bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒06‒21
27 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. Cancer Discov. 2020 Jun 16. pii: CD-19-1536. [Epub ahead of print]
    Han T, Goswami S, Hu Y, Tang F, Zafra MP, Murphy C, Cao Z, Poirier JT, Khurana E, Elemento O, Hechtman JF, Ganesh K, Yaeger R, Dow LE.
      The WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of p53 and SMAD4, transient TGFB exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work identifies genetic and microenvironmental factors that drive WNT inhibitor resistance, defines a new mechanism for WNT-independent CRC growth and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1536
  2. Nat Commun. 2020 Jun 15. 11(1): 3017
    Howe EN, Burnette MD, Justice ME, Schnepp PM, Hedrick V, Clancy JW, Guldner IH, Lamere AT, Li J, Aryal UK, D'Souza-Schorey C, Zartman JJ, Zhang S.
      Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for 30% of mortality; however, mechanisms governing adaptation to the brain microenvironment remain poorly defined. We combine time-course RNA-sequencing of BCBM development with a Drosophila melanogaster genetic screen, and identify Rab11b as a functional mediator of metastatic adaptation. Proteomic analysis reveals that Rab11b controls the cell surface proteome, recycling proteins required for successful interaction with the microenvironment, including integrin β1. Rab11b-mediated control of integrin β1 surface expression allows efficient engagement with the brain ECM, activating mechanotransduction signaling to promote survival. Lipophilic statins prevent membrane association and activity of Rab11b, and we provide proof-of principle that these drugs prevent breast cancer adaptation to the brain microenvironment. Our results identify Rab11b-mediated recycling of integrin β1 as regulating BCBM, and suggest that the recycleome, recycling-based control of the cell surface proteome, is a previously unknown driver of metastatic adaptation and outgrowth.
    DOI:  https://doi.org/10.1038/s41467-020-16832-2
  3. Cancer Lett. 2020 Jun 16. pii: S0304-3835(20)30305-0. [Epub ahead of print]
    Todd VM, Johnson RW.
      Hypoxia is a common feature in tumors, driving pathways that promote epithelial-to-mesenchymal transition, invasion, and metastasis. Clinically, high levels of hypoxia-inducible factor (HIF) expression and stabilization at the primary site in many cancer types is associated with poor patient outcomes. Experimental evidence suggests that HIF signaling in the primary tumor promotes their dissemination to the bone, as well as the release of factors such as LOX that act distantly on the bone to stimulate osteolysis and form a pre-metastatic niche. Additionally, the bone itself is a generally hypoxic organ, fueling the activation of HIF signaling in bone resident cells, promoting tumor cell homing to the bone as well as osteoclastogenesis. The hypoxic microenvironment of the bone also stimulates the vicious cycle of tumor-induced bone destruction, further fueling tumor cell growth and osteolysis. Furthermore, hypoxia appears to regulate key tumor dormancy factors. Thus, hypoxia acts both on the tumor cells as well as the metastatic site itself to promote tumor cell metastasis.
    Keywords:  Cancer; Dormancy; HIF; Oxygen; Vasculature
    DOI:  https://doi.org/10.1016/j.canlet.2020.06.004
  4. Cancer Discov. 2020 Jun 16. pii: CD-19-1493. [Epub ahead of print]
    Deblois G, Madani Tonekaboni SA, Grillo G, Martinez C, Kao YI, Tai F, Ettayebi I, Fortier AM, Savage P, Fedor AN, Liu X, Guilhamon P, Lima-Fernandes E, Murison A, Kuasne H, Ba-Alawi W, Cescon DW, Arrowsmith CH, De Carvalho DD, Haibe-Kains B, Locasale JW, Park M, Lupien M.
      Tumor progression upon treatment arises from pre-existing resistant and/or adaptation of persister cancer cells committing to an expansion phase. Here, we show that evasion from viral mimicry response allows the growth of taxane-resistant triple-negative breast cancer (TNBC). This is enabled by an epigenetic state adapted to taxane-induced metabolic stress, where DNA hypomethylation over loci enriched in transposable elements (TEs) is compensated by large chromatin domains of H3K27me3 to warrant TE repression. This epigenetic state creates a vulnerability to epigenetic therapy against EZH2, the H3K27me3 methyltransferase, which alleviates TE repression in taxane-resistant TNBC, leading to double-stranded RNA production and growth inhibition through viral mimicry response. Collectively, our results illustrate how epigenetic states over TEs promote cancer progression under treatment and can inform of vulnerabilities to epigenetic therapy.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1493
  5. Oncogene. 2020 Jun 19.
    Zhang X, Yang L, Szeto P, Abali GK, Zhang Y, Kulkarni A, Amarasinghe K, Li J, Vergara IA, Molania R, Papenfuss AT, McLean C, Shackleton M, Harvey KF.
      Melanoma is a deadly form of skin cancer that accounts for a disproportionally large proportion of cancer-related deaths in younger people. Compared with most other skin cancers, a feature of melanoma is its high metastatic capacity, although the mechanisms that confer this are not well understood. The Hippo pathway is a key regulator of organ growth and cell fate that is deregulated in many cancers. To analyse the Hippo pathway in cutaneous melanoma, we generated a transcriptional signature of melanoma cells that overexpressed YAP, the key downstream Hippo pathway oncoprotein. YAP-mediated transcriptional activity varied in melanoma cell lines but did not cluster with known genetic drivers of melanomagenesis such as BRAF and NRAS mutations. Instead, it correlated strongly with published gene expression profiles linked to melanoma cell invasiveness and varied throughout the metastatic cascade in melanoma patient tumours. Consistent with this, YAP was both necessary and sufficient for melanoma cell invasion in vitro. In vivo, YAP promoted spontaneous melanoma metastasis, whilst the growth of YAP-expressing primary tumours was impeded. Finally, we identified the YAP target genes AXL, THBS1 and CYR61 as key mediators of YAP-induced melanoma cell invasion. These data suggest that YAP is a critical regulator of melanoma metastasis.
    DOI:  https://doi.org/10.1038/s41388-020-1362-9
  6. EMBO Mol Med. 2020 Jun 17. e11099
    Paliouras AR, Buzzetti M, Shi L, Donaldson IJ, Magee P, Sahoo S, Leong HS, Fassan M, Carter M, Di Leva G, Krebs MG, Blackhall F, Lovly CM, Garofalo M.
      A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on-target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4-ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first-, second- and third-generation ALK inhibitors.
    Keywords:  ALK/EML4 translocation; ALKi; CDKi; NSCLC; drug resistance
    DOI:  https://doi.org/10.15252/emmm.201911099
  7. Mol Cancer. 2020 Jun 17. 19(1): 106
    Chen X, Xu M, Xu X, Zeng K, Liu X, Pan B, Li C, Sun L, Qin J, Xu T, He B, Pan Y, Sun H, Wang S.
      BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of tumor-related death worldwide, and its main cause of death is distant metastasis. Methyltransferase-like 14(METTL14), a major RNA N6-adenosine methyltransferase, is involved in tumor progression via regulating RNA function. The goal of the study is to uncover the biological function and molecular mechanism of METTL14 in CRC.METHODS: Quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were employed to detect METTL14 and SOX4 in CRC cell lines and tissues. The biological functions of METTL14 were demonstrated using in vitro and in vivo experiments. Chromatin immunoprecipitation (ChIP), Transcrptomic RNA sequencing (RNA-Seq), m6A-RNA immunoprecipitation sequencing (MeRIP-Seq), RNA immunoprecipitation and luciferase reporter assays were used to explore the mechanism of METTL14 action.
    RESULTS: METTL14 expression was significantly downregulated in CRC and decreased METTL14 was associated with poor overall survival (OS). Both the univariate and multivariate Cox regression analysis indicated that METTL14 was an independent prognostic factor in CRC. Moreover, lysine-specific histone demethylase 5C(KDM5C)-mediated demethylation of histone H3 lysine 4 tri-methylation(H3K4me3) in the promoter of METTL14 inhibited METTL14 transcription. Functionally, we verified that METTL14 inhibited CRC cells migration, invasion and metastasis through in vitro and in vivo assays, respectively. Furthermore, we identified SRY-related high-mobility-group box 4(SOX4) as a target of METTL14-mediated m6A modification. Knockdown of METTL14 markedly abolished SOX4 mRNA m6A modification and elevated SOX4 mRNA expression. We also revealed that METTL14-mediated SOX4 mRNA degradation relied on the YTHDF2-dependent pathway. Lastly, we demonstrated that METTL14 might inhibit CRC malignant process partly through SOX4-mediated EMT process and PI3K/Akt signals.
    CONCLUSIONS: Decreased METTL14 facilitates tumor metastasis in CRC, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for CRC.
    Keywords:  Colorectal cancer (CRC); METTL14; N6-methyladenosine(m6A); SOX4; YTHDF2
    DOI:  https://doi.org/10.1186/s12943-020-01220-7
  8. Theranostics. 2020 ;10(15): 6928-6945
    Sun H, Wang H, Wang X, Aoki Y, Wang X, Yang Y, Cheng X, Wang Z, Wang X.
      Rationale: Cisplatin derivatives are first-line chemotherapeutic agents for epithelial ovarian cancer. However, chemoresistance remains a major hurdle for successful therapy and the underlying molecular mechanisms are poorly understood at present. Methods: RNA sequencing of organoids (PDO) established from cisplatin-sensitive and -resistant ovarian cancer tissue samples was performed. Glucose metabolism, cell senescence, and chemosensitivity properties were subsequently examined. Immunoprecipitation, mass spectrometry, Fӧrster resonance energy transfer-fluorescence lifetime imaging (FRET-FLIM), luciferase reporter assay, ChIP and animal experiments were conducted to gain insights into the specific functions and mechanisms of action of the serine/threonine kinase, Aurora-A, in ovarian cancer. Results: Aurora-A levels were significantly enhanced in cisplatin-resistant PDO. Furthermore, Aurora-A promoted chemoresistance through suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Mechanistically, Aurora-A bound directly to the transcription factor sex determining region Y-box 8 (SOX8) and phosphorylated the Ser327 site, in turn, regulating genes related to cell senescence and glycolysis, including hTERT, P16, LDHA and HK2, through enhancement of forkhead-box k1 (FOXK1) expression. Conclusions: Aurora-A regulates cell senescence and glucose metabolism to induce cisplatin resistance by participating in the SOX8/FOXK1 signaling axis in ovarian cancer. Our collective findings highlight a novel mechanism of cisplatin resistance and present potential therapeutic targets to overcome chemoresistance in ovarian cancer.
    Keywords:  Aurora-A; Chemoresistance; Ovarian cancer; PDOs; SOX8
    DOI:  https://doi.org/10.7150/thno.43811
  9. Elife. 2020 Jun 18. pii: e53600. [Epub ahead of print]9
    VanOpstall C, Perike S, Brechka H, Gillard M, Lamperis S, Zhu B, Brown R, Bhanvadia R, Vander Griend DJ.
      The molecular roles of HOX transcriptional activity in human prostate epithelial cells remain unclear, impeding the implementation of new treatment strategies for cancer prevention and therapy. MEIS proteins are transcription factors that bind and direct HOX protein activity. MEIS proteins are putative tumor suppressors that are frequently silenced in aggressive forms of prostate cancer. Here we show that MEIS1 expression is sufficient to decrease proliferation and metastasis of prostate cancer cells in vitro and in vivo murine xenograft models. HOXB13 deletion demonstrates that the tumor-suppressive activity of MEIS1 is dependent on HOXB13. Integration of ChIP-seq and RNA-seq data revealed direct and HOXB13-dependent regulation of proteoglycans including decorin (DCN) as a mechanism of MEIS1-driven tumor suppression. These results define and underscore the importance of MEIS1-HOXB13 transcriptional regulation in suppressing prostate cancer progression and provide a mechanistic framework for the investigation of HOXB13 mutants and oncogenic cofactors when MEIS1/2 are silenced.
    Keywords:  cancer biology; human; human biology; medicine; mouse
    DOI:  https://doi.org/10.7554/eLife.53600
  10. Oncogene. 2020 Jun 16.
    Zhang YH, Shi WN, Wu SH, Miao RR, Sun SY, Luo DD, Wan SB, Guo ZK, Wang WY, Yu XF, Cui SX, Qu XJ.
      Aberrant sphingolipid metabolism has been implicated in chemoresistance, but the underlying mechanisms are still poorly understood. Herein we revealed a previously unrecognized mechanism of 5-fluorouracil (5-FU) resistance contributed by high SphK2-upregulated dihydropyrimidine dehydrogenase (DPD) in colorectal cancer (CRC), which is evidenced from human CRC specimens, animal models, and cancer cell lines. TMA samples from randomly selected 60 CRC specimens firstly identified the clinical correlation between high SphK2 and increased DPD (p < 0.001). Then the regulatory mechanism was explored in CRC models of villin-SphK2 Tg mice, SphK2-/-mice, and human CRC cells xenografted nude mice. Assays of ChIP-Seq and luciferase reporter gene demonstrated that high SphK2 upregulated DPD through promoting the HDAC1-mediated H3K56ac, leading to the degradation of intracellular 5-FU into inactive α-fluoro-β-alanine (FBAL). Lastly, inhibition of SphK2 by SLR080811 exhibited excellent inhibition on DPD expression and potently reversed 5-FU resistance in colorectal tumors of villin-SphK2 Tg mice. Overall, this study manifests that SphK2high conferred 5-FU resistance through upregulating tumoral DPD, which highlights the strategies of blocking SphK2 to overcome 5-FU resistance in CRC.
    DOI:  https://doi.org/10.1038/s41388-020-1352-y
  11. Oncogene. 2020 Jun 13.
    Yi H, Li G, Long Y, Liang W, Cui H, Zhang B, Tan Y, Li Y, Shen L, Deng D, Tang Y, Mao C, Tian S, Cai Y, Zhu Q, Hu Y, Chen W, Fang L.
      Epithelial-mesenchymal transition (EMT) program, which facilitates tumor metastasis, stemness and therapy resistance, is a reversible biological process that is largely orchestrated at the epigenetic level under the regulation of different cell signaling pathways. EMT state is often heterogeneous within individual tumors, though the epigenetic drivers underlying such heterogeneity remain elusive. In colon cancer, hyperactivation of the Wnt/β-catenin signaling not only drives tumor initiation, but also promotes metastasis in late stage by promoting EMT program. However, it is unknown whether the intratumorally heterogeneous Wnt activity could directly drive EMT heterogeneity, and, if so, what are the underlying epigenetic driver(s). Here, by analyzing a phenotypically and molecularly heterogeneous colon cancer cell line using single-cell RNA sequencing, we identified two distinct cell populations with positively correlated Wnt activity and EMT state. Integrative multi-omics analysis of these two cell populations revealed RUNX2 as a critical transcription factor epigenetically driving the EMT heterogeneity. Both in vitro and in vivo genetic perturbation assays validated the EMT-enhancing effect of RUNX2, which remodeled chromatin landscape and activated a panel of EMT-associated genes through binding to their promoters and/or potential enhancers. Finally, by exploring the clinical data, we showed that RUNX2 expression is positively correlated with metastasis development and poor survival of colon cancer patients, as well as patients afflicted with other types of cancer. Taken together, our work revealed RUNX2 as a new EMT-promoting epigenetic regulator in colon cancer, which may potentially serve as a prognostic marker for tumor metastasis.
    DOI:  https://doi.org/10.1038/s41388-020-1351-z
  12. Cancer Discov. 2020 Jun 19.
      A liquid biopsy-based method, dubbed EV-CLUE, discerned breast cancer invasiveness and metastasis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-092
  13. Cell Rep. 2020 Jun 16. pii: S2211-1247(20)30745-2. [Epub ahead of print]31(11): 107765
    Li X, Karras P, Torres R, Rambow F, van den Oord J, Marine JC, Kos L.
      Tumor cell plasticity, including transdifferentiation, is thought to be a key driver of therapy failure, tumor dormancy, and metastatic dissemination. Although melanoma cells have been shown to adopt various phenotypic features in vitro, direct in vivo evidence of metastatic cell plasticity remains sparse. Here, we combine lineage tracing in a spontaneous metastatic mouse model of melanoma, advanced imaging, and single-cell RNA sequencing approaches to search for pathophysiologically relevant melanoma cellular states. We identify melanoma cells in intravascular niches of various metastatic organs. These cells are quiescent, are negative for characteristic melanoma markers, and acquire endothelial cell features. We replicate the endothelial transdifferentiation (EndT) finding in another mouse model and provide evidence of EndT in BRAFV600E-metastatic biopsies from human lung, brain, and small intestine, thus highlighting the clinical relevance of these findings. The tumor-vasculature pattern described herein may contribute to melanoma dormancy within metastatic organs and represent a putative target for therapies.
    Keywords:  EndMT; dormancy; dormant niche; endothelial-mesenchymal transition; melanoma metastasis; melanoma mouse model; tumor vasculature; tumor-derived endothelial cells
    DOI:  https://doi.org/10.1016/j.celrep.2020.107765
  14. Cancer Res. 2020 Jun 18. pii: canres.1420.2020. [Epub ahead of print]
    Li J, Stanger BZ.
      Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. While tumor antigens are needed for effective immunotherapy, a favorable tumor immune microenvironment is also critical. In this review, we discuss emerging evidence that tumor cells exploit cellular plasticity and dedifferentiation programs to avoid immune surveillance, which in turn drives metastatic dissemination and resistance to immunotherapy. A deeper understanding of these programs may provide novel opportunities to enhance the efficacy of existing immunotherapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1420
  15. Cancer Res. 2020 Jun 19. pii: canres.2416.2019. [Epub ahead of print]
    Giurisato E, Lonardi S, Telfer B, Lussoso S, Risa-Ebrí B, Zhang J, Russo I, Wang J, Santucci A, Finegan KG, Gray NS, Vermi W, Tournier C.
      The presence of immunosuppressive macrophages that become activated in the tumor microenvironment constitutes a major factor responsible for tumor growth and malignancy. In line with this knowledge, we report here that macrophage proliferation is a significant feature of advanced stages of cancer. Moreover, we have found that a high proportion of proliferating macrophages in human tumors express extracellular-regulated protein kinase 5 (ERK5). ERK5 was required for supporting the proliferation of macrophages in tumor grafts in mice. Furthermore, myeloid ERK5 deficiency negatively impacted the proliferation of both resident and infiltrated macrophages in metastatic lung nodules. ERK5 maintained the capacity of macrophages to proliferate by suppressing p21 expression to halt their differentiation program. Collectively, these data provide insight into the mechanism underpinning macrophage proliferation to support malignant tumor development, thereby strengthening the value of ERK5-targeted therapies to restore anti-tumor immunity through the blockade of pro-tumorigenic macrophage activation.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-2416
  16. Nat Commun. 2020 Jun 15. 11(1): 3018
    Perkail S, Andricovich J, Kai Y, Tzatsos A.
      Chronic pancreatitis represents a risk factor for the development of pancreatic cancer. We find that heterozygous loss of histone H2A lysine 119 deubiquitinase BAP1 (BRCA1 Associated Protein-1) associates with a history of chronic pancreatitis and occurs in 25% of pancreatic ductal adenocarcinomas and 40% of acinar cell carcinomas. Deletion or heterozygous loss of Bap1 in murine pancreata causes genomic instability, tissue damage, and pancreatitis with full penetrance. Concomitant expression of KrasG12D leads to predominantly intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, while pancreatic intraepithelial neoplasias are rarely detected. These lesions progress to metastatic pancreatic cancer with high frequency. Lesions with histological features mimicking Acinar Cell Carcinomas are also observed in some tumors. Heterozygous mice also develop pancreatic cancer suggesting a haploinsufficient tumor suppressor role for BAP1. Mechanistically, BAP1 regulates genomic stability, in a catalytic independent manner, and its loss confers sensitivity to irradiation and platinum-based chemotherapy in pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41467-020-16589-8
  17. Cancer Res. 2020 Jun 14. pii: canres.3791.2019. [Epub ahead of print]
    Kikuchi H, Maishi N, Annan DA, Towfik Alam M, Ibrahim Hassan Dawood R, Sato M, Morimoto M, Takeda R, Ishizuka K, Matsumoto R, Akino T, Tsuchiya K, Abe T, Osawa T, Miyajima N, Maruyama S, Harabayashi T, Azuma M, Yamashiro K, Ameda K, Kashiwagi A, Matsuno Y, Hida Y, Shinohara N, Hida K.
      Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TEC resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL-8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL-8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3791
  18. Sci Transl Med. 2020 Jun 17. pii: eaav9760. [Epub ahead of print]12(548):
    De La Fuente A, Zilio S, Caroli J, Van Simaeys D, Mazza EMC, Ince TA, Bronte V, Bicciato S, Weed DT, Serafini P.
      Local delivery of anticancer agents has the potential to maximize treatment efficacy and minimize the acute and long-term systemic toxicities. Here, we used unsupervised systematic evolution of ligands by exponential enrichment to identify four RNA aptamers that specifically recognized mouse and human myeloid cells infiltrating tumors but not their peripheral or circulating counterparts in multiple mouse models and from patients with head and neck squamous cell carcinoma (HNSCC). The use of these aptamers conjugated to doxorubicin enhanced the accumulation and bystander release of the chemotherapeutic drug in both primary and metastatic tumor sites in breast and fibrosarcoma mouse models. In the 4T1 mammary carcinoma model, these doxorubicin-conjugated aptamers outperformed Doxil, the first clinically approved highly optimized nanoparticle for targeted chemotherapy, promoting tumor regression after just three administrations with no detected changes in weight loss or blood chemistry. These RNA aptamers recognized tumor infiltrating myeloid cells in a variety of mouse tumors in vivo and from human HNSCC ex vivo. This work suggests the use of RNA aptamers for the detection of myeloid-derived suppressor cells in humans and for a targeted delivery of chemotherapy to the tumor microenvironment in multiple malignancies.
    DOI:  https://doi.org/10.1126/scitranslmed.aav9760
  19. Cancer Res. 2020 Jun 19. pii: canres.0005.2020. [Epub ahead of print]
    Yang YC, Pan KF, Lee WJ, Chang JH, Tan P, Gu CC, Chang WM, Yang SF, Hsiao M, Hua KT, Chien MH.
      Although new generations of EGFR-tyrosine kinase inhibitors (EGFR-TKI) have been developed for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR-mutant tumors, TKI resistance often returns as a result of additional EGFR mutations. In addition to seeking for next generation EGFR-TKI, developing novel EGFR-targeting strategies may hold the key to overcome the vicious cycle of TKI resistance. Endocan is known as a receptor tyrosine kinase ligand enhancer in tumorigenesis, but the impact of endocan on EGFR-driven NSCLC progression remains unknown. In this study, higher endocan levels were found in lung tumors compared with cancer-free tissues and correlated with poor prognosis in NSCLC patients harboring mutant EGFR; circulating endocan levels were also significantly higher in patients with mutant EGFR. Endocan facilitated EGFR signaling via direct binding and enhancing of the EGF-EGFR interaction and supported the growth of tumors driven by mutated EGFR. Activated EGFR in turn upregulated expression of endocan via JAK/STAT3 and ERK/ELK cascades, thus forming a positive regulatory loop of endocan-EGFR signaling. Based on the binding region between endocan and EGFR, we designed therapeutic peptides and demonstrated promising therapeutic effects in xenografts harboring EGFR mutations including TKI-resistant T790M. Together, our findings highlight the novel interaction between endocan and EGFR and new opportunities to effectively target endocan-EGFR regulatory axis in TKI-resistant NSCLC patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0005
  20. Mol Cell. 2020 Jun 18. pii: S1097-2765(20)30355-5. [Epub ahead of print]78(6): 1019-1033
    Bader JE, Voss K, Rathmell JC.
      The growing field of immune metabolism has revealed promising indications for metabolic targets to modulate anti-cancer immunity. Combination therapies involving metabolic inhibitors with immune checkpoint blockade (ICB), chemotherapy, radiation, and/or diet now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment (TME). Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. These changes also reveal opportunities to reshape the TME by targeting metabolic pathways to favor immunity. Here we explore current strategies that shift immune cell metabolism to pro-inflammatory states in the TME and highlight a need to better replicate physiologic conditions to select targets, clarify mechanisms, and optimize metabolic inhibitors. Unifying our understanding of these pathways and interactions within the heterogenous TME will be instrumental to advance this promising field and enhance immunotherapy.
    DOI:  https://doi.org/10.1016/j.molcel.2020.05.034
  21. Cancer Discov. 2020 Jun 19.
      DNA-protein complexes called neutrophil extracellular traps were chemoattractants for metastatic cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-094
  22. Theranostics. 2020 ;10(15): 6561-6580
    Zhang C, Liao Y, Liu P, Du Q, Liang Y, Ooi S, Qin S, He S, Yao S, Wang W.
      Patients with cervical cancer (CCa) with lymph node metastasis (LNM) have an extremely poor prognosis. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa. Upregulation of fatty acid-binding protein 5 (FABP5) expression in CCa tumours was demonstrated to positively correlate with LNM. However, the precise role and mechanisms of FABP5 in the LNM of CCa remain unknown. Methods: The diagnostic value of FABP5 as a predictor of LNM in CCa was evaluated in CCa tumour samples. The functional role of FABP5 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. A mouse model of LNM was used to determine the effect of FABP5 on LNM and the therapeutic value of FABP5 targeting. Results: We demonstrated that FABP5 was markedly upregulated in CCa with LNM and correlated with poor prognosis. FABP5 protein was an independent predictor of LNM in a multivariate logistic analysis. Furthermore, FABP5 promoted epithelial-mesenchymal transition, lymphangiogenesis, and LNM by reprogramming fatty acid (FA) metabolism. Mechanistically, FABP5 promoted lipolysis and FA synthesis, which led to an increase in intracellular fatty acids (FAs) that activated NF-κB signalling, thus inducing LNM. Importantly, administration of orlistat, which attenuates FA metabolism reprogramming, inhibited FABP5-induced LNM in CCa. The pro-metastatic effect of FABP5 was reduced by miR-144-3p. Moreover, miR-144-3p was significantly downregulated and FABP5 was upregulated in CCa in a hypoxic microenvironment. Conclusion: Our findings highlight a FA metabolism-dependent mechanism of FABP5-induced LNM. Moreover, the expression and biological function of FABP5 can be regulated by miR-144-3p in hypoxia. Our study identifies FABP5 as a potential diagnostic biomarker and therapeutic target for LNM in CCa.
    Keywords:  FABP5; NF-κB signaling pathway; cervical cancer; fatty acid metabolism; lymph node metastasis
    DOI:  https://doi.org/10.7150/thno.44868
  23. Clin Cancer Res. 2020 Jun 18. pii: clincanres.4110.2019. [Epub ahead of print]
    Rao G, Latha K, Ott M, Sabbagh A, Marisetty A, Ling X, Zamler DB, Doucette T, Yang Y, Kong LY, Wei J, Fuller GN, Benavides F, Sonabend AM, Long JP, Li S, Curran MA, Heimberger AB.
      PURPOSE: Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated inconsistent therapeutic results in patients with glioblastoma (GBM) including those with profound impairments in CD8 T cell effector responses Experimental Design: . We observed a survival benefit in immunocompetent mice with endogenously-arising intracranial glioblastomas after intravenous administration of anti-PD-1. The therapeutic effect of PD-1 administration persisted in mice even after genetic ablation of the CD8 gene (CD8-/-). CD11b+ and Iba1+ monocytes and macrophages were enriched in the glioma microenvironment of the CD8-/- mice Results: The macrophages and microglia assumed a proinflammatory M1 response signature in the setting of anti-PD-1 blockade through the elimination of PD-1-expressing macrophages and microglia in the tumor microenvironment. Anti-PD-1 can inhibit the proliferation of and induce apoptosis of microglia through Ab-dependent cellular cytotoxicity (ADCC), as fluorescently-labeled anti-PD-1 was shown to gain direct access to the glioma microenvironment.CONCLUSIONS: Our results show that the therapeutic effect of anti-PD-1 blockade in GBM may be mediated by the innate immune system, rather than by CD8 T cells.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-4110
  24. Cancers (Basel). 2020 Jun 13. pii: E1566. [Epub ahead of print]12(6):
    Osumi H, Shinozaki E, Yamaguchi K.
      Liquid biopsy is a minimally invasive method for detecting soluble factors, including circulating tumor DNA (ctDNA), in body fluids. ctDNA carrying tumor-specific genetic or epigenetic alterations is released into circulation from tumor cells. ctDNA in the plasma contains somatic mutations that have occurred in the tumor, and reflects tumor progression and therapeutic effects promptly and accurately. Furthermore, ctDNA is useful for early detection of recurrence and estimation of prognosis and may be utilized for diagnosis and personalized medicine for treatment selection. Thus, in the near future, it will be possible to select the most appropriate treatment based on real-time genetic information using ctDNA.
    Keywords:  and biomarker; circulating tumor DNA; colorectal cancer; liquid biopsy; minimal residual disease
    DOI:  https://doi.org/10.3390/cancers12061566
  25. Proc Natl Acad Sci U S A. 2020 Jun 19. pii: 202004707. [Epub ahead of print]
    Tan J, Liu R, Zhu G, Umbricht CB, Xing M.
      Combination use of BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib has become a standard treatment for human cancers harboring BRAF V600E. Its anticancer efficacies vary, however, with dramatic efficacy in some patients and drug resistance/tumor recurrence in others, which is poorly understood. Using thyroid cancer, melanoma, and colon cancer cell models, we showed that dabrafenib and trametinib induced robust apoptosis of cancer cells harboring both BRAF V600E and TERT promoter mutations but had little proapoptotic effect in cells harboring only BRAF V600E. Correspondingly, the inhibitors nearly completely abolished the growth of in vivo tumors harboring both mutations but had little effect on tumors harboring only BRAF V600E. Upon drug withdrawal, tumors harboring both mutations remained hardly measurable but tumors harboring only BRAF V600E regrew rapidly. BRAF V600E/MAP kinase pathway is known to robustly activate mutant promoter of TERT, a strong apoptosis suppressor. Thus, for survival, cancer cells harboring both mutations may have evolved to rely on BRAF V600E-promoted and high-TERT expression-mediated suppression of apoptosis. As such, inhibition of BRAF/MEK can trigger strong apoptosis-induced cell death and hence tumor abolishment. This does not happen in cells harboring only BRAF V600E as they have not developed reliance on TERT-mediated suppression of apoptosis due to the lack of mutant promoter-driven high-TERT expression. TERT promoter mutation governs BRAF-mutant cancer cells' apoptotic and hence therapeutic responses to BRAF/MEK inhibitors. Thus, the genetic duet of BRAF V600E and TERT promoter mutation represents an Achilles Heel for effective therapeutic targeting and response prediction in cancer.
    Keywords:  BRAF V600E; BRAF inhibitor; MEK inhibitor; TERT promoter mutation; apoptosis
    DOI:  https://doi.org/10.1073/pnas.2004707117
  26. Cancer Res. 2020 Jun 19. pii: canres.0056.2020. [Epub ahead of print]
    Irurzun-Arana I, McDonald TO, Troconiz IF, Michor F.
      Identification of optimal schedules for combination drug administration relies on accurately estimating the correct pharmacokinetics, pharmacodynamics, and drug interaction effects. Misspecification of pharmacokinetics can lead to wrongly predicted timing or order of treatments, leading to schedules recommended based on incorrect assumptions about absorption and elimination of a drug and its effect on tumor growth. Here we developed a computational modeling platform and software package for combination treatment strategies with flexible pharmacokinetic profiles and multidrug interaction curves that are estimated from data. The software can be used to compare pre-specified schedules based on the number of resistant cells where drug interactions and pharmacokinetic curves can be estimated from user-provided data or models. We applied our approach to publicly available in vitro data of treatment with different tyrosine kinase inhibitors of BT-20 triple-negative breast cancer cells and of treatment with erlotinib of PC-9 non-small cell lung cancer cells. Our approach is publicly available in the form of an R package called ACESO (https://github.com/Michorlab/aceso) and can be used to investigate optimum dosing for any combination treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0056
  27. Nat Commun. 2020 Jun 15. 11(1): 3020
    Schiano Lomoriello I, Giangreco G, Iavarone C, Tordonato C, Caldieri G, Serio G, Confalonieri S, Freddi S, Bianchi F, Pirroni S, Bertalot G, Viale G, Disalvatore D, Tosoni D, Malabarba MG, Disanza A, Scita G, Pece S, Pilcher BK, Vecchi M, Sigismund S, Di Fiore PP.
      The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and therapeutic relevance in breast cancer. Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a β-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFβ-dependent autocrine loop that sustains EMT. EPN3-induced partial EMT is instrumental for the transition from in situ to invasive breast carcinoma, and, accordingly, high EPN3 levels are detected at the invasive front of human breast cancers and independently predict metastatic rather than loco-regional recurrence. Thus, we uncover an endocytic-based mechanism able to generate TGFβ-dependent regulatory loops conferring cellular plasticity and invasive behavior.
    DOI:  https://doi.org/10.1038/s41467-020-16836-y