bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒07‒12
forty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. JCI Insight. 2020 Jul 07. pii: 134290. [Epub ahead of print]
    Franklin DA, Sharick JT, Gonzalez-Ericsson PI, Sanchez V, Dean P, Opalenik SR, Cairo S, Judde JG, Lewis MT, Chang JC, Sanders ME, Cook RS, Skala MC, Bordeaux J, Bender JO, Vaupel CA, Geiss G, Hinerfeld D, Balko JM.
      Triple-negative breast cancers (TNBCs) are highly heterogeneous and aggressive, with high mortality rates. Although TNBC is typically more responsive to chemotherapy than other breast cancer subtypes, many patients develop chemo-resistance. The molecular processes contributing to chemo-resistance, and the roles of tumor cell-stromal crosstalk in establishing chemo-resistance are complex and largely unclear. Here we report molecular studies of paired TNBC patient-derived xenografts (PDX) established from patient biopsies before and after the development of chemo-resistance. Interestingly, the chemo-resistant model acquired a distinct KRASQ61R mutation that activates K-Ras. The chemo-resistant KRAS-mutant model showed gene expression and proteomic changes indicative of altered tumor cell metabolism. Specifically, KRAS-mutant PDXs exhibit increased redox ratios and decreased activation of AMPK, a protein involved in responding to metabolic homeostasis. Additionally, the chemo-resistant model exhibited increased immunosuppression including expression of CXCL1 and CXCL2, cytokines responsible for recruiting immunosuppressive leukocytes to tumors. Notably, chemo-resistant KRAS-mutant tumors harbored increased numbers of granulocytic myeloid-derived suppressor cells (gMDSCs). Interestingly, previously established gene expression signatures of Ras/MAPK activity correlated with myeloid/neutrophil-recruiting CXCL1/2 expression and negatively with T-cell recruiting chemokines (CXCL9/10/11) across TNBC patients, even in the absence of KRAS mutations. Importantly, MEK inhibition induced tumor suppression in mice while simultaneously reversing metabolic and immunosuppressive phenotypes including chemokine production and gMDSC tumor recruitment in the chemo-resistant KRAS mutant tumors. These results suggest that Ras/MAPK pathway inhibitors may be effective in some breast cancer patients to reverse Ras/MAPK-driven tumor metabolism and immunosuppression, particularly in the setting of chemo-resistance.
    Keywords:  Breast cancer; Immunology; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.134290
  2. Genome Biol. 2020 Jul 06. 21(1): 162
    Ramesh N, Sei E, Tsai PC, Bai S, Zhao Y, Troncoso P, Corn PG, Logothetis C, Zurita AJ, Navin NE.
      BACKGROUND: Investigating genome evolution in response to therapy is difficult in human tissue samples. To address this challenge, we develop an unbiased whole-genome plasma DNA sequencing approach that concurrently measures genomic copy number and exome mutations from archival cryostored plasma samples. This approach is applied to study longitudinal blood plasma samples from prostate cancer patients, where longitudinal tissue biopsies from the bone and other metastatic sites have been challenging to collect.RESULTS: A molecular characterization of archival plasma DNA from 233 patients and genomic profiling of 101 patients identifies clinical correlations of aneuploid plasma DNA profiles with poor survival, increased plasma DNA concentrations, and lower plasma DNA size distributions. Deep-exome sequencing and genomic copy number profiling are performed on 23 patients, including 9 patients with matched metastatic tissues and 12 patients with serial plasma samples. These data show a high concordance in genomic alterations between the plasma DNA and metastatic tissue samples, suggesting the plasma DNA is highly representative of the tissue alterations. Longitudinal sequencing of 12 patients with 2-5 serial plasma samples reveals clonal dynamics and genome evolution in response to hormonal and chemotherapy. By performing an integrated evolutionary analysis, minor subclones are identified in 9 patients that expanded in response to therapy and harbored mutations associated with resistance.
    CONCLUSIONS: This study provides an unbiased evolutionary approach to non-invasively delineate clonal dynamics and identify clones with mutations associated with resistance in prostate cancer.
    Keywords:  Liquid biopsies; Non-invasive; Tumor evolution
    DOI:  https://doi.org/10.1186/s13059-020-02045-9
  3. Theranostics. 2020 ;10(16): 7083-7099
    Shen CJ, Chang KY, Lin BW, Lin WT, Su CM, Tsai JP, Liao YH, Hung LY, Chang WC, Chen BK.
      Background: Colorectal cancer (CRC) progression and related mortality are highly associated with metabolic disorders. However, the molecular mechanism involved in the regulation of hyperlipidemia-associated CRC metastasis remains unclear. This study aimed to investigate the effects of angiopoietin-like 4 (ANGPTL4) on NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) production, which might provide new targets for improving outcomes in patients with hyperlipidemia-associated CRC metastasis. Methods: The clinical relevance of relationship between NOX4 expression and ANGPTL4 was examined in CRC patients by the Oncomine and TCGA data set. Expressions of NOX4, epithelial-mesenchymal transition (EMT) markers, and gene regulation of NOX4 in free fatty acids (FFAs)-treated CRC cells were determined. The FFAs-triggered metastatic ability of CRC cells under treatments of antioxidants or knockdown of NOX4, ANGPTL4, and MMPs was evaluated in vitro and in vivo. In addition, effects of antioxidants and depletion of metastasis-associated molecules on the correlation between ROS production and FFAs-promoted CRC metastasis were also clarified. Results: In this study, we found that the induction of NOX4, followed by the increased ROS was essential for oleic acid (OA)-promoted CRC cell metastasis. The depletion of ANGPTL4 significantly inhibited c-Jun-mediated transactivation of NOX4 expression, accompanied with reduced levels of ROS, MMP-1, and MMP-9, resulting in the disruption of OA-promoted CRC cell metastasis. Moreover, knockdown of ANGPTL4, NOX4, MMP-1, and MMP-9 or the treatment of antioxidants dramatically inhibited circulating OA-enhanced tumor cell extravasation and metastatic seeding of tumor cells in lungs, indicating that the ANGPTL4/NOX4 axis was critical for dyslipidemia-associated tumor metastasis. Conclusion: The coincident expression of NOX4 and ANGPTL4 in CRC tumor specimens provides the insight into the potential therapeutic targets for the treatment of dyslipidemia-associated CRC metastasis.
    Keywords:  ANGPTL4; NOX4; colorectal cancer; metastasis; oleic acid
    DOI:  https://doi.org/10.7150/thno.44744
  4. J Cell Biol. 2020 Sep 07. pii: e202001134. [Epub ahead of print]219(9):
    Chan IS, Knútsdóttir H, Ramakrishnan G, Padmanaban V, Warrier M, Ramirez JC, Dunworth M, Zhang H, Jaffee EM, Bader JS, Ewald AJ.
      Natural killer (NK) cells have potent antitumor and antimetastatic activity. It is incompletely understood how cancer cells escape NK cell surveillance. Using ex vivo and in vivo models of metastasis, we establish that keratin-14+ breast cancer cells are vulnerable to NK cells. We then discovered that exposure to cancer cells causes NK cells to lose their cytotoxic ability and promote metastatic outgrowth. Gene expression comparisons revealed that healthy NK cells have an active NK cell molecular phenotype, whereas tumor-exposed (teNK) cells resemble resting NK cells. Receptor-ligand analysis between teNK cells and tumor cells revealed multiple potential targets. We next showed that treatment with antibodies targeting TIGIT, antibodies targeting KLRG1, or small-molecule inhibitors of DNA methyltransferases (DMNT) each reduced colony formation. Combinations of DNMT inhibitors with anti-TIGIT or anti-KLRG1 antibodies further reduced metastatic potential. We propose that NK-directed therapies targeting these pathways would be effective in the adjuvant setting to prevent metastatic recurrence.
    DOI:  https://doi.org/10.1083/jcb.202001134
  5. Mol Cancer Res. 2020 Jul 09. pii: molcanres.0165.2020. [Epub ahead of print]
    Buckarma EH, Werneberg NW, Conboy CB, Kabashima A, O'Brien DR, Wang C, Rizvi SH, Smoot RL.
      The Hippo pathway effector Yes-associated protein (YAP) is localized to the nucleus and transcriptionally active in a number of tumor types, including a majority of human cholangiocarcinomas (CCA). YAP activity has been linked to chemotherapy resistance and has been shown to rescue KRAS and BRAF inhibition in RAS/RAF driven cancers; however the underlying mechanisms of YAP-mediated chemoresistance have yet to be elucidated. Herein, we report that the tyrosine phosphatase SHP2 directly regulates the activity of YAP by dephosphorylating pYAPY357 even in the setting of RAS/RAF mutations, and that diminished SHP2 phosphatase activity is associated with chemoresistance in CCA. A screen for YAP interacting tyrosine phosphatases identified SHP2, and characterization of CCA cell lines demonstrated an inverse relationship between SHP2 levels and pYAPY357. Human sequencing data demonstrated lower SHP2 levels in CCA tumors as compared to normal liver. Cell lines with low SHP2 expression and higher levels of pYAPY357 were resistant to gemcitabine and cisplatin. In CCA cells with high levels of SHP2, pharmacologic inhibition or genetic deletion of SHP2 increased YAPY357 phosphorylation and expression of YAP target genes, including the anti-apoptotic regulator MCL1, imparting resistance to gemcitabine and cisplatin. In vivo evaluation of chemotherapy sensitivity demonstrated significant resistance in xenografts with genetic deletion of SHP2; which could be overcome utilizing an MCL1 inhibitor. Implications: These findings demonstrate a role for SHP2 in regulating YAP activity and chemosensitivity, and suggest that decreased phosphatase activity may be a mechanism of chemoresistance in cholangiocarcinoma via a MCL1 mediated mechanism.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0165
  6. Cancer Discov. 2020 Jul 08. pii: CD-19-1008. [Epub ahead of print]
    Aroua N, Boet E, Ghisi M, Nicolau-Travers ML, Saland E, Gwilliam R, de Toni F, Hosseini M, Mouchel PL, Farge T, Bosc C, Stuani L, Sabatier M, Mazed F, Larrue C, Jarrou L, Gandarillas S, Bardotti M, Picard M, Syrykh C, Laurent C, Gotanegre M, Bonnefoy N, Bellvert F, Portais JC, Nicot N, Azuaje F, Kaoma T, Joffre C, Tamburini J, Recher C, Vergez F, Sarry JE.
      Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine (AraC)-resistant leukemic cells from both AML cell lines and patient samples in vivo and in vitro. CD39 cell surface expression and activity is increased in AML patients upon chemotherapy compared to diagnosis and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes AraC resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated adaptive mitochondrial stress response. Finally, genetic and pharmacological inhibition of CD39 eATPase activity blocks the mitochondrial reprogramming triggered by AraC treatment and markedly enhances its cytotoxicity in AML cells in vitro and in vivo. Together, these results reveal CD39 as a new residual disease marker and a promising therapeutic target to improve chemotherapy response in AML.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1008
  7. Nat Commun. 2020 Jul 08. 11(1): 3406
    Couturier CP, Ayyadhury S, Le PU, Nadaf J, Monlong J, Riva G, Allache R, Baig S, Yan X, Bourgey M, Lee C, Wang YCD, Wee Yong V, Guiot MC, Najafabadi H, Misic B, Antel J, Bourque G, Ragoussis J, Petrecca K.
      Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.
    DOI:  https://doi.org/10.1038/s41467-020-17186-5
  8. Cancer Res. 2020 Jul 08. pii: canres.0225.2020. [Epub ahead of print]
    Midorikawa Y, Yamamoto S, Tatsuno K, Renard-Guillet C, Tsuji S, Hayashi A, Ueda H, Fukuda S, Fujita T, Katoh H, Ishikawa S, Covington KR, Creighton CJ, Sugitani M, Wheeler DA, Shibata T, Nagae G, Takayama T, Aburatani H.
      Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC regardless of CTNNB1 mutation status because β-catenin did not translocate into the nucleus due to the E-Cadherin/β-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in target genes. Similarly, cell cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC with TP53 or RB1 gene mutations associated with chromosomal deletion of 4q or 16q. HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Collectively, these data show that as HCC progresses, additional molecular events exclusive of driver gene mutations cooperatively contribute to transcriptional activation of downstream targets according to methylation status.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0225
  9. Theranostics. 2020 ;10(16): 7335-7350
    Du F, Cao T, Xie H, Li T, Sun L, Liu H, Guo H, Wang X, Liu Q, Kim T, Franklin JL, Graves-Deal R, Han W, Tian Z, Ge M, Nie Y, Fan D, Coffey RJ, Lu Y, Zhao X.
      Introduction: Colorectal cancer (CRC) frequently harbors KRAS mutations that result in chemoresistance and metastasis. MicroRNAs (miRNAs) are usually dysregulated and play important regulatory roles in tumor progression. However, the KRAS mutation-responsive miRNA profile in CRC remains uninvestigated. Methods: miR-139-5p was identified and evaluated by small RNA sequencing, qRT-PCR and in situ hybridization. The roles of miR-139-5p in CRC cells with and without KRAS mutation were determined by Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry and transwell assays in vitro and by tumorigenesis and metastasis assays in vivo. Microarrays followed by bioinformatic analyses, luciferase reporter assays and Western blotting were applied for mechanistic studies. Results: miR-139-5p was significantly downregulated in KRAS-mutated CRC cells and tissues compared with their wild-type counterparts. Low miR-139-5p expression was associated with aggressive phenotypes and poor prognosis in CRC patients. miR-139-5p overexpression inhibited CRC cell proliferation, migration and invasion in vitro, sensitized tumors to chemotherapy, and impaired tumor growth and metastasis in vivo. Transcriptomic profiling identified multiple modulators in the Ras (JUN and FOS) and Wnt (CTNNB1 and DVL1) signaling pathways and the epithelial-to-mesenchymal transition (EMT) process (ZEB1) as direct targets of miR-139-5p, and inverse correlations were confirmed in CRC clinical tissues. Aberrantly activated Wnt signaling in KRAS-mutant cells was demonstrated to transcriptionally repress miR-139-5p through TCF4, forming a miR-139-5p/Wnt signaling double-negative feedback loop. Conclusions: We identified miR-139-5p as a KRAS-responsive miRNA and demonstrated its involvement in CRC progression. KRAS mutation disrupted the miR-139-5p/Wnt signaling reciprocal negative feedback mechanism, which might cause miR-139-5p downregulation and derepression of oncogenic signaling pathways and EMT. These results reveal a transcriptional regulatory mode of KRAS-driven malignant transformation and highlight miR-139-5p as a novel regulator of crosstalk between the Ras and Wnt signaling pathways in CRC.
    Keywords:  CRC; KRAS mutation; Ras signaling; Wnt/β-catenin signaling; miR-139-5p
    DOI:  https://doi.org/10.7150/thno.45971
  10. Cancers (Basel). 2020 Jul 02. pii: E1757. [Epub ahead of print]12(7):
    Cuyàs E, Verdura S, Martin-Castillo B, Alarcón T, Lupu R, Bosch-Barrera J, Menendez JA.
      One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune system's ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells. We have learned that cancer cell-associated metabolic activities trigger shifts in the abundance of some metabolites with immunosuppressory roles in the tumor microenvironment. Yet very little is known about the tumor cell-intrinsic metabolic traits that control the immune checkpoint contexture in cancer cells. Likewise, we lack a comprehensive understanding of how systemic metabolic perturbations in response to dietary interventions can reprogram the immune checkpoint landscape of tumor cells. We here review state-of-the-art molecular- and functional-level interrogation approaches to uncover how cell-autonomous metabolic traits and diet-mediated changes in nutrient availability and utilization might delineate new cancer cell-intrinsic metabolic dependencies of tumor immunogenicity. We propose that clinical monitoring and in-depth molecular evaluation of the cancer cell-intrinsic metabolic traits involved in primary, adaptive, and acquired resistance to cancer immunotherapy can provide the basis for improvements in therapeutic responses to ICIs. Overall, these approaches might guide the use of metabolic therapeutics and dietary approaches as novel strategies to broaden the spectrum of cancer patients and indications that can be effectively treated with ICI-based cancer immunotherapy.
    Keywords:  diet; immune checkpoint inhibitors; immune checkpoints; metabolism; nutrition
    DOI:  https://doi.org/10.3390/cancers12071757
  11. Cancer Rep (Hoboken). 2020 Feb;pii: e1156. [Epub ahead of print]3(1):
    Mayhew V, Omokehinde T, Johnson RW.
      Background: Bone marrow is a common site of metastasis for a number of tumor types, including breast, prostate, and lung cancer, but the mechanisms controlling tumor dormancy in bone are poorly understood. In breast cancer, while advances in drug development, screening practices, and surgical techniques have dramatically improved survival rates in recent decades, metastatic recurrence in the bone remains common and can develop years or decades after elimination of the primary tumor.Recent Findings: It is now understood that tumor cells disseminate to distant metastatic sites at early stages of tumor progression, leaving cancer survivors at a high risk of recurrence. This review will discuss mechanisms of bone lesion development and current theories of how dormant cancer cells behave in bone, as well as a number of processes suspected to be involved in the maintenance of and exit from dormancy in the bone microenvironment.
    Conclusions: The bone is a complex microenvironment with a multitude of cell types and processes. Many of these factors, including angiogenesis, immune surveillance, and hypoxia, are thought to regulate tumor cell entry and exit from dormancy in different bone marrow niches.
    Keywords:  angiogenesis; bone marrow; dormancy; hypoxia; immune surveillance; metastasis
    DOI:  https://doi.org/10.1002/cnr2.1156
  12. Immunity. 2020 Jul 01. pii: S1074-7613(20)30271-5. [Epub ahead of print]
    Kumagai S, Togashi Y, Sakai C, Kawazoe A, Kawazu M, Ueno T, Sato E, Kuwata T, Kinoshita T, Yamamoto M, Nomura S, Tsukamoto T, Mano H, Shitara K, Nishikawa H.
      Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB.
    Keywords:  PI3K inhibitor; RHOA mutation; fatty acid metabolism; gastric cancer; non-inflamed tumor; regulatory T cell
    DOI:  https://doi.org/10.1016/j.immuni.2020.06.016
  13. Mol Ther. 2020 Jun 24. pii: S1525-0016(20)30314-2. [Epub ahead of print]
    Liu L, Wu Y, Li Q, Liang J, He Q, Zhao L, Chen J, Cheng M, Huang Z, Ren H, Chen J, Peng L, Gao F, Chen D, Wang A.
      RNA modification plays an essential function in regulating gene expression and diverse biological processes. RNA modification enzyme methyltransferase-like 3 (METTL3) affects tumor progression by regulating the N6-methyladenosine (m6A) modification in the mRNAs of critical oncogenes or tumor suppressors, but its effect in oral squamous cell carcinoma (OSCC) remains unknown. In this study, we revealed that METTL3 was consistently upregulated in two OSCC cohorts, and high METTL3 expression was associated with poor prognosis. Functionally, cell proliferation, self-renewal, migration, and invasion ability in vitro and tumor growth and metastasis in vivo were decreased after METTL3 knockdown in OSCC cells. In contrast, the opposite results were obtained after METTL3 overexpression. In addition, the results obtained with the Mettl3 genetically modified mouse model validated the essential role of Mettl3 in chemical-induced oral carcinogenesis. In mechanism, methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-quantitative real-time PCR, and luciferase reporter and mutagenesis assays identified that METTL3 mediates the m6A modification in the 3' UTR of BMI1 mRNA. METTL3 promotes BMI1 translation in OSCC under the cooperation with m6A reader IGF2BP1. Our findings revealed that METTL3 promotes OSCC proliferation and metastasis through BMI1 m6A methylation, suggesting that the METTL3-m6A-BMI1 axis may serve as a prognostic biomarker or therapeutic target in patients with OSCC.
    Keywords:  BMI1; METTL3; OSCC; RNA modification
    DOI:  https://doi.org/10.1016/j.ymthe.2020.06.024
  14. Cancers (Basel). 2020 Jul 04. pii: E1790. [Epub ahead of print]12(7):
    Cash TP, Alcalá S, Rico-Ferreira MDR, Hernández-Encinas E, García J, Albarrán MI, Valle S, Muñoz J, Martínez-González S, Blanco-Aparicio C, Pastor J, Serrano M, Sainz B.
      Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.
    Keywords:  cancer stem cells; compound library; lysosomal membrane permeabilization; pancreatic ductal adenocarcinoma; patient-derived xenografts
    DOI:  https://doi.org/10.3390/cancers12071790
  15. Cancer Discov. 2020 Jul 10. pii: CD-20-0036. [Epub ahead of print]
    Marigo I, Trovato R, Hofer F, Ingangi V, DE Sanctis F, Ugel S, Cane S, Simonelli A, Lamolinara A, Iezzi M, Fassan M, Rugge M, Boschi F, Borile G, Eisenhaure T, Sarkizova S, Lieb D, Hacohen N, Azzolin L, Piccolo S, Lawlor R, Scarpa A, Carbognin L, Bria E, Bicciato S, Murray PJ, Bronte V.
      Tumor-associated macrophages (TAMs) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor invasive front, participate in integrin recycling, ECM remodeling and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor Yes-Associated Protein. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for cancer patient stratification. DAB2 is therefore central for the pro-metastatic activity of TAMs.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0036
  16. Oncogene. 2020 Jul 09.
    Nair J, Huang TT, Murai J, Haynes B, Steeg PS, Pommier Y, Lee JM.
      High grade serous ovarian cancer (HGSOC) is a fatal gynecologic malignancy in the U.S. with limited treatment options. New therapeutic strategies include targeting of the cell cycle checkpoints, e.g., ATR and CHK1. We recently reported a promising clinical activity of the CHK1 inhibitor (CHK1i) prexasertib monotherapy in BRCA wild-type (BRCAwt) HGSOC patients. In this study, biopsies of treated patients and cell line models were used to investigate possible mechanisms of resistance to CHK1i. We report that BRCAwt HGSOC develops resistance to prexasertib monotherapy via a prolonged G2 delay induced by lower CDK1/CyclinB1 activity, thus preventing cells from mitotic catastrophe and cell death. On the other hand, we noted CHK1's regulation on RAD51-mediated homologous recombination (HR) repair was not altered in CHK1i-resistant cells. Therefore, CHK1i sensitizes CHK1i-resistant cells to DNA damaging agents such as gemcitabine or hydroxyurea by inhibition of HR. In summary, our results demonstrate new mechanistic insights of functionally distinct CHK1 activities and highlight a potential combination treatment approach to overcome CHK1i resistance in BRCAwt HGSOC.
    DOI:  https://doi.org/10.1038/s41388-020-1383-4
  17. Cancer Res. 2020 Jul 08. pii: canres.0291.2020. [Epub ahead of print]
    Valiente M, Van Swearingen AED, Anders CK, Bairoch A, Boire A, Bos PD, Cittelly DM, Erez N, Ferraro GB, Fukumura D, Gril B, Herlyn M, Holmen SL, Jain RK, Joyce JA, Lorger M, Massague J, Neman J, Sibson NR, Steeg PS, Thorsen F, Young LS, Varešlija D, Vultur A, Weis-Garcia F, Winkler F.
      Spread of cancer to the brain remains an unmet clinical need in spite of the increasing number of cases among patients with lung, breast cancer and melanoma most notably. Although research on brain metastasis was considered a minor aspect in the past due to its untreatable nature and invariable lethality, nowadays limited but encouraging examples have questioned this statement making it more attractive for basic and clinical researchers. Evidences of its own biological identity (i.e. specific microenvironment) and particular therapeutic requirements (i.e. presence of blood-brain barrier, blood-tumor barrier, molecular differences with the primary tumor) are thought to be critical aspects that must be functionally exploited using preclinical models. We present the coordinated effort of 19 laboratories to compile comprehensive information related to brain metastasis experimental models. Each lab has provided details on the cancer cell lines they have generated or characterized as being capable of forming metastatic colonies in the brain, as well as principle methodologies of brain metastasis research. The Brain Metastasis Cell Lines Panel (BrMPanel) represents the first of its class and includes information about the cell line, how tropism to the brain was established and the behavior of each model in vivo. These and other aspects described are intended to assist investigators in choosing the most suitable cell line for research on brain metastasis. The main goal of this effort is to facilitate research on this unmet clinical need, to improve models through a collaborative environment, and to promote the exchange of information on these valuable resources.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0291
  18. Cancer Res. 2020 Jul 08. pii: canres.0788.2020. [Epub ahead of print]
    Asare-Werehene M, Communal L, Carmona E, Han Y, Song YS, Burger D, Mes-Masson AM, Tsang BK.
      Although initial treatment of ovarian cancer (OVCA) is successful, tumors typically relapse and become resistant to treatment. Due to poor infiltration of effector T cells, patients are mostly unresponsive to immunotherapy. Plasma gelsolin (pGSN) is transported by exosomes (sEV) and plays a key role in OVCA chemoresistance, yet little is known about its role in immunosurveillance. Here we report the immunomodulatory roles of sEV-pGSN in OVCA chemoresistance. In chemosensitive conditions, secretion of sEV-pGSN was low, allowing for optimal CD8+ T cell function. This resulted in increased T cell secretion of IFNγ, which reduced intracellular glutathione (GSH) production and sensitized chemosensitive cells to cisplatin (CDDP)-induced apoptosis. In chemoresistant conditions, increased secretion of sEV-pGSN by OVCA cells induced apoptosis in CD8+ T cells. IFNγ secretion was therefore reduced, resulting in high GSH production and resistance to CDDP-induced death in OVCA cells. These findings support our hypothesis that sEV-pGSN attenuates immunosurveillance and regulates GSH biosynthesis, a phenomenon that contributes to chemoresistance in OVCA.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0788
  19. Cell Rep. 2020 Jul 07. pii: S2211-1247(20)30860-3. [Epub ahead of print]32(1): 107879
    Zhang S, Wang C, Ma B, Xu M, Xu S, Liu J, Tian Y, Fu Y, Luo Y.
      Mutant p53 (mutp53) loses its tumor suppressor properties but gains oncogenic functions of driving malignancy. However, it remains largely unknown how mutp53 drives cancer metastasis. Here, we show that wild-type p53 (WTp53) suppresses the secretion of heat shock protein 90-alpha (Hsp90α), whereas mutp53 enhances Hsp90α vesicular trafficking and exosome-mediated secretion. Long-term delivery of an antibody that blocks extracellular Hsp90α (eHsp90α) function extends the survival of p53-/- mice and attenuates the invasiveness of p53 mutant tumors. Furthermore, mass spectrometry and functional analysis identified a critical role for Rab coupling protein (RCP) in mutp53-induced Hsp90α secretion. RCP knockdown decreases eHsp90α levels and inhibits malignant progression. Notably, recombinant Hsp90α re-introduction markedly rescues the impaired migration and invasion abilities caused by RCP depletion. Taken together, these findings elucidate the molecular mechanisms by which mutp53 executes oncogenic activities via its downstream RCP-mediated Hsp90α secretion and a strategy to treat human cancers expressing mutp53 proteins.
    Keywords:  Rab coupling protein; cancer metastasis; extracellular Hsp90α; mutant p53; vesicular trafficking
    DOI:  https://doi.org/10.1016/j.celrep.2020.107879
  20. Theranostics. 2020 ;10(16): 7178-7192
    Wang Z, Qin J, Zhao J, Li J, Li D, Popp M, Popp F, Alakus H, Kong B, Dong Q, Nelson PJ, Zhao Y, Bruns CJ.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide and effective therapy remains a challenge. IFIT3 is an interferon-stimulated gene with antiviral and pro-inflammatory functions. Our previous work has shown that high expression of IFIT3 is correlated with poor survival in PDAC patients who receive chemotherapy suggesting a link between IFIT3 and chemotherapy resistance in PDAC. However, the exact role and molecular mechanism of IFIT3 in chemotherapy resistance in PDAC has been unclear. Methods: A group of transcriptome datasets were downloaded and analyzed for the characterization of IFIT3 in PDAC. Highly metastatic PDAC cell line L3.6pl and patient-derived primary cell TBO368 were used and IFIT3 knockdown and the corresponding knockin cells were established for in vitro studies. Chemotherapy-induced apoptosis, ROS production, confocal immunofluorescence, subcellular fractionation, chromatin-immunoprecipitation, co-immunoprecipitation and mass spectrometry analysis were determined to further explore the biological role of IFIT3 in chemotherapy resistance of PDAC. Results: Based on PDAC transcriptome data, we show that IFIT3 expression is associated with the squamous molecular subtype of PDAC and an increase in inflammatory response and apoptosis pathways. We further identify a crucial role for IFIT3 in the regulation of mitochondria-associated apoptosis during chemotherapy. Knockdown of IFIT3 attenuates the chemotherapy resistance of PDAC cells to gemcitabine, paclitaxel, and FOLFIRINOX regimen treatments, independent of individual chemotherapy regimens. While IFIT3 overexpression was found to promote drug resistance. Co-immunoprecipitation identified a direct interaction between IFIT3 and the mitochondrial channel protein VDAC2, an important regulator of mitochondria-associated apoptosis. It was subsequently found that IFIT3 regulates the post-translational modification-O-GlcNAcylation of VDAC2 by stabilizing the interaction of VDAC2 with O-GlcNAc transferase. Increased O-GlcNAcylation of VDAC2 protected PDAC cells from chemotherapy induced apoptosis. Conclusions: These results effectively demonstrate a central mechanism by which IFIT3 expression can affect chemotherapy resistance in PDAC. Targeting IFIT3/VDAC2 may represent a novel strategy to sensitize aggressive forms of pancreatic cancer to conventional chemotherapy regimens.
    Keywords:  Chemotherapy resistance; IFIT3; PDAC; VDAC2; post-translational modification
    DOI:  https://doi.org/10.7150/thno.43093
  21. Cancers (Basel). 2020 Jul 02. pii: E1772. [Epub ahead of print]12(7):
    Cho J, Min HY, Pei H, Wei X, Sim JY, Park SH, Hwang SJ, Lee HJ, Hong S, Shin YK, Lee HY.
      Slow-cycling cancer cells (SCCs) with a quiescence-like phenotype are believed to perpetrate cancer relapse and progression. However, the mechanisms that mediate SCC-derived tumor recurrence are poorly understood. Here, we investigated the mechanisms underlying cancer recurrence after chemotherapy, focusing on the interplay between SCCs and the tumor microenvironment. We established a preclinical model of SCCs by exposing non-small-cell lung cancer (NSCLC) cells to either the proliferation-dependent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) or chemotherapeutic drugs. An RNA sequencing analysis revealed that the established SCCs exhibited the upregulation of a group of genes, especially epidermal growth factor (EGF). Increases in the number of vascular endothelial growth factor receptor (VEGFR)-positive vascular endothelial cells and epidermal growth factor receptor (EGFR) activation were found in NSCLC cell line- and patient-derived xenograft tumors that progressed upon chemotherapy. EGFR tyrosine kinase inhibitors effectively suppressed the migration and tube formation of vascular endothelial cells. Furthermore, activating transcription factor 6 (ATF6) induced the upregulation of EGF, and its antagonism effectively suppressed these SCC-mediated events and inhibited tumor recurrence after chemotherapy. These results suggest that the ATF6-EGF signaling axis in SCCs functions to trigger the angiogenesis switch in residual tumors after chemotherapy and is thus a driving force for the switch from SCCs to actively cycling cancer cells, leading to tumor recurrence.
    Keywords:  angiogenesis; chemoresistance; slow-cycling cancer cells; tumor recurrence
    DOI:  https://doi.org/10.3390/cancers12071772
  22. Cancers (Basel). 2020 Jul 08. pii: E1830. [Epub ahead of print]12(7):
    Porru M, Zizza P, Panera N, Alisi A, Biroccio A, Leonetti C.
      Metastatic colorectal cancer (mCRC) remains challenging because of the emergence of resistance mechanisms to anti-epidermal growth factor receptor (EGFR) therapeutics, so more effective strategies to improve the patients' outcome are needed. During the last decade, the application of a multi-omics approach has contributed to a deeper understanding of the complex molecular landscape of human CRC, identifying a plethora of drug targets for precision medicine. Target validation relies on the use of experimental models that would retain the molecular and clinical features of human colorectal cancer, thus mirroring the clinical characteristics of patients. In particular, organoids and patient-derived-xenografts (PDXs), as well as genetically engineered mouse models (GEMMs) and patient-derived orthotopic xenografts (PDOXs), should be considered for translational purposes. Overall, omics and advanced mouse models of cancer represent a portfolio of sophisticated biological tools that, if optimized for use in concert with accurate data analysis, could accelerate the anticancer discovery process and provide new weapons against cancer. In this review, we highlight success reached following the integration of omics and experimental models; moreover, results produced by our group in the field of mCRC are also presented.
    Keywords:  GEMM; PDXs; anti-EGF; colon cancer; new therapies; omics technologies; organoids; orthotopic tumors
    DOI:  https://doi.org/10.3390/cancers12071830
  23. Dev Cell. 2020 Jun 30. pii: S1534-5807(20)30497-4. [Epub ahead of print]
    Li F, Simon MC.
      Solid tumors reside in harsh tumor microenvironments (TMEs) together with various stromal cell types. During tumor progression and metastasis, both tumor and stromal cells undergo rapid metabolic adaptations. Tumor cells metabolically coordinate or compete with their "neighbors" to maintain biosynthetic and bioenergetic demands while escaping immunosurveillance or therapeutic interventions. Here, we provide an update on metabolic communication between tumor cells and heterogeneous stromal components in primary and metastatic TMEs and discuss emerging strategies to target metabolic communications for improved cancer treatments.
    Keywords:  antitumor immunity; combination therapy; immunomodulation; metabolic communication; metabolic symbiosis; metabolism; metastasis; nutrient competition; signaling molecule; stromal cells; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.devcel.2020.06.018
  24. Mol Cancer. 2020 Jul 10. 19(1): 114
    Xie JW, Huang XB, Chen QY, Ma YB, Zhao YJ, Liu LC, Wang JB, Lin JX, Lu J, Cao LL, Lin M, Tu RH, Zheng CH, Huang CM, Li P.
      BACKGROUND: BATF2, also known as SARI, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive.METHODS: We obtained GC tissues and corresponding normal tissues from 8 patients and identified BATF2 as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine BATF2 levels in normal and GC tissues. The prognostic value of BATF2 was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of BATF2 in GC growth and metastasis were evaluated in vitro and in vivo.
    RESULTS: BATF2 expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that BATF2 was an independent prognostic factor and effective predictor in patients with GC. Low BATF2 expression was remarkably associated with peritoneal recurrence after curative gastrectomy. Moreover, elevated BATF2 expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, BATF2 binds to p53 and enhances its protein stability, thereby inhibiting the phosphorylation of ERK. Tissue microarray results indicated that the prognostic value of BATF2 was dependent on ERK activity. In addition, the N6-methyladenosine (m6A) modification of BATF2 mRNA by METTL3 repressed its expression in GC.
    CONCLUSIONS: Collectively, our findings indicate the pivotal role of BATF2 in GC and highlight the regulatory function of the METTL3/BATF2/p53/ERK axis in modulating GC progression, which provides potential prognostic and therapeutic targets for GC treatment.
    Keywords:  BATF2; ERK; Gastric cancer; m6A; p53
    DOI:  https://doi.org/10.1186/s12943-020-01223-4
  25. Cancer Res. 2020 Jul 07. pii: canres.2888.2019. [Epub ahead of print]
    Hayashi M, Kuga A, Suzuki M, Panda H, Kitamura H, Motohashi H, Yamamoto M.
      The transcription factor Nrf2 activates transcription of cytoprotective genes during oxidative and electrophilic insults. Nrf2 activity is regulated by Keap1 in a stress-dependent manner in normal cells, and somatic loss-of-function mutations of Keap1 are known to induce constitutive Nrf2 activation, especially in lung adenocarcinomas, conferring survival and proliferative benefits to tumors. Therefore, several therapeutic strategies that aim to inhibit Nrf2 in tumors have been developed for the treatment of Nrf2-activated cancers. Here we addressed whether targeting Nrf2 activation in the microenvironment can suppress the progression of Nrf2-activated tumors. We combined two types of Keap1-flox mice expressing variable levels of Keap1 with a Kras-driven adenocarcinoma model to generate Keap1-deficient lung tumors surrounded by normal or Keap1-knockdown host cells. In this model system, activation of Nrf2 in the microenvironment prolonged the survival of Nrf2-activated tumor-bearing mice. The Nrf2-activated microenvironment suppressed tumor burden; in particular, preinvasive lesion formation was significantly suppressed. Notably, loss of Nrf2 in bone marrow-derived cells in Nrf2-activated host cells appeared to counteract the suppression of Nrf2-activated cancer progression. Thus, these results demonstrate that microenvironmental Nrf2 activation suppresses the progression of malignant Nrf2-activated tumors and that Nrf2 activation in immune cells at least partially contributes to these suppressive effects.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-2888
  26. Lancet Oncol. 2020 Jul 06. pii: S1470-2045(20)30236-9. [Epub ahead of print]
    Kikuchi E, Hayakawa N.
      
    DOI:  https://doi.org/10.1016/S1470-2045(20)30236-9
  27. Cancer Treat Rev. 2020 Jun 23. pii: S0305-7372(20)30097-9. [Epub ahead of print]88 102059
    Parent P, Cohen R, Rassy E, Svrcek M, Taieb J, André T, Turpin A.
      Colon cancer (CC) has the highest incidence rate among gastrointestinal cancers and ranks the third in mortality among all cancers, which contributes to the current CC burden and constitutes a major public health issue. While therapeutic strategies for stage I, III, and IV CC are standardized, those for stage II CC remain debatable. The choice of adjuvant chemotherapy for patients with stage II CC depends on stage (pT4) and grade (high) of the disease, the presence of venous, perinervous, and/or lymphatic emboli, or the need of suboptimal surgery (tumor with initial occlusion or perforation needing emergency surgeries, <12 lymph nodes harvested). Several prognostic factors that have been validated in retrospective studies can potentially define a population of CC patients at low and high-risk for reccurence. The role of biomarkers is becoming increasingly important for the future personalized treatment options. We conducted a systematic overview of potential prognostic biomarkers with possible clinical implications in stage II CC.
    Keywords:  Adjuvant chemotherapy; Artificial intelligence; Carcinoembryonic antigen; Circulating Tumor DNA; Colorectal cancer; Immunoscore
    DOI:  https://doi.org/10.1016/j.ctrv.2020.102059
  28. Oncogene. 2020 Jul 06.
    Feng H, Liu J, Qiu Y, Liu Y, Saiyin H, Liang X, Zheng F, Wang Y, Jiang D, Wang Y, Yu L, Su W, Shen S, Wu J.
      RNA-binding proteins play key roles in the posttranscriptional regulation of mRNA during cancer progression. Here, we show that RNA-binding motif protein 43 (RBM43) is significantly downregulated in human tumors, and its low expression is correlated with poor prognosis in patients with HCC. Overexpression of RBM43 suppressed cell proliferation in culture and resulted in the growth arrest of tumor xenografts, whereas downregulating RBM43 played an opposite role. We have also demonstrated that overexpression or knockdown of RBM43 affects the cell-cycle progression of liver cancer cells. Mechanistically, RBM43 directly associated with the 3'UTR of Cyclin B1 mRNA and regulated its expression. Moreover, loss of Rbm43 in mice promoted liver carcinogenesis and HCC development after diethylnitrosamine (DEN)-carbon tetrachloride (CCl4) treatment. Taken together, our data indicate that RBM43 is a tumor suppressor that controls the cell cycle through modulation of Cyclin B1 expression, providing evidence that RBM43 is particularly important in HCC.
    DOI:  https://doi.org/10.1038/s41388-020-1380-7
  29. Theranostics. 2020 ;10(16): 7053-7069
    Li H, Feng Z, He ML.
      Lipids, the basic components of the cell membrane, execute fundamental roles in almost all the cell activities including cell-cell recognition, signalling transduction and energy supplies. Lipid metabolism is elementary for life sustentation that balances activity between synthesis and degradation. An accumulating amount of data has indicated abnormal lipid metabolism in cancer stem cells (CSCs), and that the alteration of lipid metabolism exerts a great impact on CSCs' properties such as the capability of self-renewal, differentiation, invasion, metastasis, and drug sensitivity and resistance. CSCs' formation and maintenance cannot do without the regulation of fatty acids and cholesterol. In normal cells and embryonic development, fatty acids and cholesterol metabolism are regulated by some important signalling pathways (such as Hedgehog, Notch, Wnt signalling pathways); these signalling pathways also play crucial roles in initiating and/or maintaining CSCs' properties, and such signalling is shown to be commonly modulated by the abnormal lipid metabolism in CSCs; on the other hand, the altered lipid metabolism in turn modifies the cell signalling and generates additional impacts on CSCs. Metabolic rewiring is considered as an ideal hallmark of CSCs, and metabolic alterations would be promising therapeutic targets of CSCs for aggressive tumors. In this review, we summarize the most updated findings of lipid metabolic abnormalities in CSCs and prospect the potential applications of targeting lipid metabolism for anticancer treatment.
    Keywords:  Cancer stem cells; lipid metabolism; self-renewal; signalling pathways
    DOI:  https://doi.org/10.7150/thno.41388
  30. Cancers (Basel). 2020 Jul 07. pii: E1827. [Epub ahead of print]12(7):
    Wong GL, Abu Jalboush S, Lo HW.
      Breast cancer is the most frequent malignancy for women in which one in eight women will be diagnosed with the disease in their lifetime. Despite advances made in treating primary breast cancer, there is still no effective treatment for metastatic breast cancer. Consequently, metastatic breast cancer is responsible for 90% of breast cancer-related deaths while only accounting for approximately one third of all breast cancer cases. To help develop effective treatments for metastatic breast cancer, it is important to gain a deeper understanding of the mechanisms by which breast cancer metastasizes, particularly, those underlying organotropism towards brain, bone, and lungs. In this review, we will primarily focus on the roles that circulating exosomal microRNAs (miRNAs) play in organotropism of breast cancer metastasis. Exosomes are extracellular vesicles that play critical roles in intercellular communication. MicroRNAs can be encapsulated in exosomes; cargo-loaded exosomes can be secreted by tumor cells into the tumor microenvironment to facilitate tumor-stroma interactions or released to circulation to prime distant organs for subsequent metastasis. Here, we will summarize our current knowledge on the biogenesis of exosomes and miRNAs, mechanisms of cargo sorting into exosomes, the exosomal miRNAs implicated in breast cancer metastasis, and therapeutic exosomal miRNAs.
    Keywords:  breast cancer; exosomes; metastasis; microRNAs; organotropism
    DOI:  https://doi.org/10.3390/cancers12071827
  31. Mol Cancer Res. 2020 Jul 09. pii: molcanres.0021.2020. [Epub ahead of print]
    Angeles AK, Heckmann D, Flosdorf N, Duensing S, Sultmann H.
      Numerous noncoding transcripts have been reported to correlate with cancer development and progression. Nevertheless, there remains a paucity of long noncoding RNAs (lncRNAs) with well elucidated functional roles. Here, we leverage the International Cancer Genome Consortium-Early Onset Prostate Cancer (ICGC-EOPC) transcriptome and identify the previously uncharacterized lncRNA LINC00920 to be upregulated in prostate tumors. Phenotypic characterization of LINC00920 revealed its positive impact on cellular proliferation, colony formation, and migration. We demonstrate that LINC00920 transcription is directly activated by ERG, an oncogenic transcription factor overexpressed in 50% of prostate cancers. Chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) revealed the interaction of LINC00920 with the 14-3-3ε protein, leading to enhanced sequestration of tumor suppressive FOXO1. Altogether, our results provide a rationale on how ERG overexpression-partly by driving LINC00920 transcription-could confer survival advantage to prostate cancer cells and potentially prime PTEN-intact prostate cells for cellular transformation through FOXO inactivation. Implications: The study describes a novel long non-coding RNA (lncRNA)-mediated mechanism of regulating the FOXO signaling pathway and provides additional insight into the role of ERG in prostate cancer cells.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0021
  32. Cancer Res. 2020 Jul 08. pii: canres.0032.2020. [Epub ahead of print]
    Guo C, Liu J, Zhou Q, Song J, Zhang Z, Li Z, Wang G, Sun Z, Yuan W.
      Tumor drug resistance is a major challenge in the treatment of cancer. Non-coding RNAs (ncRNA) play a role in the progression of drug resistance. Recent studies have indicated that exosomes, with their in vitro and in vivo compatibility, are the best natural carrier of ncRNA, and their transport of ncRNA into cells could regulate drug resistance. Exosomal ncRNA impact drug resistance through participation in drug efflux, regulation of signaling pathways, and modification of the tumor microenvironment. In this review, we evaluate the mechanism of exosomal ncRNA related to tumor drug resistance, their role in different tumors, and potential clinical applications.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0032
  33. Cancer Metastasis Rev. 2020 Jul 09.
    Lakatos G, Köhne CH, Bodoky G.
      Colorectal cancer is a clinically and molecularly heterogeneous disease. Currently, extended RAS and BRAF mutation testing is obligatory in routine clinical practice before starting any treatment in the metastatic setting. Treatment decision making also includes assessment of the clinical condition of the patient, definition of the treatment goal, and consideration of the primary tumor site. Biological treatment is part of the first-line drug combination unless contraindicated. Mutational status is significantly associated with the outcome of patients and is strongly predictive for anti-EGFR-targeted therapy. The prognosis of RAS mutant CRC is clearly inferior to wild-type cases. RAS remains an elusive target, and specific treatment options are not yet available. Recently, promising results of a direct KRAS G12C inhibitor have been reported; however, further confirmation is needed. The biomarker landscape in mCRC is evolving; new promising markers are awaited with the chance of more precise targeted treatment.
    Keywords:  BRAF; Biomarker; Colorectal cancer; RAS; Targeted therapy
    DOI:  https://doi.org/10.1007/s10555-020-09913-7
  34. Cell. 2020 Jul 09. pii: S0092-8674(20)30744-3. [Epub ahead of print]182(1): 200-225.e35
    Gillette MA, Satpathy S, Cao S, Dhanasekaran SM, Vasaikar SV, Krug K, Petralia F, Li Y, Liang WW, Reva B, Krek A, Ji J, Song X, Liu W, Hong R, Yao L, Blumenberg L, Savage SR, Wendl MC, Wen B, Li K, Tang LC, MacMullan MA, Avanessian SC, Kane MH, Newton CJ, Cornwell M, Kothadia RB, Ma W, Yoo S, Mannan R, Vats P, Kumar-Sinha C, Kawaler EA, Omelchenko T, Colaprico A, Geffen Y, Maruvka YE, da Veiga Leprevost F, Wiznerowicz M, Gümüş ZH, Veluswamy RR, Hostetter G, Heiman DI, Wyczalkowski MA, Hiltke T, Mesri M, Kinsinger CR, Boja ES, Omenn GS, Chinnaiyan AM, Rodriguez H, Li QK, Jewell SD, Thiagarajan M, Getz G, Zhang B, Fenyö D, Ruggles KV, Cieslik MP, Robles AI, Clauser KR, Govindan R, Wang P, Nesvizhskii AI, Ding L, Mani DR, Carr SA, .
      To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.
    Keywords:  CPTAC; acetylation; adenocarcinoma; genomics; lung cancer; mass spectrometry; phosphorylation; protein; proteogenomics; proteomics
    DOI:  https://doi.org/10.1016/j.cell.2020.06.013
  35. J Clin Invest. 2020 Jul 07. pii: 135373. [Epub ahead of print]
    Lovnicki JM, Gan Y, Feng T, Li Y, Xie N, Ho CH, Lee AR, Chen X, Nappi L, Han B, Fazli L, Huang J, Gleave M, Dong X.
      Therapy-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive subtype of prostate cancer with poor patient survival. Emerging evidence indicates that t-NEPC can develop when prostate adenocarcinoma cells acquire cancer stem-like cell signaling in the presence of androgen receptor inhibition, followed by re-differentiation toward neuroendocrine lineage and subsequent t-NEPC progression. Whether the stem-like signaling is controlled by the core pluripotency stem cell genes (e.g., LIN28 and SOX2) remains unknown. Here, we report that the transcription of LIN28B isoform and SOX2 are co-upregulated in t-NEPC patient tumors, patient-derived xenografts, transgenic mice, and cell models. Immunohistochemistry validated that LIN28B and SOX2 protein expression are elevated in t-NEPC patient biopsies. Using prostate adenocarcinoma and t-NEPC cell models, we demonstrated that LIN28B induces a stem-like gene network, neuroendocrine biomarkers, and neuroendocrine cell morphology. LIN28B depletion by CRISPR inhibited t-NEPC tumorigenesis and xenograft growth. These LIN28B functions were mediated mainly through the suppression of let-7 miRNA expression, resulting in de-repression of the transcription factors HMGA2 and HMGA2-mediated SOX2 expression. This study reveals a mechanism by which t-NEPC can develop through the LIN28B/let-7/SOX2 axis that regulates a cancer cell stem-like gene network, highlighting LIN28B as a potential therapeutic target in t-NEPC.
    Keywords:  Oncology; Prostate cancer; Urology
    DOI:  https://doi.org/10.1172/JCI135373
  36. Oncogene. 2020 Jul 10.
    Braggio D, Zewdu A, Londhe P, Yu P, Lopez G, Batte K, Koller D, Costas Casal de Faria F, Casadei L, Strohecker AM, Lev D, Pollock RE.
      Wnt/β-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with β-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of β-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in β-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the β-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in β-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3, thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/β-catenin signaling induced by this mutation.
    DOI:  https://doi.org/10.1038/s41388-020-1382-5
  37. Elife. 2020 Jul 06. pii: e57894. [Epub ahead of print]9
    Brunner A, Suryo Rahmanto A, Johansson H, Franco M, Viiliäinen J, Gazi M, Frings O, Fredlund E, Spruck C, Lehtiö J, Rantala JK, Larsson LG, Sangfelt O.
      Inhibition of WEE1 kinase by AZD1775 has shown promising results in clinical cancer trials, but markers predicting AZD1775 response are lacking. Here we analysed AZD1775 response in a panel of human breast cancer (BC) cell lines by global proteome/transcriptome profiling and identified two groups of basal-like BC (BLBCs): 'PTEN low' BLBCs were highly sensitive to AZD1775 and failed to recover following removal of AZD1775, while 'PTEN high' BLBCs recovered. AZD1775 induced phosphorylation of DNA-PK, protecting cells from replication-associated DNA damage and promoting cellular recovery. Deletion of DNA-PK or PTEN, or inhibition of DNA-PK sensitized recovering BLBCs to AZD1775 by abrogating replication arrest, allowing replication despite DNA damage. This was linked to reduced CHK1 activation, increased cyclin E levels and apoptosis. In conclusion, we identified PTEN and DNA-PK as essential regulators of replication checkpoint arrest in response to AZD1775 and defined PTEN as a promising biomarker for efficient WEE1 cancer therapy.
    Keywords:  AZD1775; DNA-PK; PTEN; WEE1; basal-like breast cancer; cancer biology; cyclin E; mouse
    DOI:  https://doi.org/10.7554/eLife.57894
  38. Nat Rev Gastroenterol Hepatol. 2020 Jul 07.
    Dickson I.
      
    DOI:  https://doi.org/10.1038/s41575-020-0345-1