDAC animal models. The expression levels of MARK2, HDACs, and YAP are upregulated and positively correlated in PDAC patients. Inhibition of MARK2 or class IIa HDACs potentiates paclitaxel cytotoxicity by inducing mitotic abnormalities in PDAC cells. Together, our findings identify the MARK2-HDAC axis as a druggable target for overcoming chemoresistance in PDAC.
    DOI:  https://doi.org/10.1038/s41388-022-02399-3
  5. Nature. 2022 Jul 07.
    Cell-matrix interface regulates dormancy in human colon cancer stem cells.
    Yuki Ohta, Masayuki Fujii, Sirirat Takahashi, Ai Takano, Kosaku Nanki, Mami Matano, Hikaru Hanyu, Megumu Saito, Mariko Shimokawa, Shingo Nishikori, Yoshiko Hatano, Ryota Ishii, Kazuaki Sawada, Akihito Machinaga, Wataru Ikeda, Takeshi Imamura, Toshiro Sato.
      Cancer relapse after chemotherapy remains a main cause of cancer-related death. Although the relapse is thought to result from the propagation of resident cancer stem cells (CSCs)1, a lack of experimental platforms that enable prospective analysis of CSC dynamics with sufficient spatiotemporal resolution has hindered testing of this hypothesis. Here, we develop a live genetic lineage-tracing system that allows longitudinal tracking of individual cells in xenotransplanted human colorectal cancer organoids and identify LGR5+ CSCs that display a dormant behavior in a chemo-naive state. Dormant LGR5+ cells are marked by p27 expression, and intravital imaging directly demonstrates the persistence of LGR5+p27+ cells during chemotherapy, followed by clonal expansion. Transcriptome analysis reveals an upregulation of COL17A1, a cell adhesion molecule that strengthens hemidesmosome, in dormant LGR5+p27+ cells. COL17A1-knockout organoids lose the dormant LGR5+p27+ subpopulation and become sensitive to chemotherapy, suggesting a role of cell-matrix interface in dormancy maintenance. Chemotherapy disrupts COL17A1 and breaks the dormancy in LGR5+p27+ cells through FAK-YAP activation. Abrogation of YAP signaling restrains chemo-resistant cells from exiting dormancy and delays tumor regrowth, highlighting the therapeutic potential of YAP inhibition in preventing cancer relapse. These results offer a viable therapeutic approach to overcome refractoriness of human colorectal cancer to conventional chemotherapy.
    DOI:  https://doi.org/10.1038/s41586-022-05043-y
  6. Oncogene. 2022 Jul 08.
    DNMT1-mediated epigenetic silencing of TRAF6 promotes prostate cancer tumorigenesis and metastasis by enhancing EZH2 stability.
    Zhongwei Li, Bingheng Li, Haiyuan Yu, Pengfei Wang, Wenwen Wang, Pingfu Hou, Minle Li, Sufang Chu, Junnian Zheng, Lijun Mao, Jin Bai.
      A plethora of studies have shown that both DNMT1 and EZH2 have great effects on the progression of a variety of cancers. However, it remains unclear whether the expression profiles of these two epigenetic enzymes are molecularly intertwined in prostate cancer (PC), especially in castration-resistant prostate cancer (CRPC). Here, we found that DNMT1 is highly expressed and facilitates PC cell proliferation and migration. Importantly, we demonstrate that the abrogation of DNMT1 expression can induce the decreased expression of EZH2, resulting in the less aggressive capacity of PC cells. Mechanistically, we discovered that DNMT1 promotes PC tumorigenesis and metastasis by inhibiting TRAF6 transcriptional expression and subsequent TRAF6-mediated EZH2 ubiquitination. Finally, we confirmed that there is a negative correlation between DNMT1 and TRAF6 expression and a positive correlation between DNMT1 and EZH2 expression in PC patients. In this study, we first disclose that there is a direct crosstalk between DNA methyltransferase DNMT1 expression and histone methyltransferase EZH2 expression in tumorigenesis and cancer metastasis in vitro and in vivo. Our results also show that targeting DNMT1 with its inhibitor decitabine (an FDA-approved drug) is an appealing treatment strategy for CRPC patients through epigenetic suppression of both DNMT1-mediated DNA methylation and EZH2-modulated histone methylation.
    DOI:  https://doi.org/10.1038/s41388-022-02404-9
  7. Cancer Res. 2022 Jul 08. pii: can.22.0170. [Epub ahead of print]
    Retinoic acid receptor activation reduces metastatic prostate cancer bone lesions by blocking the endothelial-to-osteoblast transition.
    Guoyu Yu, Paul G Corn, Peng-Fei Shen, Jian H Song, Yu-Chen Lee, Song-Chang Lin, Jing Pan, Sandeep K Agarwal, Theocharis Panaretakis, Maurizio Pacifici, Christopher J Logothetis, Li-Yuan Yu-Lee, Sue-Hwa Lin.
      Metastatic prostate cancer (PCa) in the bone induces bone-forming lesions that contribute to progression and therapy resistance. PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Current strategies targeting PCa-induced bone formation are lacking. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces PCa-induced bone formation. Treatment with palovarotene, an RARγ agonist being tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited EC-to-OSB transition and osteoblast mineralization in vitro and decreased tumor-induced bone formation and tumor growth in several osteogenic PCa models, and similar effects were observed with the pan-RAR agonist ATRA. Knockdown of RARα, β, or γ isoforms in ECs blocked BMP4-induced EC-to-OSB transition and osteoblast mineralization, indicating a role for all three isoforms in PCa-induced bone formation. Furthermore, treatment with palovarotene or ATRA reduced plasma Tenascin C, a factor secreted from EC-OSB cells, which may be used to monitor treatment response. Mechanistically, BMP4-activated pSmad1 formed a complex with RAR in the nucleus of ECs to activate EC-to-OSB transition. RAR activation by palovarotene or ATRA caused pSmad1 degradation by recruiting the E3-ubiquitin ligase Smurf1 to the nuclear pSmad1/RARγ complex, thus blocking EC-to-OSB transition. Collectively, these findings suggest that palovarotene can be repurposed to target PCa-induced bone formation to improve clinical outcomes for patients with bone metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0170
  8. Clin Cancer Res. 2022 Jul 07. pii: ccr.22.1052. [Epub ahead of print]
    Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models.
    Fuyang Li, Kathryn M Bondra, Samson Ghilu, Adam Studebaker, Qianqian Liu, Joel E Michalek, Mari Kogiso, Xiao-Nan Li, John A Kalapurakal, C David James, Sandeep Burma, Raushan T Kurmasheva, Peter J Houghton.
       PURPOSE: We investigated why three patient derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both LGG molecular subtypes.
    EXPERIMENTAL DESIGN: Sensitivity to trametinib (MEKi) alone or in combination with rapamycin (TORC1 inhibitor), was evaluated in pediatric PDX models. The effect of combined treatment of trametinib with rapamycin on development of trametinib resistance in vivo was examined. PDX tissue and tumor cells from trametinib-resistant xenografts were characterized.
    RESULTS: In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex TSC: consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. In mice, acquired resistance to trametinib developed within 3 cycles of therapy in all three PDX models. Resistance to trametinib developed in situ is tumor cell intrinsic and the mechanism was tumor line specific. Rapamycin, retarded or blocked development of resistance.
    CONCLUSIONS: In these three pediatric BRAF-mutant brain tumors, TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance, suggesting future therapeutic approaches using rapamycin analogs in combination with MEK inhibitors that may be therapeutically beneficial in both KIAA1549::BRAF and BRAFV600Edriven gliomas.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1052
  9. Oncogene. 2022 Jul 07.
    TTC22 promotes m6A-mediated WTAP expression and colon cancer metastasis in an RPL4 binding-dependent pattern.
    Abin You, Wei Tian, Hongfan Yuan, Liankun Gu, Jing Zhou, Dajun Deng.
      WTAP, an essential component of the RNA N-6-methyladenosine (m6A) modification complex, guides METLL3-METLL14 heteroduplexes to target RNAs in the nuclear speckles of mammalian cells. Here, we show that TTC22 is widely coexpressed with WTAP and FTO in many human tissues by mining Genotype-Tissue Expression (GTEx) datasets. Our results indicate that the direct interaction of TTC22 with 60S ribosomal protein L4 (RPL4) promotes the binding of WTAP mRNA to RPL4, enhances the stability and translation efficiency of WTAP mRNA, and consequently increases the level of WTAP protein. Also, WTAP mRNA itself is an m6A target and YTHDF1 is characterized as an essential m6A binding protein interacting with m6A-modified WTAP mRNA. TTC22 triggers a positive feedback loop between WTAP expression and WTAP mRNA m6A modification, leading to an increased m6A level in total RNA. The knockdown of RPL4, WTAP, or YTHDF1 expression diminishes the TTC22-induced increase in the m6A level of total RNA. Thus, TTC22 caused dramatic expression changes in genes related to metabolic pathways, ribosomal biogenesis, the RNA spliceosome, and microorganism infections. Importantly, TTC22 upregulates the expression of SNAI1 by increasing m6A level and thus promotes lung metastases of colon cancer cells in mice. In conclusion, our study showed that TTC22 upregulates WTAP and SNAI1 expression, which contributes to TTC22-induced colon cancer metastasis.
    DOI:  https://doi.org/10.1038/s41388-022-02402-x
  10. Cell. 2022 Jul 07. pii: S0092-8674(22)00712-7. [Epub ahead of print]185(14): 2591-2608.e30
    Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
    Jana Biermann, Johannes C Melms, Amit Dipak Amin, Yiping Wang, Lindsay A Caprio, Alcida Karz, Somnath Tagore, Irving Barrera, Miguel A Ibarra-Arellano, Massimo Andreatta, Benjamin T Fullerton, Kristjan H Gretarsson, Varun Sahu, Vaibhav S Mangipudy, Trang T T Nguyen, Ajay Nair, Meri Rogava, Patricia Ho, Peter D Koch, Matei Banu, Nelson Humala, Aayushi Mahajan, Zachary H Walsh, Shivem B Shah, Daniel H Vaccaro, Blake Caldwell, Michael Mu, Florian Wünnemann, Margot Chazotte, Simon Berhe, Adrienne M Luoma, Joseph Driver, Matthew Ingham, Shaheer A Khan, Suthee Rapisuwon, Craig L Slingluff, Thomas Eigentler, Martin Röcken, Richard Carvajal, Michael B Atkins, Michael A Davies, Albert Agustinus, Samuel F Bakhoum, Elham Azizi, Markus Siegelin, Chao Lu, Santiago J Carmona, Hanina Hibshoosh, Antoni Ribas, Peter Canoll, Jeffrey N Bruce, Wenya Linda Bi, Praveen Agrawal, Denis Schapiro, Eva Hernando, Evan Z Macosko, Fei Chen, Gary K Schwartz, Benjamin Izar.
      Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.
    Keywords:  brain metastasis; chromosomal instability; melanoma; neuronal-like cell state; single-cell genomics; spatial transcriptomics; tumor-microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2022.06.007
  11. Oncogene. 2022 Jul 02.
    GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair.
    Hui Xu, Jing Jin, Ying Chen, Guoqing Wu, Hua Zhu, Qing Wang, Ji Wang, Shenggang Li, Florina-Nicoleta Grigore, Jun Ma, Clark C Chen, Qing Lan, Ming Li.
      Glioblastoma is the most common malignant brain cancer with dismal survival and prognosis. Temozolomide (TMZ) is a first-line chemotherapeutic agent for glioblastoma, but the emergence of drug resistance limits its anti-tumor activity. We previously discovered that the interferon inducible guanylate binding protein 3 (GBP3) is highly elevated and promotes tumorigenicity of glioblastoma. Here, we show that TMZ treatment significantly upregulates the expression of GBP3 and stimulator of interferon genes (STING), both of which increase TMZ-induced DNA damage repair and reduce cell apoptosis of glioblastoma cells. Mechanistically, relying on its N-terminal GTPase domain, GBP3 physically interacts with STING to stabilize STING protein levels, which in turn induces expression of p62 (Sequestosome 1), nuclear factor erythroid 2 like 2 (NFE2L2, NRF2), and O6-methlyguanine-DNA-methyltransferase (MGMT), leading to the resistance to TMZ treatment. Reducing GBP3 levels by RNA interference in glioblastoma cells markedly increases the sensitivity to TMZ treatment in vitro and in murine glioblastoma models. Clinically, GBP3 expression is high and positively correlated with STING, NRF2, p62, and MGMT expression in human glioblastoma tumors, and is associated with poor outcomes. These findings provide novel insight into TMZ resistance and suggest that GBP3 may represent a novel potential target for the treatment of glioblastoma.
    DOI:  https://doi.org/10.1038/s41388-022-02397-5
  12. Nat Commun. 2022 Jul 08. 13(1): 3955
    PRMT5 activates AKT via methylation to promote tumor metastasis.
    Lei Huang, Xiao-Ou Zhang, Esteban J Rozen, Xiaomei Sun, Benjamin Sallis, Odette Verdejo-Torres, Kim Wigglesworth, Daniel Moon, Tingting Huang, John P Cavaretta, Gang Wang, Lei Zhang, Jason M Shohet, Mary M Lee, Qiong Wu.
      Protein arginine methyltransferase 5 (PRMT5) is the primary methyltransferase generating symmetric-dimethyl-arginine marks on histone and non-histone proteins. PRMT5 dysregulation is implicated in multiple oncogenic processes. Here, we report that PRMT5-mediated methylation of protein kinase B (AKT) is required for its subsequent phosphorylation at Thr308 and Ser473. Moreover, pharmacologic or genetic inhibition of PRMT5 abolishes AKT1 arginine 15 methylation, thereby preventing AKT1 translocation to the plasma membrane and subsequent recruitment of its upstream activating kinases PDK1 and mTOR2. We show that PRMT5/AKT signaling controls the expression of the epithelial-mesenchymal-transition transcription factors ZEB1, SNAIL, and TWIST1. PRMT5 inhibition significantly attenuates primary tumor growth and broadly blocks metastasis in multiple organs in xenograft tumor models of high-risk neuroblastoma. Collectively, our results suggest that PRMT5 inhibition augments anti-AKT or other downstream targeted therapeutics in high-risk metastatic cancers.
    DOI:  https://doi.org/10.1038/s41467-022-31645-1
  13. Proc Natl Acad Sci U S A. 2022 Jul 12. 119(28): e2111003119
    STING activation promotes robust immune response and NK cell-mediated tumor regression in glioblastoma models.
    Gilles Berger, Erik H Knelson, Jorge L Jimenez-Macias, Michal O Nowicki, Saemi Han, Eleni Panagioti, Patrick H Lizotte, Kwasi Adu-Berchie, Alexander Stafford, Nikolaos Dimitrakakis, Lanlan Zhou, E Antonio Chiocca, David J Mooney, David A Barbie, Sean E Lawler.
      Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The stimulator of interferon genes (STING) DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils, and natural killer (NK) populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, chimeric antigen receptor T cells, NK therapies, and immune checkpoint blockade.
    Keywords:  NK cells; STING; glioblastoma; immunotherapy
    DOI:  https://doi.org/10.1073/pnas.2111003119
  14. Oncogene. 2022 Jul 07.
    A synthetic lethal strategy using PARP and ATM inhibition for overcoming trastuzumab resistance in HER2-positive cancers.
    Kyoung-Seok Oh, Ah-Rong Nam, Ju-Hee Bang, Hye-Rim Seo, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh.
      Despite its clinical efficacy in HER2-positive cancers, resistance to trastuzumab inevitably occurs. The DNA damage response (DDR) pathway is essential for maintaining genomic stability and cell survival. However, the role of the DDR pathway in HER2-positive tumors and trastuzumab resistance remains elusive. In this study, we verified that increased PARP1 expression in trastuzumab-resistant (TR) cells, owing to its augmented stability by escape from proteasomal degradation, confers tolerability to trastuzumab-induced DNA damage. Interruption of PARP1 in TR cells restrains its cellular growth, while simultaneously activating ATM to retain its genome stability. Dual inhibition of PARP and ATM induces synthetic lethality in TR cells by favoring the toxic NHEJ pathway instead of the HRR pathway. Our results highlight the potential of clinical development of DDR-targeting strategies for trastuzumab-resistant HER2-positive cancer patients.
    DOI:  https://doi.org/10.1038/s41388-022-02384-w
  15. Cancer Discov. 2022 Jul 05. pii: cd.21.1671. [Epub ahead of print]
    PRC2 Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1 Targeted Therapy via Enhanced Viral Mimicry.
    Amish J Patel, Sarah Warda, Jesper L V Maag, Rohan Misra, Miguel A Miranda-Roman, Mohini R Pachai, Cindy J Lee, Dan Li, Naitao Wang, Gabriella Bayshtok, Eve Fishinevich, Yinuo Meng, Elissa W P Wong, Juan Yan, Emily Giff, Melissa B Pappalardi, Michael T McCabe, Jonathan A Fletcher, Charles M Rudin, Sarat Chandarlapaty, Joseph M Scandura, Richard P Koche, Jacob L Glass, Cristina R Antonescu, Deyou Zheng, Yu Chen, Ping Chi.
      Polycomb Repressive Complex 2 (PRC2) has oncogenic and tumor suppressor roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2 inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2-inactivation increases sensitivity to genetic or small molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor (DNMTi) mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through PKR-dependent double stranded-RNA (dsRNA) sensor. Collectively, our observations posit DNA methylation as a safeguard against anti-tumorigenic cell fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1 targeted therapy.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1671
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