bims-tucedo 2020-06-07 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2020–06–07
29 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology

The dormant cancer cell life cycle.
Investigation of the role and mechanism of ARHGAP5-mediated colorectal cancer metastasis.
Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer.
Epigenetics and metabolism at the crossroads of stress-induced plasticity, stemness and therapeutic resistance in cancer.
Chemotherapy and Tumor Evolution Shape Pancreatic Cancer Recurrence after Resection.
Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma.
The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer.
Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance.
Taxane resistance in prostate cancer is mediated by decreased drug-target engagement.
Stromal CAVIN1 controls prostate cancer microenvironment and metastasis by modulating lipid distribution and inflammatory signaling.
MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer.
A S100A14-CCL2/CXCL5 signaling axis drives breast cancer metastasis.
Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities.
Changes in Aged Fibroblast Lipid Metabolism Induce Age-dependent Melanoma Cell Resistance to Targeted Therapy Via the Fatty Acid Transporter FATP2.
Proof-of-Concept with PROTACs in Prostate Cancer.
STIM1 is a metabolic checkpoint regulating the invasion and metastasis of hepatocellular carcinoma.
The EMT transcription factor ZEB2 promotes proliferation of primary and metastatic melanoma while suppressing an invasive, mesenchymal-like phenotype.
Ubiquitin ligase CHIP regulates OTUD3 stability and suppresses tumour metastasis in lung cancer.
A TGFβ-dependent stromal subset underlies immune checkpoint inhibitor efficacy in DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer.
CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p.
Bridging the Translational Divide in Oncology: In Vivo Testing of Chemo-Sensitivity.
Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition.
Comprehensive landscape of extracellular vesicle-derived RNAs in cancer initiation, progression, metastasis and cancer immunology.
The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase.
Epithelial-Mesenchymal Transition Programs and Cancer Stem Cell Phenotypes: Mediators of Breast Cancer Therapy Resistance.
Autoantibody profiling identifies predictive biomarkers of response to anti-PD1 therapy in cancer patients.
Hypoxia-mediated changes in bone marrow microenvironment in breast cancer dormancy.
Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics.
Long Noncoding RNAs Involved in the Endocrine Therapy Resistance of Breast Cancer.

Nat Rev Cancer. 2020 Jun 02.

The dormant cancer cell life cycle.

Tri Giang Phan, Peter I Croucher.

The success of targeted therapies and immunotherapies has created optimism that cancers may be curable. However, not all patients respond, drug resistance is common and many patients relapse owing to dormant cancer cells. These rare and elusive cells can disseminate early and hide in specialized niches in distant organs before being reactivated to cause disease relapse after successful treatment of the primary tumour. Despite their importance, we are yet to leverage knowledge generated from experimental models and translate the potential of targeting dormant cancer cells to prevent disease relapse in the clinic. This is due, at least in part, to the lack of adherence to consensus definitions by researchers, limited models that faithfully recapitulate this stage of metastatic spread and an absence of interdisciplinary approaches. However, the application of new high-resolution, single-cell technologies is starting to revolutionize the field and transcend classical reductionist models of studying individual cell types or genes in isolation to provide a global view of the complex underlying cellular ecosystem and transcriptional landscape that controls dormancy. In this Perspective, we synthesize some of these recent advances to describe the hallmarks of cancer cell dormancy and how the dormant cancer cell life cycle offers opportunities to target not only the cancer but also its environment to achieve a durable cure for seemingly incurable cancers.

DOI: https://doi.org/10.1038/s41568-020-0263-0
Theranostics. 2020 ;10(13): 5998-6010

Investigation of the role and mechanism of ARHGAP5-mediated colorectal cancer metastasis.

Tian Tian, Zhan-Hong Chen, Zongheng Zheng, Yubo Liu, Qi Zhao, Yuying Liu, Huijun Qiu, Qian Long, Miao Chen, Liren Li, Fangyun Xie, Guangyu Luo, Xiaojun Wu, Wuguo Deng.

  Background: Metastatic colorectal cancer (CRC) is a lethal disease; however, the underlying molecular mechanisms remain unclear and require further study. Methods: RNA-Seq, PCR, Western blotting, immunohistochemistry, ChIP and RNAi assays were performed to investigate Rho GTPase-activating protein 5 (ARHGAP5, aslo known as p190RhoGAP-B, p190-B) expression and the clinical relevance, functional roles and regulatory mechanisms of this protein using human CRC cells and tissues. In vivo, two cell-based xenograft models were used to evaluate the roles of ARHGAP5 in CRC metastasis. Results: Here, we report that ARHGAP5 expression is significantly increased in metastatic CRC tissues and is inversely associated with patient overall survival. The suppression of ARHGAP5 reduces CRC cell metastasis in vitro and in cell-based xenograft models. Furthermore, we show that ARHGAP5 promotes CRC cell epithelial-mesenchymal transition by negatively regulating RhoA activity. Mechanistically, cAMP response element-binding protein (CREB1) transcriptionally upregulates ARHGAP5 expression, and decreased miR-137 further contributes to ARHGAP5 mRNA stability in CRC. Conclusions: Overall, our study highlights the crucial function of ARHGAP5 in CRC metastasis, thus suggesting novel prognostic biomarkers and hypothetical therapeutic targets.

Keywords:  ARHGAP5; CREB1; colorectal cancer; miR-137; tumor metastasis

DOI:  https://doi.org/10.7150/thno.43427
Cell Rep. 2020 Jun 02. pii: S2211-1247(20)30671-9. [Epub ahead of print]31(9): 107701

Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer.

Lisa M Becker, Joyce T O'Connell, Annie P Vo, Margo P Cain, Desiree Tampe, Lauren Bizarro, Hikaru Sugimoto, Anna K McGow, John M Asara, Sara Lovisa, Kathleen M McAndrews, Rafal Zielinski, Philip L Lorenzi, Michael Zeisberg, Sughra Raza, Valerie S LeBleu, Raghu Kalluri.

  The mechanistic contributions of cancer-associated fibroblasts (CAFs) in breast cancer progression remain to be fully understood. While altered glucose metabolism in CAFs could fuel cancer cells, how such metabolic reprogramming emerges and is sustained needs further investigation. Studying fibroblasts isolated from patients with benign breast tissues and breast cancer, in conjunction with multiple animal models, we demonstrate that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells. The depletion or suppression of the lactate production of CAFs alter the tumor metabolic profile and impede tumor growth. The glycolytic phenotype of the CAFs is in part sustained through epigenetic reprogramming of HIF-1α and glycolytic enzymes. Hypoxia induces epigenetic reprogramming of normal fibroblasts, resulting in a pro-glycolytic, CAF-like transcriptome. Our findings suggest that the glucose metabolism of CAFs evolves during tumor progression, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.

Keywords:  breast cancer; cancer-associated fibroblasts; epigenetic alterations; hypoxia; metabolism

DOI:  https://doi.org/10.1016/j.celrep.2020.107701
Theranostics. 2020 ;10(14): 6261-6277

Epigenetics and metabolism at the crossroads of stress-induced plasticity, stemness and therapeutic resistance in cancer.

Dinoop Ravindran Menon, Heinz Hammerlindl, Joachim Torrano, Helmut Schaider, Mayumi Fujita.

  Despite the recent advances in the treatment of cancers, acquired drug resistance remains a major challenge in cancer management. While earlier studies suggest Darwinian factors driving acquired drug resistance, recent studies point to a more dynamic process involving phenotypic plasticity and tumor heterogeneity in the evolution of acquired drug resistance. Chronic stress after drug treatment induces intrinsic cellular reprogramming and cancer stemness through a slow-cycling persister state, which subsequently drives cancer progression. Both epigenetic and metabolic mechanisms play an important role in this dynamic process. In this review, we discuss how epigenetic and metabolic reprogramming leads to stress-induced phenotypic plasticity and acquired drug resistance, and how the two reprogramming mechanisms crosstalk with each other.

Keywords:  Epigenetics; metabolism; stemness; stress-induced plasticity

DOI:  https://doi.org/10.7150/thno.42523
Cancer Discov. 2020 Jun;10(6): 762-764

Chemotherapy and Tumor Evolution Shape Pancreatic Cancer Recurrence after Resection.

Filip Bednar, Marina Pasca di Magliano.

Most patients with pancreatic cancer who undergo curative resection and systemic chemotherapy still relapse with local or systemic recurrence. In this issue, Sakamoto and colleagues use advanced genomic tools to investigate the evolutionary origins of pancreatic cancer recurrence and discover an increased mutational burden that might be promoted by therapeutic intervention and might provide an opportunity for therapeutic intervention.See related article by Sakamoto et al., p. 792.

DOI: https://doi.org/10.1158/2159-8290.CD-20-0359
Nat Cell Biol. 2020 Jun 01.

Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma.

Dan Liao, Li Zhong, Junqiang Yin, Cuiling Zeng, Xin Wang, Xingchuan Huang, Jinna Chen, Hong Zhang, Ruhua Zhang, Xin-Yuan Guan, Xintao Shuai, Jianhua Sui, Song Gao, Wuguo Deng, Yi-Xin Zeng, Jing-Nan Shen, Jian Chen, Tiebang Kang.

Osteosarcoma is a type of aggressive malignant bone tumour that frequently metastasizes to lungs, resulting in poor prognosis. However, the molecular mechanisms of lung metastasis of osteosarcoma remain poorly understood. Here we identify exon-intron fusion genes in osteosarcoma cell lines and tissues. These fusion genes are derived from chromosomal translocations that juxtapose the coding region for amino acids 1-38 of Rab22a (Rab22a1-38) with multiple inverted introns and untranslated regions of chromosome 20. The resulting translation products, designated Rab22a-NeoFs, acquire the ability to drive lung metastasis of osteosarcoma. The Rab22a1-38 moiety governs the function of Rab22a-NeoFs by binding to SmgGDS-607, a GTP-GDP exchange factor of RhoA. This association facilitates the release of GTP-bound RhoA from SmgGDS-607, which induces increased activity of RhoA and promotes metastasis. Disrupting the interaction between Rab22a-NeoF1 and SmgGDS-607 with a synthetic peptide prevents lung metastasis in an orthotopic model of osteosarcoma. Our findings may provide a promising strategy for a subset of osteosarcoma patients with lung metastases.

DOI: https://doi.org/10.1038/s41556-020-0522-z
Nat Commun. 2020 Jun 01. 11(1): 2689

The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer.

Keliang Wang, Jie Luo, Shuyuan Yeh, Bosen You, Jialin Meng, Philip Chang, Yuanjie Niu, Gonghui Li, Changxue Lu, Yezi Zhu, Emmanuel S Antonarakis, Jun Luo, Chi-Ping Huang, Wanhai Xu, Chawnshang Chang.

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.

DOI: https://doi.org/10.1038/s41467-020-15396-5
Cancers (Basel). 2020 May 28. pii: E1393. [Epub ahead of print]12(6):

Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance.

Colleen M Garvey, Roy Lau, Alyssa Sanchez, Ren X Sun, Emma J Fong, Michael E Doche, Oscar Chen, Anthony Jusuf, Heinz-Josef Lenz, Brent Larson, Shannon M Mumenthaler.

  Targeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack of understanding of how these therapies affect the unsuspecting bystanders of the stromal microenvironment. Cetuximab, a monoclonal antibody therapy targeting the epidermal growth factor receptor (EGFR), is given in combination with chemotherapy as the standard of care for a subset of metastatic colorectal cancer patients. The overall response to this treatment is underwhelming and, while genetic mutations that confer resistance have been identified, it is still not known why this drug is ineffective for some patients. We discovered that cancer-associated fibroblasts (CAFs), a major cellular subset of the tumor stroma, can provide a source of cancer cell resistance. Specifically, we observed that upon treatment with cetuximab, CAFs increased their secretion of EGF, which was sufficient to render neighboring cancer cells resistant to cetuximab treatment through sustained mitogen-activated protein kinases (MAPK) signaling. Furthermore, we show the cetuximab-induced EGF secretion to be specific to CAFs and not to cancer cells or normal fibroblasts. Altogether, this work emphasizes the importance of the tumor microenvironment and considering the potential unintended consequences of therapeutically targeting cancer-driving proteins on non-tumorigenic cell types.

Keywords:  cancer-associated fibroblasts; cetuximab; colorectal cancer; drug-resistance; epidermal growth factor; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers12061393
J Clin Invest. 2020 Jun 01. pii: 132184. [Epub ahead of print]130(6): 3287-3298

Taxane resistance in prostate cancer is mediated by decreased drug-target engagement.

Ada Gjyrezi, Fang Xie, Olga Voznesensky, Prateek Khanna, Carla Calagua, Yang Bai, Justin Kung, Jim Wu, Eva Corey, Bruce Montgomery, Sandrine Mace, Diego A Gianolio, Glenn J Bubley, Steven P Balk, Paraskevi Giannakakou, Rupal S Bhatt.

  Despite widespread use of taxanes, mechanisms of action and resistance in vivo remain to be established, and there is no way of predicting who will respond to therapy. This study examined prostate cancer (PCa) xenografts and patient samples to identify in vivo mechanisms of taxane action and resistance. Docetaxel drug-target engagement was assessed by confocal anti-tubulin immunofluorescence to quantify microtubule bundling in interphase cells and aberrant mitoses. Tumor biopsies from metastatic PCa patients obtained 2 to 5 days after their first dose of docetaxel or cabazitaxel were processed to assess microtubule bundling, which correlated with clinical response. Microtubule bundling was evident in PCa xenografts 2 to 3 days after docetaxel treatment but was decreased or lost with acquired resistance. Biopsies after treatment with leuprolide plus docetaxel showed extensive microtubule bundling as did biopsies obtained 2 to 3 days after initiation of docetaxel or cabazitaxel in 2 patients with castration-resistant PCa with clinical responses. In contrast, microtubule bundling in biopsies 2 to 3 days after the first dose of docetaxel was markedly lower in 4 nonresponding patients. These findings indicate that taxanes target both mitotic and interphase cells in vivo and that resistance is through mechanisms that impair drug-target engagement. Moreover, the findings suggest that microtubule bundling after initial taxane treatment may be a predictive biomarker for clinical response.

Keywords:  Oncology; Prostate cancer

DOI:  https://doi.org/10.1172/JCI132184
Mol Cancer Res. 2020 Jun 03. pii: molcanres.0364.2020. [Epub ahead of print]

Stromal CAVIN1 controls prostate cancer microenvironment and metastasis by modulating lipid distribution and inflammatory signaling.

Jin-Yih Low, W Nathaniel Brennen, Alan K Meeker, Elina Ikonen, Brian W Simons, Marikki Laiho.

Lipid uptake occurs through caveolae, plasma membrane invaginations formed by caveolins (CAV) and caveolae-associated protein 1 (CAVIN1). Genetic alterations of CAV1N1 and CAV1 modify lipid metabolism and underpin lipodystrophy syndromes. Lipids contribute to tumorigenesis by providing fuel to cancer metabolism and supporting growth and signaling. Tumor stroma promotes tumor proliferation, invasion and metastasis but how stromal lipids influence these processes remain to be defined. Here we show that stromal CAVIN1 regulates lipid abundance in the prostate cancer microenvironment and suppresses metastasis. We show that depletion of CAVIN1 in prostate stromal cells markedly reduces their lipid droplet accumulation and increases inflammation. Stromal cells lacking CAVIN1 enhance prostate cancer cell migration and invasion. Remarkably, they increase lipid uptake and M2 inflammatory macrophage infiltration in the primary tumors and metastasis to distant sites. Our data support the concept that stromal cells contribute to prostate cancer aggressiveness by modulating lipid content and inflammation in the tumor microenvironment. Implications: This study showed that stromal CAVIN1 suppresses prostate cancer metastasis by modulating tumor microenvironment, lipid content and inflammatory response.

DOI: https://doi.org/10.1158/1541-7786.MCR-20-0364
Science. 2020 Jun 05. 368(6495): 1127-1131

MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer.

Arcadi Cipponi, David L Goode, Justin Bedo, Mark J McCabe, Marina Pajic, David R Croucher, Alvaro Gonzalez Rajal, Simon R Junankar, Darren N Saunders, Pavel Lobachevsky, Anthony T Papenfuss, Danielle Nessem, Max Nobis, Sean C Warren, Paul Timpson, Mark Cowley, Ana C Vargas, Min R Qiu, Daniele G Generali, Shivakumar Keerthikumar, Uyen Nguyen, Niall M Corcoran, Georgina V Long, Jean-Yves Blay, David M Thomas.

In microorganisms, evolutionarily conserved mechanisms facilitate adaptation to harsh conditions through stress-induced mutagenesis (SIM). Analogous processes may underpin progression and therapeutic failure in human cancer. We describe SIM in multiple in vitro and in vivo models of human cancers under nongenotoxic drug selection, paradoxically enhancing adaptation at a competing intrinsic fitness cost. A genome-wide approach identified the mechanistic target of rapamycin (MTOR) as a stress-sensing rheostat mediating SIM across multiple cancer types and conditions. These observations are consistent with a two-phase model for drug resistance, in which an initially rapid expansion of genetic diversity is counterbalanced by an intrinsic fitness penalty, subsequently normalizing to complete adaptation under the new conditions. This model suggests synthetic lethal strategies to minimize resistance to anticancer therapy.

DOI: https://doi.org/10.1126/science.aau8768
Theranostics. 2020 ;10(13): 5687-5703

A S100A14-CCL2/CXCL5 signaling axis drives breast cancer metastasis.

Xukun Li, Minjie Wang, Tongyang Gong, Xuemeng Lei, Ting Hu, Maoqing Tian, Fang Ding, Fei Ma, Hongyan Chen, Zhihua Liu.

  Rationale: Chemokines contribute to cancer metastasis and have long been regarded as attractive therapeutic targets for cancer. However, controversy exists about whether neutralizing chemokines by antibodies promotes or inhibits tumor metastasis, suggesting that the approach to directly target chemokines needs to be scrutinized. Methods: Transwell assay, mouse metastasis experiments and survival analysis were performed to determine the functional role of S100A14 in breast cancer. RNA-Seq, secreted proteomics, ChIP, Western blot, ELISA, transwell assay and neutralizing antibody experiments were employed to investigate the underlying mechanism of S100A14 in breast cancer metastasis. Immunohistochemistry and ELISA were performed to examine the expression and serum levels of S100A14, CCL2 and CXCL5, respectively. Results: Overexpression of S100A14 significantly enhanced migration, invasion and metastasis of breast cancer cells. In contrast, knockout of S100A14 exhibited the opposite effects. Mechanistic studies demonstrated that S100A14 promotes breast cancer metastasis by upregulating the expression and secretion of CCL2 and CXCL5 via NF-κB mediated transcription. The clinical sample analyses showed that S100A14 expression is strongly associated with CCL2/CXCL5 expression and high expression of these three proteins is correlated with worse clinical outcomes. Notably, the serum levels of S100A14, CCL2/CXCL5 have significant diagnostic value for discerning breast cancer patients from healthy individuals. Conclusions: S100A14 is significantly upregulated in breast cancer, it can promote breast cancer metastasis by increasing the expression and secretion of CCL2/CXCL5 via RAGE-NF-κB pathway. And S100A14 has the potential to serve as a serological marker for diagnosis of breast cancer. Collectively, we identify S100A14 as an upstream regulator of CCL2/CXCL5 signaling and a metastatic driver of breast cancer.

Keywords:  Breast cancer; CCL2; CXCL5; Metastasis; S100A14

DOI:  https://doi.org/10.7150/thno.42087
Cancers (Basel). 2020 May 31. pii: E1436. [Epub ahead of print]12(6):

Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities.

Alice Turdo, Gaetana Porcelli, Caterina D'Accardo, Simone Di Franco, Francesco Verona, Stefano Forte, Dario Giuffrida, Lorenzo Memeo, Matilde Todaro, Giorgio Stassi.

  Although improvement in early diagnosis and treatment ameliorated life expectancy of cancer patients, metastatic disease still lacks effective therapeutic approaches. Resistance to anticancer therapies stems from the refractoriness of a subpopulation of cancer cells-termed cancer stem cells (CSCs)-which is endowed with tumor initiation and metastasis formation potential. CSCs are heterogeneous and diverge by phenotypic, functional and metabolic perspectives. Intrinsic as well as extrinsic stimuli dictated by the tumor microenvironment (TME)have critical roles in determining cell metabolic reprogramming from glycolytic toward an oxidative phenotype and vice versa, allowing cancer cells to thrive in adverse milieus. Crosstalk between cancer cells and the surrounding microenvironment occurs through the interchange of metabolites, miRNAs and exosomes that drive cancer cells metabolic adaptation. Herein, we identify the metabolic nodes of CSCs and discuss the latest advances in targeting metabolic demands of both CSCs and stromal cells with the scope of improving current therapies and preventing cancer progression.

Keywords:  OXPHOS; cancer metabolism; cancer stem cells; glycolysis; lipid metabolism; metabolic reprogramming; metabolism-based anticancer drugs; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers12061436
Cancer Discov. 2020 Jun 04. pii: CD-20-0329. [Epub ahead of print]

Changes in Aged Fibroblast Lipid Metabolism Induce Age-dependent Melanoma Cell Resistance to Targeted Therapy Via the Fatty Acid Transporter FATP2.

Gretchen M Alicea, Vito W Rebecca, Aaron R Goldman, Mitchell E Fane, Stephen M Douglass, Reeti Behera, Marie R Webster, Curtis H Kugel, Brett L Ecker, M Cecilia Caino, Andrew V Kossenkov, Hsin-Yao Tang, Dennie T Frederick, Keith T Flaherty, Xiaowei Xu, Qin Liu, Dmitry I Gabrilovich, Meenhard Herlyn, Ian A Blair, Zachary T Schug, David W Speicher, Ashani T Weeraratna.

Older melanoma patients (>50 years old) have poorer prognoses and response rates to targeted therapy compared to young patients (<50 years old), which can be driven, in part, by the aged microenvironment. Here, we show that aged dermal fibroblasts increase the secretion of neutral lipids, especially ceramides. When melanoma cells are exposed to the aged fibroblast lipid secretome, or co-cultured with aged fibroblasts, they increase the uptake of lipids, via the fatty acid transporter, fatty acid transport protein (FATP) 2, which is upregulated in melanoma cells in the aged microenvironment and known to play roles in lipid synthesis and accumulation. We show that blocking FATP2 in melanoma cells in an aged microenvironment inhibits their accumulation of lipids, and disrupts their mitochondrial metabolism. Inhibiting FATP2 overcomes age-related resistance to BRAF/MEK inhibition in animal models, ablates tumor relapse, and significantly extends survival time in older animals.

DOI: https://doi.org/10.1158/2159-8290.CD-20-0329
Cancer Discov. 2020 Jun 05.

Proof-of-Concept with PROTACs in Prostate Cancer.

Preliminary clinical data for ARV-110, a proteolysis-targeting chimera that flags the androgen receptor for degradation, indicate that the drug is safe and shows some efficacy in men with metastatic castration-resistant prostate cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-NB2020-054
Theranostics. 2020 ;10(14): 6483-6499

STIM1 is a metabolic checkpoint regulating the invasion and metastasis of hepatocellular carcinoma.

Huakan Zhao, Guifang Yan, Lu Zheng, Yu Zhou, Halei Sheng, Lei Wu, Qi Zhang, Juan Lei, Jiangang Zhang, Rong Xin, Lu Jiang, Xiao Zhang, Yu Chen, Jingchun Wang, Yanquan Xu, Dingshan Li, Yongsheng Li.

  Background: Cancer cells undergoing invasion and metastasis possess a phenotype with attenuated glycolysis, but enhanced fatty acid oxidation (FAO). Calcium (Ca2+)-mediated signaling pathways are implicated in tumor metastasis and metabolism regulation. Stromal-interaction molecule 1 (STIM1) triggered store-operated Ca2+ entry (SOCE) is the major route of Ca2+ influx for non-excitable cells including hepatocellular carcinoma (HCC) cells. However, whether and how STIM1 regulates the invasion and metastasis of HCC via metabolic reprogramming is unclear. Methods: The expressions of STIM1 and Snail1 in the HCC tissues and cells were measured by immunohistochemistry, Western-blotting and quantitative PCR. STIM1 knockout-HCC cells were generated by CRISPR-Cas9, and gene-overexpression was mediated via lentivirus transfection. Besides, the invasive and metastatic activities of HCC cells were assessed by transwell assay, anoikis rate in vitro and lung metastasis in vivo. Seahorse energy analysis and micro-array were used to evaluate the glucose and lipid metabolism. Results: STIM1 was down-regulated in metastatic HCC cells rather than in proliferating HCC cells, and low STIM1 levels were associated with poor outcome of HCC patients. During tumor growth, STIM1 stabilized Snail1 protein by activating the CaMKII/AKT/GSK-3β pathway. Subsequently, the upregulated Snail1 suppressed STIM1/SOCE during metastasis. STIM1 restoration significantly diminished anoikis-resistance and metastasis induced by Snail1. Mechanistically, the downregulated STIM1 shifted the anabolic/catabolic balance, i.e., from aerobic glycolysis towards AMPK-activated fatty acid oxidation (FAO), which contributed to Snail1-driven metastasis and anoikis-resistance. Conclusions: Our data provide the molecular basis that STIM1 orchestrates invasion and metastasis via reprogramming HCC metabolism.

Keywords:  SOCE; STIM1; Snail1; invasion and metastasis; metabolic reprogramming

DOI:  https://doi.org/10.7150/thno.44025
Cancer Res. 2020 Jun 05. pii: canres.2373.2019. [Epub ahead of print]

The EMT transcription factor ZEB2 promotes proliferation of primary and metastatic melanoma while suppressing an invasive, mesenchymal-like phenotype.

Niels Vandamme, Geertrui Denecker, Kenneth Bruneel, Gillian Blancke, Özden Akay, Joachim Taminau, Jordy De Coninck, Eva De Smedt, Nicolas Skrypek, Wouter Van Loocke, Jasper Wouters, David Nittner, Corinna Köhler, Douglas S Darling, Phil F Cheng, Marieke I G Raaijmakers, Mitchell P Levesque, Udupi Girish Mallya, Mairin Rafferty, Balazs Balint, William M Gallagher, Lieve Brochez, Danny Huylebroeck, Jody J Haigh, Vanessa Andries, Florian Rambow, Pieter Van Vlierberghe, Steven Goossens, Joost J van den Oord, Jean-Christophe Marine, Geert Berx.

EMT-inducing transcription factors (TF) are well known for their ability to induce mesenchymal states associated with increased migratory and invasive properties. Unexpectedly, nuclear expression of the EMT-TF ZEB2 in human primary melanoma has been shown to correlate with reduced invasion. We report here that ZEB2 is required for outgrowth for primary melanomas and metastases at secondary sites. Ablation of Zeb2 hampered outgrowth of primary melanomas in vivo, whereas ectopic expression enhanced proliferation and growth at both primary and secondary sites. Gain of Zeb2 expression in pulmonary-residing melanoma cells promoted the development of macroscopic lesions. In vivo fate mapping made clear that melanoma cells undergo a conversion in state where ZEB2 expression is replaced by ZEB1 expression associated with gain of an invasive phenotype. These findings suggest that reversible switching of the ZEB2/ZEB1 ratio enhances melanoma metastatic dissemination.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-2373
Cell Death Differ. 2020 Jun 01.

Ubiquitin ligase CHIP regulates OTUD3 stability and suppresses tumour metastasis in lung cancer.

Pengfei Zhang, Chaonan Li, Hongchang Li, Lin Yuan, Hongmiao Dai, Zhiqiang Peng, Zhikang Deng, Zhijie Chang, Chun-Ping Cui, Lingqiang Zhang.

Ovarian tumour domain-containing protein 3 (OTUD3), a key OTU (ovarian tumour protease) family deubiquitylase, plays context-dependent roles in cancers. It suppresses tumorigenesis in breast, colon, liver and cervical cancer through stabilizing PTEN (phosphatase and tension homologue deleted on chromosome 10) while promotes lung tumorigenesis through stabilizing GRP78 (The glucose-regulated protein 78 kDa). The regulation especially post-translational modification of OTUD3 remains unclear. Here, we report that the carboxyl terminus of Hsc70-interacting protein (CHIP) is a ubiquitin ligase for OTUD3. CHIP interacts with, polyubiquitylates OTUD3 and promotes OTUD3 degradation. Knockdown of CHIP stabilizes OTUD3 which leads to elevated GRP78 levels in lung cancer cells. CHIP-knockdown lung cancer cells exhibit increased invasion in OTUD3 and GRP78 dependent manner. Further study demonstrates that CHIP-knockdown lung cancer cells are more prone to metastasize to mice lung when injected intravenously or subcutaneously. Moreover, the expression of CHIP is low in human lung cancer tissues and inversely correlates with OTUD3 expression and GRP78 expression. Furthermore, we identified CHIP mutations in human lung cancers, which reduce CHIP catalytic activity. These findings demonstrate that CHIP is a negative regulator of OTUD3 and CHIP suppresses lung cancer metastasis through inhibiting OTUD3-GRP78 signaling axis.

DOI: https://doi.org/10.1038/s41418-020-0571-7
Mol Cancer Res. 2020 Jun 03. pii: molcanres.0308.2020. [Epub ahead of print]

A TGFβ-dependent stromal subset underlies immune checkpoint inhibitor efficacy in DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer.

Eisei Endo, Hirokazu Okayama, Katsuharu Saito, Shotaro Nakajima, Leo Yamada, Daisuke Ujiie, Koji Kase, Shotaro Fujita, Hisahito Endo, Wataru Sakamoto, Motonobu Saito, Zenichiro Saze, Tomoyuki Momma, Shinji Ohki, Kosaku Mimura, Koji Kono.

Patients with DNA mismatch-repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) represent a biomarker-defined population with distinct clinicopathological features who are susceptible to immune checkpoint inhibitors (ICIs). However, their survival outcomes vary considerably and nearly half of them exhibit primary resistance to current ICIs, suggesting substantial molecular heterogeneity even among tumors with dMMR/MSI-H. We conducted an extensive analysis of the tumor microenvironment (TME) using multiple transcriptomic, proteomic and immunohistochemistry cohorts of CRC, comprising 222 dMMR/MSI-H and 1440 MMR proficient/microsatellite stable tumors. We developed a TGFβ-responsive stromal gene signature and then identified a unique poor prognostic subgroup of patients with dMMR/MSI-H CRCs, characterized by the upregulation of transcriptional programs, including the TGFβ-rich active TME, angiogenesis, M2 macrophage polarization, and the extracellular matrix signature predictive of ICI resistance. The TGFβ-dependent stromal subset within dMMR/MSI-H tumors exhibiting poor survival outcomes was further recapitulated by proteomic datasets and immunohistochemistry for VCAN protein expressed by cancer-associated fibroblasts. Meanwhile, this dMMR/MSI-H stromal subgroup was enriched neither with CD8+ T cell infiltration nor common genomic alterations, such as mutation density and BRAF mutations, compared with dMMR/MSI-H tumors without TGFβ-dependent stromal activation. In conclusions, this study revealed a novel stromal subgroup of patients with dMMR/MSI-H CRC, demonstrating a TGFβ-rich tumor-promoting TME and unfavorable survival outcomes. Implications: Dual inhibition of immune checkpoints and the TGFβ signaling may offer a promising strategy for those patients.

DOI: https://doi.org/10.1158/1541-7786.MCR-20-0308
Mol Cancer. 2020 Jun 05. 19(1): 103

CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p.

Jianfa Li, Chenchen Huang, Yifan Zou, Jing Ye, Jing Yu, Yaoting Gui.

   BACKGROUND: Circular RNAs (circRNAs), a novel type of noncoding RNA (ncRNA), are covalently linked circular configurations that form via a loop structure. Accumulating evidence indicates that circRNAs are potential biomarkers and key regulators of tumor development and progression. However, the precise roles of circRNAs in renal cell carcinoma (RCC) remain unknown.
METHODS: Through circRNA high-throughput sequencing of RCC cell lines, we identified the circRNA TLK1 (circTLK1) as a novel candidate circRNA derived from the TLK1 gene. qRT-PCR detected the mRNA, circRNA and miRNA expression levels in RCC tissues and cells. Loss-of function experiments were executed to detect the biological roles of circTLK1 in the RCC cell phenotypes in vitro and in vivo. RNA-FISH, RNA pull-down, dual-luciferase reporter, western blot and immunohistochemistry assays were used to investigate the molecular mechanisms underlying the functions of circTLK1.
RESULTS: circTLK1 is overexpressed in RCC, and expression is positively correlated with distant metastasis and unfavorable prognosis. Silencing circTLK1 significantly inhibited RCC cell proliferation, migration and invasion in vitro and in vivo. circTLK1 was mainly distributed in the cytoplasm and positively regulated CBX4 expression by sponging miR-136-5p. Forced CBX4 expression reversed the circTLK1 suppression-induced phenotypic inhibition of RCC cells. Moreover, CBX4 expression was positively correlated with VEGFA expression in RCC tissues. CBX4 knockdown significantly inhibited VEGFA expression in RCC cells.
CONCLUSION: Collectively, our findings demonstrate that circTLK1 plays a critical role in RCC progression by sponging miR-136-5p to increase CBX4 expression. circTLK1 may act as a diagnostic biomarker and therapeutic target for RCC.

Keywords:  CBX4; Renal cell carcinoma; VEGFA; circTLK1; miR-136-5p

DOI:  https://doi.org/10.1186/s12943-020-01225-2
Clin Cancer Res. 2020 Jun 01. pii: clincanres.1452.2020. [Epub ahead of print]

Bridging the Translational Divide in Oncology: In Vivo Testing of Chemo-Sensitivity.

Stefan Sleijfer, Martijn Lolkema.

A study was presented in which sarcomas were microinjected simultaneously with several drugs to study the pharmacodynamic response after resection. This platform may represent a future way of probing efficacy of anticancer agents in the relevant model system: human tumors.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-1452
Cancer. 2020 Jun 02.

Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition.

Alicia M Blessing, Janice M Santiago-O'Farrill, Weiqun Mao, Lan Pang, Jing Ning, Daewoo Pak, Lakshmi Reddy Bollu, Philip Rask, LaKesla Iles, Hailing Yang, Samantha Tran, Ezzeddine Elmir, Geoffrey Bartholomeusz, Robert Langley, Zhen Lu, Robert C Bast.

   BACKGROUND: Poor outcomes for patients with ovarian cancer relate to dormant, drug-resistant cancer cells that survive after primary surgery and chemotherapy. Ovarian cancer (OvCa) cells persist in poorly vascularized scars on the peritoneal surface and depend on autophagy to survive nutrient deprivation. The authors have sought drugs that target autophagic cancer cells selectively to eliminate residual disease.
METHODS: By using unbiased small-interfering RNA (siRNA) screens, the authors observed that knockdown of anaplastic lymphoma kinase (ALK) reduced the survival of autophagic OvCa cells. Small-molecule ALK inhibitors were evaluated for their selective toxicity against autophagic OvCa cell lines and xenografts. Autophagy was induced by reexpression of GTP-binding protein Di-Ras3 (DIRAS3) or serum starvation and was evaluated with Western blot analysis, fluorescence imaging, and transmission electron microscopy. Signaling pathways required for crizotinib-induced apoptosis of autophagic cells were explored with flow cytometric analysis, Western blot analysis, short-hairpin RNA knockdown of autophagic proteins, and small-molecule inhibitors of STAT3 and BCL-2.
RESULTS: Induction of autophagy by reexpression of DIRAS3 or serum starvation in multiple OvCa cell lines significantly reduced the 50% inhibitory concentration of crizotinib and other ALK inhibitors. In 2 human OvCa xenograft models, the DIRAS3-expressing tumors treated with crizotinib had significantly decreased tumor burden and long-term survival in 67% to 79% of mice. Crizotinib treatment of autophagic cancer cells further enhanced autophagy and induced autophagy-mediated apoptosis by decreasing phosphorylated STAT3 and BCL-2 signaling.
CONCLUSIONS: Crizotinib may eliminate dormant, autophagic, drug-resistant OvCa cells that remain after conventional cytoreductive surgery and combination chemotherapy. A clinical trial of ALK inhibitors as maintenance therapy after second-look operations should be seriously considered.

Keywords:  GTP-binding protein Di-Ras3 (DIRAS3); anaplastic lymphoma kinase (ALK); autophagy; crizotinib; dormancy; ovarian cancer

DOI:  https://doi.org/10.1002/cncr.32985
Mol Cancer. 2020 Jun 05. 19(1): 102

Comprehensive landscape of extracellular vesicle-derived RNAs in cancer initiation, progression, metastasis and cancer immunology.

Wei Hu, Cong Liu, Zhuo-Yue Bi, Qun Zhou, Han Zhang, Lin-Lin Li, Jian Zhang, Wei Zhu, Yang-Yi-Yan Song, Feng Zhang, Hui-Min Yang, Yong-Yi Bi, Qi-Qiang He, Gong-Jun Tan, Cheng-Cao Sun, De-Jia Li.

  Extracellular vesicles (EVs), a class of heterogeneous membrane vesicles, are generally divided into exosomes and microvesicles on basis of their origination from the endosomal membrane or the plasma membrane, respectively. EV-mediated bidirectional communication among various cell types supports cancer cell growth and metastasis. EVs derived from different cell types and status have been shown to have distinct RNA profiles, comprising messenger RNAs and non-coding RNAs (ncRNAs). Recently, ncRNAs have attracted great interests in the field of EV-RNA research, and growing numbers of ncRNAs ranging from microRNAs to long ncRNAs have been investigated to reveal their specific functions and underlying mechanisms in the tumor microenvironment and premetastatic niches. Emerging evidence has indicated that EV-RNAs are essential functional cargoes in modulating hallmarks of cancers and in reciprocal crosstalk within tumor cells and between tumor and stromal cells over short and long distance, thereby regulating the initiation, development and progression of cancers. In this review, we discuss current findings regarding EV biogenesis, release and interaction with target cells as well as EV-RNA sorting, and highlight biological roles and molecular mechanisms of EV-ncRNAs in cancer biology.

Keywords:  Cancer; Circular RNA; Exosome; Extracellular vesicle; Long non-coding RNA; Micro RNA; Microvesicle; Premetastatic niche; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-020-01199-1
Theranostics. 2020 ;10(13): 6048-6060

The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase.

Xinyuan Ding, Yuting Gu, Min Jin, Xin Guo, Sudong Xue, Caihong Tan, Jiefang Huang, Wanlin Yang, Mingxing Xue, Qianjun Zhou, Wenjuan Wang, Yanyun Zhang.

  Rationale: Resistance to pemetrexed (PEM)-based chemotherapy is a major cause of progression in non-small cell lung cancer (NSCLC) patients. The deubiquitinating enzyme UCHL1 was recently found to play important roles in chemoresistance and tumor progression. However, the potential roles and mechanisms of UCHL1 in PEM resistance remain unclear. Methods: Bioinformatics analyses and immunohistochemistry were used to evaluate UCHL1 expression in NSCLC specimens. Kaplan-Meier analysis with the log-rank test was used for survival analyses. We established PEM-resistant NSCLC cell lines by exposing them to step-wise increases in PEM concentrations, and in vitro and in vivo assays were used to explore the roles and mechanisms of UCHL1 in PEM resistance using the NSCLC cells. Results: In chemoresistant tumors from NSCLC patients, UCHL1 was highly expressed and elevated UCHL1 expression was strongly associated with poor outcomes. Furthermore, UCHL1 expression was significantly upregulated in PEM-resistant NSCLC cells, while genetic silencing or inhibiting UCHL1 suppressed resistance to PEM and other drugs in NSCLC cells. Mechanistically, UCHL1 promoted PEM resistance in NSCLC by upregulating the expression of thymidylate synthase (TS), based on reduced TS expression after UCHL1 inhibition and re-emergence of PEM resistance upon TS restoration. Furthermore, UCHL1 upregulated TS expression, which mitigated PEM-induced DNA damage and cell cycle arrest in NSCLC cells, and also conferred resistance to PEM and other drugs. Conclusions: It appears that UCHL1 promotes PEM resistance by upregulating TS in NSCLC cells, which mitigated DNA damage and cell cycle arrest. Thus, UCHL1 may be a therapeutic target for overcoming PEM resistance in NSCLC patients.

Keywords:  UCHL1; chemoresistance; non-small cell lung cancer; pemetrexed; thymidylate synthase

DOI:  https://doi.org/10.7150/thno.42096
Mol Cancer Res. 2020 Jun 05. pii: molcanres.0067.2020. [Epub ahead of print]

Epithelial-Mesenchymal Transition Programs and Cancer Stem Cell Phenotypes: Mediators of Breast Cancer Therapy Resistance.

Alex J Gooding, William P Schiemann.

Epithelial-mesenchymal transition (EMT) programs play essential functions in normal morphogenesis and organogenesis, including that occurring during mammary gland development and glandular regeneration. Historically, EMT programs were believed to reflect a loss of epithelial gene expression signatures and morphologies that give way to those associated with mesenchymal cells and their enhanced migratory and invasive behaviors. However, accumulating evidence now paints EMT programs as representing a spectrum of phenotypic behaviors that also serve to enhance cell survival, immune tolerance, and perhaps even metastatic dormancy. Equally important, the activation of EMT programs in transformed mammary epithelial cells not only enhances their acquisition of invasive and metastatic behaviors, but also expands their generation of chemoresistant breast cancer stem cells (BCSCs). Importantly, the net-effect of these events results in the appearance of recurrent metastatic lesions that remain refractory to the armamentarium of chemotherapies and targeted therapeutic agents deployed against advanced-stage breast cancers. Here we review the molecular and cellular mechanisms that contribute to the pathophysiology of EMT programs in human breast cancers and how these events impact their "stemness" and acquisition of chemoresistant phenotypes.

DOI: https://doi.org/10.1158/1541-7786.MCR-20-0067
Theranostics. 2020 ;10(14): 6399-6410

Autoantibody profiling identifies predictive biomarkers of response to anti-PD1 therapy in cancer patients.

Qiaoyun Tan, Dan Wang, Jianliang Yang, Puyuan Xing, Sheng Yang, Yang Li, Yan Qin, Xiaohui He, Yutao Liu, Shengyu Zhou, Hu Duan, Te Liang, Haoyu Wang, Yanrong Wang, Shiyu Jiang, Fengyi Zhao, Qiaofeng Zhong, Yu Zhou, Shasha Wang, Jiayu Dai, Jiarui Yao, Di Wu, Zhishang Zhang, Yan Sun, Xiaohong Han, Xiaobo Yu, Yuankai Shi.

  Background: Programmed cell death protein 1 (PD1) inhibitors have revolutionized cancer therapy, yet many patients fail to respond. Thus, the identification of accurate predictive biomarkers of therapy response will improve the clinical benefit of anti-PD1 therapy. Method: We assessed the baseline serological autoantibody (AAb) profile against ~2300 proteins in 10 samples and ~4600 proteins in 35 samples with alveolar soft part sarcoma (ASPS), non-small-cell lung cancer (NSCLC) and lymphoma using Nucleic Acid Programmable Protein Arrays (NAPPA). 23 selected potential AAb biomarkers were verified using simple, affordable and rapid enzyme linked immune sorbent assay (ELISA) technology with baseline plasma samples from 12 ASPS, 16 NSCLC and 46 lymphoma patients. SIX2 and EIF4E2 AAbs were further validated in independent cohorts of 17 NSCLC and 43 lymphoma patients, respectively, using ELISA. The IgG subtypes in response to therapy were also investigated. Results: Distinct AAb profiles between ASPS, NSCLC and lymphoma were observed. In ASPS, the production of P53 and PD1 AAbs were significantly increased in non-responders (p=0.037). In NSCLC, the SIX2 AAb was predictive of response with area under the curve (AUC) of 0.87, 0.85 and 0.90 at 3 months, 4.5 months, 6 months evaluation time points, respectively. In the validation cohort, the SIX2 AAb was consistently up-regulated in non-responders (p=0.024). For lymphoma, the EIF4E2 AAb correlated with a favorable response with AUCs of 0.68, 0.70, and 0.70 at 3 months, 4.5 months, and 6 months, respectively. In the validation cohort, the AUCs were 0.74, 0.75 and 0.66 at 3 months, 4.5 months, and 6 months, respectively. The PD1 and PD-L1 IgG2 AAbs were highly produced in ~20% of lymphoma responders. Furthermore, bioinformatics analysis revealed antigen functions of these AAb biomarkers. Conclusion: This study provides the first evidence that AAb biomarkers selected using high-throughput protein microarrays can predict anti-PD1 therapeutic response and guide anti-PD1 therapy.

Keywords:  Anti-PD1 therapy; Autoantibody; Biomarker; Protein microarray

DOI:  https://doi.org/10.7150/thno.45816
Cancer Lett. 2020 May 29. pii: S0304-3835(20)30288-3. [Epub ahead of print]

Hypoxia-mediated changes in bone marrow microenvironment in breast cancer dormancy.

Alejandra Ferrer, Christopher T Roser, Markos H El-Far, Vibha Harindra Savanur, Adam Eljarrah, Marina Gergues, Joshua A Kra, Jean-Pierre Etchegaray, Pranela Rameshwar.

  Breast cancer (BC) remains a clinical challenge despite improved treatments and public awareness to ensure early diagnosis. A major issue is the ability of BC cells (BCCs) to survive as dormant cancer cells in the bone marrow (BM), resulting in the cancer surviving for decades with the potential to resurge as metastatic cancer. The experimental evidence indicates similarity between dormant BCCs and other stem cells, resulting in the preponderance of data to show dormant BCCs being cancer stem cells (CSCs). The BM niche and their secretome support BCC dormancy. Lacking in the literature is a comprehensive research to describe how the hypoxic environment within the BM may influence the behavior of BCCs. This information is relevant to understand the prognosis of BC in young and aged individuals whose oxygen levels differ in BM. This review discusses the changing information on vascularity in different regions of the BM and the impact on endogenous hematopoietic stem cells (HSCs). This review highlights the necessary information to provide insights on vascularity of different BM regions on the behavior of BCCs, in particular a dormant phase. For instance, how the transcription factor HIF1-α (hypoxia-inducible factor 1 alpha), functioning as first responder under hypoxic conditions, affects the expression of specific gene networks involved in energy metabolism, cell survival, tumor invasion and angiogenesis. This enables cell fate transition and facilitates tumor heterogeneity, which in turn favors tumor progression and resistance to anticancer treatments Thus, HIF1-α could be a potential target for cancer treatment. This review describes epigenetic mechanisms involved in hypoxic responses during cancer dormancy in the bone marrow. The varied hypoxic environment in the BM is relevant to understand the complex process of the aging bone marrow for insights on breast cancer outcome between the young and aged.

Keywords:  Cytokines; Dormancy; Hematopoiesis; Non-coding RNA; Stem cell; Vascularity

DOI:  https://doi.org/10.1016/j.canlet.2020.05.026
Proc Natl Acad Sci U S A. 2020 Jun 03. pii: 202001569. [Epub ahead of print]

Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics.

Colin G Buss, Sangeeta N Bhatia.

  The recent advent of immune checkpoint inhibitor (CPI) antibodies has revolutionized many aspects of cancer therapy, but the efficacy of these breakthrough therapeutics remains limited, as many patients fail to respond for reasons that still largely evade understanding. An array of studies in human patients and animal models has demonstrated that local signaling can generate strongly immunosuppressive microenvironments within tumors, and emerging evidence suggests that delivery of immunostimulatory molecules into tumors can have therapeutic effects. Nanoparticle formulations of these cargoes offer a promising way to maximize their delivery and to enhance the efficacy of checkpoint inhibitors. We developed a modular nanoparticle system capable of encapsulating an array of immunostimulatory oligonucleotides that, in some cases, greatly increase their potency to activate inflammatory signaling within immune cells in vitro. We hypothesized that these immunostimulatory nanoparticles could suppress tumor growth by activating similar signaling in vivo, and thereby also improve responsiveness to immune checkpoint inhibitor antibody therapies. We found that our engineered nanoparticles carrying a CpG DNA ligand of TLR9 can suppress tumor growth in several animal models of various cancers, resulting in an abscopal effect on distant tumors, and improving responsiveness to anti-CTLA4 treatment with combinatorial effects after intratumoral administration. Moreover, by incorporating tumor-homing peptides, immunostimulatory nucleotide-bearing nanoparticles facilitate antitumor efficacy after systemic intravenous (i.v.) administration.

Keywords:  cancer; immunotherapy; nanoparticle; oiligonucleotides

DOI:  https://doi.org/10.1073/pnas.2001569117
Cancers (Basel). 2020 May 31. pii: E1424. [Epub ahead of print]12(6):

Long Noncoding RNAs Involved in the Endocrine Therapy Resistance of Breast Cancer.

Toshihiko Takeiwa, Kazuhiro Ikeda, Yuichi Mitobe, Kuniko Horie-Inoue, Satoshi Inoue.

  Long noncoding RNAs (lncRNAs) are defined as RNAs longer than 200 nucleotides that do not encode proteins. Recent studies have demonstrated that numerous lncRNAs are expressed in humans and play key roles in the development of various types of cancers. Intriguingly, some lncRNAs have been demonstrated to be involved in endocrine therapy resistance for breast cancer through their own mechanisms, suggesting that lncRNAs could be promising new biomarkers and therapeutic targets of breast cancer. Here, we summarize the functions and mechanisms of lncRNAs related to the endocrine therapy resistance of breast cancer.

Keywords:  breast cancer; endocrine therapy; endocrine therapy resistance; long noncoding RNA

DOI:  https://doi.org/10.3390/cancers12061424