bims-tucedo 2020-07-05 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2020‒07‒05
twenty-six papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition.
Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing β1 integrin, enhancing drug resistance.
Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target.
Exosomal PD-L1: Roles in Tumor Progression and Immunotherapy.
Fibroblast-tumor cell signaling limits HER2 kinase therapy response via activation of MTOR and antiapoptotic pathways.
Gastrointestinal stromal tumor: challenges and opportunities for a new decade.
SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways.
SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7.
Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination.
Turning Cold into Hot: Firing up the Tumor Microenvironment.
Neutrophil 'safety net' causes cancer cells to metastasize and proliferate.
Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent pathways.
Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients.
HDAC6 plays a non-canonical role in the regulation of anti-tumor immune responses, dissemination, and invasiveness of breast cancer.
Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma.
Lymphatic vessels in tumor dissemination vs. immunotherapy.
Pharmacological disruption of the Notch transcription factor complex.
MGMT Promoter Methylation as a Target In Metastatic Colorectal Cancer: Rapid Turnover and Use of Folates Alter its Study-Response.
Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression.
Radiation with STAT3 blockade triggers dendritic cell-T cell interactions in the glioma microenvironment and therapeutic efficacy.
Glioma escape signature and clonal development under immune pressure.
Inhibition of FGF2-Mediated Signaling in GIST-Promising Approach for Overcoming Resistance to Imatinib.
Measurement Tool of Chemotherapy Sensitivity in Advanced Ovarian Cancer.
Early Relapse Risk in Newly Diagnosed Multiple Myeloma Patients Characterized by Next-Generation Sequencing.
Long non-coding RNA: A recently accentuated molecule in chemoresistance in cancer.
Repurposing old drugs to fight multidrug resistant cancers.

Cancer Discov. 2020 Jun 30. pii: CD-19-1469. [Epub ahead of print]

Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition.

Sheng F Cai, S Haihua Chu, Aaron D Goldberg, Salma Parvin, Richard P Koche, Jacob L Glass, Eytan M Stein, Martin S Tallman, Filiz Sen, Christopher A Famulare, Monica Cusan, Chun-Hao Huang, Chun-Wei Chen, Lihua Zou, Keith B Cordner, Nicole L DelGaudio, Vidushi Durani, Mitali Kini, Madison Rex, Helen S Tian, Johannes Zuber, Timour Baslan, Scott W Lowe, Hugh Y Rienhoff, Anthony Letai, Ross L Levine, Scott A Armstrong.

The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor Evi1 compared to leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for Evi1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 inhibitors in addition to classical genotoxic stresses. p53 loss-of-function in Evi1-low progenitor-derived leukemias induces resistance to LSD1 inhibition, and Evi1-high leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant EVI1-high AML.

DOI: https://doi.org/10.1158/2159-8290.CD-19-1469
Cancer Res. 2020 Jun 30. pii: canres.3803.2019. [Epub ahead of print]

Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing β1 integrin, enhancing drug resistance.

Tomoyuki Uchihara, Keisuke Miyake, Atsuko Yonemura, Yoshihiro Komohara, Rumi Itoyama, Mayu Koiwa, Tadahito Yasuda, Kota Arima, Kazuto Harada, Kojiro Eto, Hiromitsu Hayashi, Masaaki Iwatsuki, Shiro Iwagami, Yoshifumi Baba, Naoya Yoshida, Masakazu Yashiro, Mari Masuda, Jaffer A Ajani, Patrick Tan, Hideo Baba, Takatsugu Ishimoto.

Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAF impact the aggressive characteristics of gastric cancer (GC) cells, the contribution of CAF-EV to GC progression has not been elucidated. Here we investigated the molecular mechanism of the changes in GC characteristics induced by CAF-EV. CAF abundance in GC tissues was associated with poor prognosis of GC patients receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of GC cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified annexin A6 plays a pivotal role in network formation and drug resistance of GC cells in the ECM via activation of β1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated GC drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by annexin A6 in CAF-EV and provide a potential avenue for overcoming GC drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3803
Nat Commun. 2020 Jul 03. 11(1): 3303

Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target.

Joseph W Franses, Julia Philipp, Pavlos Missios, Irun Bhan, Ann Liu, Chittampalli Yashaswini, Eric Tai, Huili Zhu, Matteo Ligorio, Benjamin Nicholson, Elizabeth M Tassoni, Niyati Desai, Anupriya S Kulkarni, Annamaria Szabolcs, Theodore S Hong, Andrew S Liss, Carlos Fernandez-Del Castillo, David P Ryan, Shyamala Maheswaran, Daniel A Haber, George Q Daley, David T Ting.

Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B-an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets-in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the "seeds" of metastasis.

DOI: https://doi.org/10.1038/s41467-020-17150-3
Trends Cancer. 2020 Jul;pii: S2405-8033(20)30099-6. [Epub ahead of print]6(7): 550-558

Exosomal PD-L1: Roles in Tumor Progression and Immunotherapy.

Samantha M Morrissey, Jun Yan.

  The use of immune checkpoint therapies targeting programmed death-1 (PD-1) and its ligand (PD-L1) continue to show limited durable success in clinical cases despite widespread application. While some patients achieve complete responses and disease remission, others are completely resistant to the therapy. Recent evidence in the field suggests that tumor-derived exosomes could be responsible for mediating systemic immunosuppression that antagonizes anti-PD-1 checkpoint therapy. In this Opinion article, we discuss our claim that endogenous tumor exosomal PD-L1 and tumor-derived exosome-induced PD-L1 are two of the most notable mechanisms of exosome-mediated resistance against antitumor immunity and we discuss how this resistance could directly influence immune checkpoint therapy failure.

Keywords:  PD-L1; exosomes; immunotherapy

DOI:  https://doi.org/10.1016/j.trecan.2020.03.002
Proc Natl Acad Sci U S A. 2020 Jun 29. pii: 202000648. [Epub ahead of print]

Fibroblast-tumor cell signaling limits HER2 kinase therapy response via activation of MTOR and antiapoptotic pathways.

Ioannis K Zervantonakis, Matthew D Poskus, Alexis L Scott, Laura M Selfors, Jia-Ren Lin, Deborah A Dillon, Shailja Pathania, Peter K Sorger, Gordon B Mills, Joan S Brugge.

  Despite the implementation of multiple HER2-targeted therapies, patients with advanced HER2+ breast cancer ultimately develop drug resistance. Stromal fibroblasts represent an abundant cell type in the tumor microenvironment and have been linked to poor outcomes and drug resistance. Here, we show that fibroblasts counteract the cytotoxic effects of HER2 kinase-targeted therapy in a subset of HER2+ breast cancer cell lines and allow cancer cells to proliferate in the presence of the HER2 kinase inhibitor lapatinib. Fibroblasts from primary breast tumors, normal breast tissue, and lung tissue have similar protective effects on tumor cells via paracrine factors. This fibroblast-mediated reduction in drug sensitivity involves increased expression of antiapoptotic proteins and sustained activation of the PI3K/AKT/MTOR pathway, despite inhibition of the HER2 and the RAS-ERK pathways in tumor cells. HER2 therapy sensitivity is restored in the fibroblast cocultures by combination treatment with inhibitors of MTOR or the antiapoptotic proteins BCL-XL and MCL-1. Expression of activated AKT in tumor cells recapitulates the effects of fibroblasts resulting in sustained MTOR signaling and poor lapatinib response. Lapatinib sensitivity was not altered by fibroblasts in tumor cells that exhibited sustained MTOR signaling due to a strong gain-of-function PI3KCA mutation. These findings indicate that in addition to tumor cell-intrinsic mechanisms that cause constitutive PI3K/AKT/MTOR pathway activation, secreted factors from fibroblasts can maintain this pathway in the context of HER2 inhibition. Our integrated proteomic-phenotypic approach presents a strategy for the discovery of protective mechanisms in fibroblast-rich tumors and the design of rational combination therapies to restore drug sensitivity.

Keywords:  breast cancer; cell–cell interactions; drug resistance; fibroblasts; tumor microenvironment

DOI:  https://doi.org/10.1073/pnas.2000648117
Clin Cancer Res. 2020 Jun 29. pii: clincanres.1706.2020. [Epub ahead of print]

Gastrointestinal stromal tumor: challenges and opportunities for a new decade.

César Serrano, Suzanne George.

Gastrointestinal stromal tumor (GIST) provides a paradigm to evaluate new molecularly-targeted therapies and to identify structural and functional mechanisms for drug response and resistance. Drug development in GIST has successfully exploited the high reliance on KIT/PDGFRA oncogenic signaling as a therapeutic vulnerability. The recent arrival of avapritinib and ripretinib to the GIST arena has aimed to further improve on precision kinase inhibition and address tumor heterogeneity in imatinib-resistant GIST. The two main clinical challenges for the forthcoming years entail tumor eradication in early-stage GIST patients, and maximization of tumor response in late-stage disease. In order to succeed, we will need to better understand the mechanisms behind adaptation to KIT inhibition and apoptosis evasion, tumor evolution after successive lines of treatment, and to explore clinically novel creative therapeutic strategies, with the overarching goal to tackle the intrinsic oncogenic complexity while minimizing adverse events.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-1706
Cancer Cell. 2020 Jun 11. pii: S1535-6108(20)30272-5. [Epub ahead of print]

SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways.

Huairui Yuan, Ying Han, Xuege Wang, Ni Li, Qiuli Liu, Yuye Yin, Hanling Wang, Lulu Pan, Li Li, Kun Song, Tong Qiu, Qiang Pan, Qilong Chen, Guoying Zhang, Yi Zang, Minjia Tan, Jian Zhang, Qintong Li, Xiaoming Wang, Jun Jiang, Jun Qin.

  The level of SETD2-mediated H3K36me3 is inversely correlated with that of EZH2-catalyzed H3K27me3. Nevertheless, it remains unclear whether these two enzymatic activities are molecularly intertwined. Here, we report that SETD2 delays prostate cancer (PCa) metastasis via its substrate EZH2. We show that SETD2 methylates EZH2 which promotes EZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state that enables cells to acquire metastatic traits. Conversely, mice harboring nonmethylated EZH2 mutant or SETD2 mutant defective in binding to EZH2 develop metastatic PCa. Furthermore, we identify that metformin-stimulated AMPK signaling converges at FOXO3 to stimulate SETD2 expression. Together, our results demonstrate that the SETD2-EZH2 axis integrates metabolic and epigenetic signaling to restrict PCa metastasis.

Keywords:  AMPK; EZH2; SETD2; epigenetic and metabolic dysregulations; metformin; prostate cancer metastasis

DOI:  https://doi.org/10.1016/j.ccell.2020.05.022
Oncogene. 2020 Jul 02.

SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7.

Jie Chen, Yunzhi Dang, Weibo Feng, Chenyang Qiao, Danfei Liu, Tongyue Zhang, Yijun Wang, Dean Tian, Daiming Fan, Yongzhan Nie, Kaichun Wu, Limin Xia.

The therapeutic strategies for advanced gastric cancer (GC) remain unsatisfying and limited. Therefore, it is still imperative to fully elucidate the mechanisms underlying GC metastasis. Here, we report a novel role of SRY-box transcription factor 18 (SOX18), a member of the SOX family, in promoting GC metastasis. The elevated expression of SOX18 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in human GC. SOX18 expression was an independent and significant risk factor for the recurrence and survival in GC patients. Up-regulation of SOX18 promoted GC invasion and metastasis, whereas down-regulation of SOX18 decreased GC invasion and metastasis. Melanoma cell adhesion molecule (MCAM) and C-C motif chemokine ligand 7 (CCL7) are direct transcriptional targets of SOX18. Knockdown of MCAM and CCL7 significantly decreased SOX18-mediated GC invasion and metastasis, while the stable overexpression of MCAM and CCL7 reversed the decrease in cell invasion and metastasis that was induced by the inhibition of SOX18. A mechanistic investigation indicated that the upregulation of SOX18 that was mediated by the CCL7-CCR1 pathway relied on the ERK/ELK1 pathway. SOX18 knockdown significantly reduced CCL7-enhanced GC invasion and metastasis. Furthermore, BX471, a specific CCR1 inhibitor, significantly reduced the SOX18-mediated GC invasion and metastasis. In human GC tissues, SOX18 expression was positively correlated with CCL7 and MCAM expression, and patients with positive coexpression of SOX18/CCL7 or SOX18/MCAM had the worst prognosis. In conclusion, we defined a CCL7-CCR1-SOX18 positive feedback loop that played a pivotal role in GC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of GC.

DOI: https://doi.org/10.1038/s41388-020-1378-1
Cancers (Basel). 2020 Jun 26. pii: E1697. [Epub ahead of print]12(6):

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination.

Angelica Avagliano, Giuseppe Fiume, Maria Rosaria Ruocco, Nunzia Martucci, Eleonora Vecchio, Luigi Insabato, Daniela Russo, Antonello Accurso, Stefania Masone, Stefania Montagnani, Alessandro Arcucci.

  The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the mechanisms of breast cancer (BC) biology. In fact, the unregulated mammary fibroblast signaling pathways, associated with alterations in extracellular matrix (ECM) remodeling and branching morphogenesis, drive breast cancer microenvironment (BCM) remodeling and cancer growth. The BCM comprises a very heterogeneous tissue containing non-cancer stromal cells, namely, breast cancer-associated fibroblasts (BCAFs), which represent most of the tumor mass. Moreover, the different components of the BCM highly interact with cancer cells, thereby generating a tightly intertwined network. In particular, BC cells activate recruited normal fibroblasts in BCAFs, which, in turn, promote BCM remodeling and metastasis. Thus, comparing the roles of normal fibroblasts and BCAFs in the physiological and metastatic processes, could provide a deeper understanding of the signaling pathways regulating BC dissemination. Here, we review the latest literature describing the structure of the mammary gland and the BCM and summarize the influence of epithelial-mesenchymal transition (EpMT) and autophagy in BC dissemination. Finally, we discuss the roles of fibroblasts and BCAFs in mammary gland development and BCM remodeling, respectively.

Keywords:  ECM remodeling; breast cancer associated fibroblasts (BCAFs); breast cancer microenvironment; fibroblasts; mammary gland; metastasis

DOI:  https://doi.org/10.3390/cancers12061697
Trends Cancer. 2020 Jul;pii: S2405-8033(20)30083-2. [Epub ahead of print]6(7): 605-618

Turning Cold into Hot: Firing up the Tumor Microenvironment.

Qianqian Duan, Hualing Zhang, Junnian Zheng, Lianjun Zhang.

  Cancers develop within complex tissue environments consisting of diverse innate and adaptive immune cells, along with stromal cells, vascular networks, and many other cellular and noncellular components. The high heterogeneity within the tumor microenvironment (TME) remains a key obstacle in understanding and treating cancer. Understanding the dynamic functional interplay within this intricate ecosystem will provide important insights into the design of effective combinatorial strategies against cancer. Here, we present recent technical advances to explore the complexity of the TME. Then, we discuss how innate immune sensing machinery, genetic alterations of oncogenic signaling, cellular metabolism, and epigenetic factors are involved in modulating the TME. Finally, we summarize the potential strategies to boost antitumor immunity by therapeutically exploiting the TME.

Keywords:  epigenetic; immune checkpoint blockade; metabolism; single cell profiling; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2020.02.022
Nature. 2020 07;583(7814): 32-33

Neutrophil 'safety net' causes cancer cells to metastasize and proliferate.

Emma Nolan, Ilaria Malanchi.



Keywords:  Cancer; Medical research

DOI:  https://doi.org/10.1038/d41586-020-01672-3
Oncogene. 2020 Jul 02.

Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent pathways.

Siraj M El Jamal, Abdulhadi Alamodi, Renate U Wahl, Zakaria Grada, Mohammad Abrar Shareef, Sofie-Yasmin Hassan, Fadi Murad, Sarah-Lilly Hassan, Simeon Santourlidis, Christian R Gomez, Youssef Haikel, Mosaad Megahed, Mohamed Hassan.

Melanoma stem cells (MSCs) are characterized by their unique cell surface proteins and aberrant signaling pathways. These stemness properties are either in a causal or consequential relationship to melanoma progression, treatment resistance and recurrence. The functional analysis of CD133+ and CD133- cells in vitro and in vivo revealed that melanoma progression and treatment resistance are the consequences of CD133 signal to PI3K pathway. CD133 signal to PI3K pathway drives two downstream pathways, the PI3K/Akt/MDM2 and the PI3K/Akt/MKP-1 pathways. Activation of PI3K/Akt/MDM2 pathway results in the destabilization of p53 protein, while the activation of PI3K/Akt/MKP-1 pathway results in the inhibition of mitogen-activated protein kinases (MAPKs) JNK and p38. Activation of both pathways leads to the inhibition of fotemustine-induced apoptosis. Thus, the disruption of CD133 signal to PI3K pathway is essential to overcome Melanoma resistance to fotemustine. The pre-clinical verification of in vitro data using xenograft mouse model of MSCs confirmed the clinical relevance of CD133 signal as a therapeutic target for melanoma treatment. In conclusion, our study provides an insight into the mechanisms regulating MSCs growth and chemo-resistance and suggested a clinically relevant approach for melanoma treatment.

DOI: https://doi.org/10.1038/s41388-020-1373-6
Nat Commun. 2020 Jun 29. 11(1): 3272

Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients.

Nicolas Gonzalo Núñez, Jimena Tosello Boari, Rodrigo Nalio Ramos, Wilfrid Richer, Nicolas Cagnard, Cyrill Dimitri Anderfuhren, Leticia Laura Niborski, Jeremy Bigot, Didier Meseure, Philippe De La Rochere, Maud Milder, Sophie Viel, Delphine Loirat, Louis Pérol, Anne Vincent-Salomon, Xavier Sastre-Garau, Becher Burkhard, Christine Sedlik, Olivier Lantz, Sebastian Amigorena, Eliane Piaggio.

Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, and that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic signature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41467-020-17046-2
Cancer Res. 2020 Jun 30. pii: canres.3738.2019. [Epub ahead of print]

HDAC6 plays a non-canonical role in the regulation of anti-tumor immune responses, dissemination, and invasiveness of breast cancer.

Debarati Banik, Satish Noonepalle, Melissa Hadley, Erica Palmer, Maria Gracia-Hernandez, Christian Zevallos-Delgado, Namratta Manhas, Hayk Simonyan, Colin N Young, Anastas Popratiloff, Katherine B Chiappinelli, Rohan Fernandes, Eduardo M Sotomayor, Alejandro Villagra.

Despite the outstanding clinical results of immune checkpoint blockade (ICB) in melanoma and other cancers, clinical trials in breast cancer have reported low responses to these therapies. Current efforts are now focused on improving the treatment efficacy of ICB in breast cancer using new combination designs such as molecularly targeted agents, including histone deacetylase inhibitors (HDACi). These epigenetic drugs have been widely described as potent cytotoxic agents for cancer cells. In this work, we report new non-canonical regulatory properties of ultra-selective HDAC6i over the expression and function of epithelial-mesenchymal transition pathways and the invasiveness potential of breast cancer. These unexplored roles position HDAC6i as attractive options to potentiate ongoing immunotherapeutic approaches. These new functional activities of HDAC6i involved regulation of the E-cadherin/STAT3 axis. Pre-treatment of tumors with HDAC6i induced critical changes in the tumor microenvironment, resulting in improved effectiveness of ICB and preventing dissemination of cancer cells to secondary niches. Our results demonstrate for the first time that HDAC6i can both improve ICB antitumor immune responses and diminish the invasiveness of BC with minimal cytotoxic effects, thus departing from the cytotoxicity-centric paradigm previously assigned to HDACi.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3738
Mol Cancer. 2020 06 27. 19(1): 110

Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma.

Peng-Fei Zhang, Chao Gao, Xiao-Yong Huang, Jia-Cheng Lu, Xiao-Jun Guo, Guo-Ming Shi, Jia-Bin Cai, Ai-Wu Ke.

OBJECTIVE: Natural killer (NK) cells play a critical role in the innate antitumor immune response. Recently, NK cell dysfunction has been verified in various malignant tumors, including hepatocellular carcinoma (HCC). However, the molecular biological mechanisms of NK cell dysfunction in human HCC are still obscure.METHODS: The expression of circular ubiquitin-like with PHD and ring finger domain 1 RNA (circUHRF1) in HCC tissues, exosomes, and cell lines was detected by qRT-PCR. Exosomes were isolated from the culture medium of HCC cells and plasma of HCC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit and then characterized by transmission electronic microscopy, NanoSight and western blotting. The role of circUHRF1 in NK cell dysfunction was assessed by ELISA. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore the molecular mechanisms of circUHRF1 in NK cells. In a retrospective study, the clinical characteristics and prognostic significance of circUHRF1 were determined in HCC tissues.
RESULTS: Here, we report that the expression of circUHRF1 is higher in human HCC tissues than in matched adjacent nontumor tissues. Increased levels of circUHRF1 indicate poor clinical prognosis and NK cell dysfunction in patients with HCC. In HCC patient plasma, circUHRF1 is predominantly secreted by HCC cells in an exosomal manner, and circUHRF1 inhibits NK cell-derived IFN-γ and TNF-α secretion. A high level of plasma exosomal circUHRF1 is associated with a decreased NK cell proportion and decreased NK cell tumor infiltration. Moreover, circUHRF1 inhibits NK cell function by upregulating the expression of TIM-3 via degradation of miR-449c-5p. Finally, we show that circUHRF1 may drive resistance to anti-PD1 immunotherapy in HCC patients.
CONCLUSIONS: Exosomal circUHRF1 is predominantly secreted by HCC cells and contributes to immunosuppression by inducing NK cell dysfunction in HCC. CircUHRF1 may drive resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for patients with HCC.

DOI: https://doi.org/10.1186/s12943-020-01222-5
Cancer Res. 2020 Jun 30. pii: canres.0156.2020. [Epub ahead of print]

Lymphatic vessels in tumor dissemination vs. immunotherapy.

Kari Vaahtomeri, Kari Alitalo.

During the growth of various cancers, primary tumors can escape anti-tumor immune responses of their host and eventually disseminate into distant organs. Peritumoral lymphatic vessels connect the primary tumor to lymph nodes, facilitating tumor entry into lymph nodes, systemic circulation, and metastasis. Lymph node metastases that occur frequently provide sites of tumor cell spread, whereas tumor antigen transfer into and presentation in tumor-draining lymph nodes induce activation of tumor-specific T-lymphocyte responses that can result in cytolytic targeting of the tumor. Here we discuss the recently emerged controversial role of the lymphatic vessels in tumor dissemination and cancer immunotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-0156
Proc Natl Acad Sci U S A. 2020 Jun 29. pii: 201922606. [Epub ahead of print]

Pharmacological disruption of the Notch transcription factor complex.

Rajwinder Lehal, Jelena Zaric, Michele Vigolo, Charlotte Urech, Viktoras Frismantas, Nadine Zangger, Linlin Cao, Adeline Berger, Irene Chicote, Sylvain Loubéry, Sung Hee Choi, Ute Koch, Stephen C Blacklow, Hector G Palmer, Beat Bornhauser, Marcos González-Gaitán, Yvan Arsenijevic, Vincent Zoete, Jon C Aster, Jean-Pierre Bourquin, Freddy Radtke.

  Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.

Keywords:  Notch; cancer; small-molecule inhbitor

DOI:  https://doi.org/10.1073/pnas.1922606117
Clin Cancer Res. 2020 Jul 01. 26(13): 3495

MGMT Promoter Methylation as a Target In Metastatic Colorectal Cancer: Rapid Turnover and Use of Folates Alter its Study-Response.

Giovanni Randon, Filippo Pagani, Filippo Pietrantonio.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-0817
Mol Ther. 2020 Jun 15. pii: S1525-0016(20)30303-8. [Epub ahead of print]

Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression.

Wei Zhang, Xiaolei Shi, Rui Chen, Yasheng Zhu, Shihong Peng, Yifan Chang, Xinwen Nian, Guang'an Xiao, Ziyu Fang, Yaoming Li, Zhexu Cao, Lin Zhao, Guang Liu, Yinghao Sun, Shancheng Ren.

  Long non-coding RNAs (lncRNAs) participate in the development and progression of prostate cancer (PCa). We aimd to identify a novel lncRNA, named lncRNA activated in metastatic PCa (lncAMPC), and investigate its mechanisms and clinical significance in PCa. First, the biological capacity of lncAMPC in PCa was demonstrated both in vitro and in vivo. The lncAMPC was overexpressed in tumor tissue and urine of metastatic PCa patients and promoted PCa tumorigenesis and metastasis. Then, a mechanism study was conducted to determine how the lncAMPC-activated pathway contributed to PCa metastasis and immunosuppression. In the cytoplasm, lncAMPC upregulated LIF expression by sponging miR-637 and inhibiting its activity. In the nucleus, lncAMPC enhanced LIFR transcription by decoying histone H1.2 away from the upstream sequence of the LIFR gene. The lncAMPC-activated LIF/LIFR expressions stimulated the Jak1-STAT3 pathway to simultaneously maintain programmed death-ligand 1 (PD-L1) protein stability and promote metastasis-associated gene expression. Finally, the prognostic value of the expression of lncAMPC and its downstream genes in PCa patients was evaluated. High LIF/LIFR levels indicated shorter biochemical recurrence-free survival among patients who underwent radical prostatectomy. Therefore, the lncAMPC/LIF/LIFR axis plays a critical role in PCa metastasis and immunosuppression and may serve as a prognostic biomarker and potential therapeutic target.

Keywords:  LIF/LIFR/Jak1/STAT3 pathway; competing endogenous RNA; histone H1.2; long non-coding RNA; prostate cancer

DOI:  https://doi.org/10.1016/j.ymthe.2020.06.013
Clin Cancer Res. 2020 Jun 30. pii: clincanres.4092.2019. [Epub ahead of print]

Radiation with STAT3 blockade triggers dendritic cell-T cell interactions in the glioma microenvironment and therapeutic efficacy.

Martina Ott, Cynthia Kassab, Anantha Marisetty, Yuuri Hashimoto, Jun Wei, Daniel B Zamler, Jia-Shiun Leu, Karl-Heinz Tomaszowski, Aria Sabbagh, Dexing Fang, Pravesh Gupta, Waldemar Priebe, Rafal Zielinski, Jared K Burks, James P Long, Ling-Yuan Kong, Gregory N Fuller, John F de Groot, Erik P Sulman, Amy B Heimberger.

BACKGROUND: Patients with central nervous system (CNS) tumors are typically treated with radiation therapy, but this is not curative and results in the upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiation therapy (WBRT) in a murine model of glioma.METHODS: C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood-brain barrier (BBB)-penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and nanostring gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment.
RESULTS: The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control p<0.0001). Immunological memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. The therapeutic effect of the combination was completely lost in immune incompetent animals. Nanostring analysis and immunofluorescence revealed immunological reprograming in the CNS tumor microenvironment specifically affecting dendritic-cell antigen presentation and T cell effector functions.
CONCLUSION: This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic cell and T cell interactions in the CNS tumor.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-4092
J Clin Invest. 2020 Jun 30. pii: 138760. [Epub ahead of print]

Glioma escape signature and clonal development under immune pressure.

Cecile L Maire, Malte Mohme, Michael Bockmayr, Krystian D Fita, Kristoffer Riecken, Daniela Börnigen, Malik Alawi, Antonio Virgilio Failla, Katharina Kolbe, Svenja Zapf, Mareike Holz, Katrin Neumann, Lasse Dührsen, Tobias Lange, Boris Fehse, Manfred Westphal, Katrin Lamszus.

  Immunotherapeutic strategies are increasingly important in neuro-oncology and the elucidation of escape mechanisms which lead to treatment resistance is crucial. We investigated the impact of immune pressure on the clonal dynamics and immune escape signature by comparing glioma growth in immunocompetent versus immunodeficient mice. Glioma-bearing wildtype and Pd-1-/- mice survived significantly longer than immunodeficient Pfp-/- Rag2-/- mice. While tumors in Pfp-/- Rag2-/- mice were highly polyclonal, immunoedited tumors in WT and Pd-1-/- mice displayed reduced clonality with emergence of immune escape clones. Tumor cells in wildtype mice were distinguished by an interferon-γ-mediated response signature with upregulation of genes involved in immunosuppression. Tumor-infiltrating stromal cells, which include macrophages/microglia, contributed even stronger to the immunosuppressive signature than the actual tumor cells. The identified murine immune escape signature was reflected in human patients and correlated with poor survival. In conclusion, immune pressure profoundly shapes the clonal composition and gene regulation in malignant gliomas.

Keywords:  Brain cancer; Immunology; Oncology

DOI:  https://doi.org/10.1172/JCI138760
Cancers (Basel). 2020 Jun 24. pii: E1674. [Epub ahead of print]12(6):

Inhibition of FGF2-Mediated Signaling in GIST-Promising Approach for Overcoming Resistance to Imatinib.

Sergei Boichuk, Aigul Galembikova, Ekaterina Mikheeva, Firuza Bikinieva, Aida Aukhadieva, Pavel Dunaev, Dinar Khalikov, Semen Petrov, Refat Kurtasanov, Elena Valeeva, Igor Kireev, Vera Dugina, Anna Lushnikova, Maria Novikova, Pavel Kopnin.

  Inhibition of KIT-signaling is a major molecular target for gastrointestinal stromal tumor (GIST) therapy, and imatinib mesylate (IM) is known as the most effective first-line treatment option for patients with advanced, unresectable, and/or metastatic GISTs. We show here for the first time that the inhibition of KIT-signaling in GISTs induces profound changes in the cellular secretome, leading to the release of multiple chemokines, including FGF-2. IM increased migration, invasion, and colony formation of IM-resistant GISTs in an FGF2-dependent manner, whereas the use of blocking anti-FGF2 antibodies or BGJ398, a selective FGFR inhibitor, abolished these effects, thus suggesting that the activation of FGF2-mediated signaling could serve as a compensatory mechanism of KIT-signaling inhibited in GISTs. Conversely, FGF-2 rescued the growth of IM-naive GISTs treated by IM and protected them from IM-induced apoptosis, consistent with the possible involvement of FGF-2 in tumor response to IM-based therapy. Indeed, increased FGF-2 levels in serum and tumor specimens were found in IM-treated mice bearing IM-resistant GIST xenografts, whereas BGJ398 used in combination with IM effectively inhibited their growth. Similarly, increased FGF-2 expression in tumor specimens from IM-treated patients revealed the activation of FGF2-signaling in GISTs in vivo. Collectively, the continuation of IM-based therapy for IM-resistant GISTs might facilitate disease progression by promoting the malignant behavior of tumors in an FGF2-dependent manner. This provides a rationale to evaluate the effectiveness of the inhibitors of FGF-signaling for IM-resistant GISTs.

Keywords:  FGF-2; autocrine pathway; c-KIT and FGFR-signaling; gastrointestinal stromal tumors (GISTs); imatinib (IM); receptor tyrosine kinase (RTK); resistance; sunitinib (SU)

DOI:  https://doi.org/10.3390/cancers12061674
Clin Cancer Res. 2020 Jun 29. pii: clincanres.1376.2020. [Epub ahead of print]

Measurement Tool of Chemotherapy Sensitivity in Advanced Ovarian Cancer.

Taymaa May, Amit M Oza.

The modeled Ca125 ELIMination rate constant K (KELIM) can be used as a measure of chemotherapy sensitivity in women with newly diagnosed advanced epithelial ovarian cancer who are being treated with neoadjuvant chemotherapy. This marker may aid in decision making regarding surgical resection and alternate systemic treatments in this cohort.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-1376
Clin Cancer Res. 2020 Jul 02. pii: clincanres.0951.2020. [Epub ahead of print]

Early Relapse Risk in Newly Diagnosed Multiple Myeloma Patients Characterized by Next-Generation Sequencing.

Mattia D'Agostino, Gian Maria Zaccaria, Bachisio Ziccheddu, Even H Rustad, Elisa Genuardi, Andrea Capra, Stefania Oliva, Daniel Auclair, Jennifer Yesil, Paola Colucci, Jonathan J Keats, Manuela Gambella, Sara Bringhen, Alessandra Larocca, Mario Boccadoro, Niccolò Bolli, Francesco Maura, Francesca Gay.

INTRODUCTION: Duration of first remission is important for the survival of multiple myeloma (MM) patients.METHODS: From the CoMMpass study (NCT01454297), 926 newly diagnosed MM patients, characterized by next-generation sequencing, were analyzed to evaluate those who experienced early progressive disease (PD) (time to progression, TTP≤18 months).
RESULTS: After a median follow-up of 39 months, early PD was detected in 191/926 (20.6%) patients, 228/926 (24.6%) patients had late PD (TTP>18 months), while 507/926 (54.8%) did not have PD at the current follow-up. Compared to Late PD patients, Early PD patients had a lower at least very good partial response rate (47% vs 82%, p<0.001) and more frequently acquired double refractoriness to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) (21% vs 8%, p<0.001). Early PD patients were at higher risk of death compared to Late PD and No PD patients (HR 3.65, 95% CI 2.7-4.93, p<0.001), showing a dismal median overall survival (32.8 months). In a multivariate logistic regression model, independent factors increasing the Early PD risk were TP53 mutation (OR 3.78, p<0.001), high LDH levels (OR 3.15, p=0.006), λ-chain translocation (OR 2.25, p=0.033) and IGLL5 mutation (OR 2.15, p=0.007). Carfilzomib-based induction (OR 0.15, p=0.014), autologous stem-cell transplantation (OR 0.27, p<0.001) and continuous therapy with PIs and IMiDs (OR 0.34, p=0.024) mitigated the risk of early PD.
CONCLUSION: Early PD identifies a high-risk MM population. Further research is needed to better identify baseline features predicting early PD and the optimal treatment approaches for patients at risk.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-0951
Cancer Metastasis Rev. 2020 Jun 27.

Long non-coding RNA: A recently accentuated molecule in chemoresistance in cancer.

Yang Peng, Dihong Tang, Meng Zhao, Hiroaki Kajiyama, Fumitaka Kikkawa, Yutaka Kondo.

  Chemotherapy is one of the important and effective options for cancer treatment in the past decades. Although the response rate of initial chemotherapy is considerably high in certain types of cancers, such as ovarian cancer and lung cancer, the patients frequently suffer from chemoresistance and recurrence of disease. Recent genome-wide studies have shown that the large number of long non-coding RNAs (lncRNAs) are transcribed from the human genome and involved in many biological processes including carcinogenesis. They aberrantly regulate variety of cell functions, such as cell cycle, apoptosis, autophagy, and metabolisms, which are associated with chemosensitivity. Therefore, understanding the biological and clinical impacts of lncRNAs on tumor behavior and its potential as a predictive biomarker for chemotherapy effectiveness is highly desired. In this review, we classify the major mechanisms of lncRNA-related chemoresistance and provide theoretical evidences for targeting lncRNAs in certain types of cancers that may open up new therapeutic paradigm for cancer treatment.

Keywords:  Cancer; Chemoresistance; Epigenetics; Long non-coding RNA

DOI:  https://doi.org/10.1007/s10555-020-09910-w
Drug Resist Updat. 2020 Jun 25. pii: S1368-7646(20)30042-X. [Epub ahead of print]52 100713

Repurposing old drugs to fight multidrug resistant cancers.

Jelena Dinić, Thomas Efferth, Alfonso T García-Sosa, Jelena Grahovac, José M Padrón, Ilza Pajeva, Flavio Rizzolio, Simona Saponara, Gabriella Spengler, Ivanka Tsakovska.

  Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.

Keywords:  Clinical cancer trials; Drug repurposing; Multidrug resistant cancer; Pharmacophore modelling; Virtual screening

DOI:  https://doi.org/10.1016/j.drup.2020.100713