bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒06‒07
twenty-nine papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. Nat Rev Cancer. 2020 Jun 02.
    Phan TG, Croucher PI.
      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
  2. Theranostics. 2020 ;10(13): 5998-6010
    Tian T, Chen ZH, Zheng Z, Liu Y, Zhao Q, Liu Y, Qiu H, Long Q, Chen M, Li L, Xie F, Luo G, Wu X, Deng W.
      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
  3. Cell Rep. 2020 Jun 02. pii: S2211-1247(20)30671-9. [Epub ahead of print]31(9): 107701
    Becker LM, O'Connell JT, Vo AP, Cain MP, Tampe D, Bizarro L, Sugimoto H, McGow AK, Asara JM, Lovisa S, McAndrews KM, Zielinski R, Lorenzi PL, Zeisberg M, Raza S, LeBleu VS, Kalluri R.
      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
  4. Theranostics. 2020 ;10(14): 6261-6277
    Ravindran Menon D, Hammerlindl H, Torrano J, Schaider H, Fujita M.
      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
  5. Cancer Discov. 2020 Jun;10(6): 762-764
    Bednar F, Pasca di Magliano M.
      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
  6. Nat Cell Biol. 2020 Jun 01.
    Liao D, Zhong L, Yin J, Zeng C, Wang X, Huang X, Chen J, Zhang H, Zhang R, Guan XY, Shuai X, Sui J, Gao S, Deng W, Zeng YX, Shen JN, Chen J, Kang T.
      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
  7. Nat Commun. 2020 Jun 01. 11(1): 2689
    Wang K, Luo J, Yeh S, You B, Meng J, Chang P, Niu Y, Li G, Lu C, Zhu Y, Antonarakis ES, Luo J, Huang CP, Xu W, Chang C.
      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
  8. Cancers (Basel). 2020 May 28. pii: E1393. [Epub ahead of print]12(6):
    Garvey CM, Lau R, Sanchez A, Sun RX, Fong EJ, Doche ME, Chen O, Jusuf A, Lenz HJ, Larson B, Mumenthaler SM.
      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
  9. J Clin Invest. 2020 Jun 01. pii: 132184. [Epub ahead of print]130(6): 3287-3298
    Gjyrezi A, Xie F, Voznesensky O, Khanna P, Calagua C, Bai Y, Kung J, Wu J, Corey E, Montgomery B, Mace S, Gianolio DA, Bubley GJ, Balk SP, Giannakakou P, Bhatt RS.
      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
  10. Mol Cancer Res. 2020 Jun 03. pii: molcanres.0364.2020. [Epub ahead of print]
    Low JY, Brennen WN, Meeker AK, Ikonen E, Simons BW, Laiho M.
      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
  11. Science. 2020 Jun 05. 368(6495): 1127-1131
    Cipponi A, Goode DL, Bedo J, McCabe MJ, Pajic M, Croucher DR, Rajal AG, Junankar SR, Saunders DN, Lobachevsky P, Papenfuss AT, Nessem D, Nobis M, Warren SC, Timpson P, Cowley M, Vargas AC, Qiu MR, Generali DG, Keerthikumar S, Nguyen U, Corcoran NM, Long GV, Blay JY, Thomas DM.
      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
  12. Theranostics. 2020 ;10(13): 5687-5703
    Li X, Wang M, Gong T, Lei X, Hu T, Tian M, Ding F, Ma F, Chen H, Liu Z.
      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
  13. Cancers (Basel). 2020 May 31. pii: E1436. [Epub ahead of print]12(6):
    Turdo A, Porcelli G, D'Accardo C, Franco SD, Verona F, Forte S, Giuffrida D, Memeo L, Todaro M, Stassi G.
      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
  14. Cancer Discov. 2020 Jun 04. pii: CD-20-0329. [Epub ahead of print]
    Alicea GM, Rebecca VW, Goldman AR, Fane ME, Douglass SM, Behera R, Webster MR, Kugel CH, Ecker BL, Caino MC, Kossenkov AV, Tang HY, Frederick DT, Flaherty KT, Xu X, Liu Q, Gabrilovich DI, Herlyn M, Blair IA, Schug ZT, Speicher DW, Weeraratna AT.
      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
  15. Cancer Discov. 2020 Jun 05.
      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
  16. Theranostics. 2020 ;10(14): 6483-6499
    Zhao H, Yan G, Zheng L, Zhou Y, Sheng H, Wu L, Zhang Q, Lei J, Zhang J, Xin R, Jiang L, Zhang X, Chen Y, Wang J, Xu Y, Li D, Li Y.
      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
  17. Cancer Res. 2020 Jun 05. pii: canres.2373.2019. [Epub ahead of print]
    Vandamme N, Denecker G, Bruneel K, Blancke G, Akay Ö, Taminau J, De Coninck J, De Smedt E, Skrypek N, Van Loocke W, Wouters J, Nittner D, Köhler C, Darling DS, Cheng PF, Raaijmakers MIG, Levesque MP, Mallya UG, Rafferty M, Balint B, Gallagher WM, Brochez L, Huylebroeck D, Haigh JJ, Andries V, Rambow F, Van Vlierberghe P, Goossens S, van den Oord JJ, Marine JC, Berx G.
      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
  18. Cell Death Differ. 2020 Jun 01.
    Zhang P, Li C, Li H, Yuan L, Dai H, Peng Z, Deng Z, Chang Z, Cui CP, Zhang L.
      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
  19. Mol Cancer Res. 2020 Jun 03. pii: molcanres.0308.2020. [Epub ahead of print]
    Endo E, Okayama H, Saito K, Nakajima S, Yamada L, Ujiie D, Kase K, Fujita S, Endo H, Sakamoto W, Saito M, Saze Z, Momma T, Ohki S, Mimura K, Kono K.
      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
  20. Mol Cancer. 2020 Jun 05. 19(1): 103
    Li J, Huang C, Zou Y, Ye J, Yu J, Gui Y.
      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
  21. Clin Cancer Res. 2020 Jun 01. pii: clincanres.1452.2020. [Epub ahead of print]
    Sleijfer S, Lolkema M.
      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
  22. Cancer. 2020 Jun 02.
    Blessing AM, Santiago-O'Farrill JM, Mao W, Pang L, Ning J, Pak D, Bollu LR, Rask P, Iles L, Yang H, Tran S, Elmir E, Bartholomeusz G, Langley R, Lu Z, Bast RC.
      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
  23. Mol Cancer. 2020 Jun 05. 19(1): 102
    Hu W, Liu C, Bi ZY, Zhou Q, Zhang H, Li LL, Zhang J, Zhu W, Song YY, Zhang F, Yang HM, Bi YY, He QQ, Tan GJ, Sun CC, Li DJ.
      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
  24. Theranostics. 2020 ;10(13): 6048-6060
    Ding X, Gu Y, Jin M, Guo X, Xue S, Tan C, Huang J, Yang W, Xue M, Zhou Q, Wang W, Zhang Y.
      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
  25. Mol Cancer Res. 2020 Jun 05. pii: molcanres.0067.2020. [Epub ahead of print]
    Gooding AJ, Schiemann WP.
      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
  26. Theranostics. 2020 ;10(14): 6399-6410
    Tan Q, Wang D, Yang J, Xing P, Yang S, Li Y, Qin Y, He X, Liu Y, Zhou S, Duan H, Liang T, Wang H, Wang Y, Jiang S, Zhao F, Zhong Q, Zhou Y, Wang S, Dai J, Yao J, Wu D, Zhang Z, Sun Y, Han X, Yu X, Shi Y.
      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
  27. Cancer Lett. 2020 May 29. pii: S0304-3835(20)30288-3. [Epub ahead of print]
    Ferrer A, Roser CT, El-Far MH, Savanur VH, Eljarrah A, Gergues M, Kra JA, Etchegaray JP, Rameshwar P.
      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
  28. Proc Natl Acad Sci U S A. 2020 Jun 03. pii: 202001569. [Epub ahead of print]
    Buss CG, Bhatia SN.
      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
  29. Cancers (Basel). 2020 May 31. pii: E1424. [Epub ahead of print]12(6):
    Takeiwa T, Ikeda K, Mitobe Y, Horie-Inoue K, Inoue S.
      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