bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒05‒03
twenty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Gut. 2020 Apr 27. pii: gutjnl-2019-319748. [Epub ahead of print]
    Ajani JA, Xu Y, Huo L, Wang R, Li Y, Wang Y, Pizzi MP, Scott A, Harada K, Ma L, Yao X, Jin J, Zhao W, Dong X, Badgwell BD, Shanbhag N, Tatlonghari G, Estrella JS, Roy-Chowdhuri S, Kobayashi M, Vykoukal JV, Hanash SM, Calin GA, Peng G, Lee JS, Johnson RL, Wang Z, Wang L, Song S.
      OBJECTIVE: Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 (YAP1) oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target.METHODS: Patient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases.
    RESULTS: YAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1high PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1high PC cells especially in combination with cytotoxics in vivo PDX model.
    CONCLUSIONS: YAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.
    Keywords:  gastric adenocarcinoma; gene regulation; molecular oncology
  2. Nat Commun. 2020 May 01. 11(1): 2156
    Silva-Fisher JM, Dang HX, White NM, Strand MS, Krasnick BA, Rozycki EB, Jeffers GGL, Grossman JG, Highkin MK, Tang C, Cabanski CR, Eteleeb A, Mudd J, Goedegebuure SP, Luo J, Mardis ER, Wilson RK, Ley TJ, Lockhart AC, Fields RC, Maher CA.
      Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings of RAMS11-dependent regulation of TOP2α supports the potential use of RAMS11 as a biomarker and therapeutic target for mCRC.
  3. Clin Cancer Res. 2020 Apr 27. pii: clincanres.4100.2019. [Epub ahead of print]
    Malihi PD, Graf RP, Rodriguez A, Ramesh N, Lee J, Sutton R, Jiles R, Ruiz Velasco C, Sei E, Kolatkar A, Logothetis C, Navin NE, Corn P, Aparicio AM, Dittamore R, Hicks J, Kuhn P, Zurita AJ.
      PURPOSE: Aggressive variant prostate cancer (AVPC) represents a clinical subset distinguished by therapy resistance and poor prognosis, linked to combined losses of the tumor suppressor genes (TSG) PTEN, RB1, and TP53. Circulating tumor cells (CTC) provide a minimally-invasive opportunity for identification and molecular characterization of AVPC. We aimed to evaluate the incidence and clinical significance of compound (2+)TSG losses and genomic instability in prostate cancer CTC, and to expand the set genomic biomarkers relevant to AVPC.EXPERIMENTAL DESIGN: Genomic analysis of chromosomal copy number alterations (CNA) at single-cell resolution was performed in CTC from patients with and without AVPC before initiating chemotherapy with cabazitaxel or cabazitaxel and carboplatin. We evaluated associations between single-CTC genomics and clinical features, PFS and OS.
    RESULTS: 257 individual CTC were sequenced from 47 patients (1-22 CTC/patient). Twenty patients (42.6%) had concurrent 2+TSG losses in at least 1 CTC in association with poor survival and increased genomic instability, inferred by high large-scale transitions scores (LST). Higher LST in CTC were independent of CTC enumerated, clinically more indicative of aggressive behavior than co-occurring TSG losses, and molecularly associated to gains in chromosomal regions including PTK2, Myc and NCOA2, increased androgen receptor (AR) expression, and BRCA2 loss. In 57 patients with matched cell-free tumor DNA (ctDNA) data, CTC were more frequently detectable and evaluable for CNA analysis (in 73.7% vs 42.1%, respectively).
    CONCLUSIONS: Our findings suggest that genomic instability in CTC is a hallmark of advanced prostate cancer aggressiveness, and support single-CTC sequencing as a compelling tool to non-invasively characterize cancer heterogeneity.
  4. Clin Cancer Res. 2020 Apr 27. pii: clincanres.3790.2019. [Epub ahead of print]
    Li J, Pan C, Boese AC, Kang J, Umano AD, Magliocca KR, Yang W, Zhang Y, Lonial S, Jin L, Kang S.
      PURPOSE: Although platinum compounds are the first-line treatment for ovarian cancer, the majority of patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. The goal of our study is to decipher the mechanism by which a metabolic kinase, diacylglycerol kinase alpha (DGKA), confers platinum resistance in ovarian cancer.EXPERIMENTAL DESIGN: Metabolic kinase RNAi synthetic lethal screening was used to identify a cisplatin resistance driver in ovarian cancer. DGKA variants were used to demonstrate the need for DGKA activity in cisplatin resistance. Phospho-proteomic and genomic screens were performed to identify downstream effectors of DGKA. Therapeutic efficacy of targeting DGKA was confirmed and clinical relevance of DGKA signaling was validated using ovarian cancer patient-derived tumors that had different responses to platinum-based therapy.
    RESULTS: We found that platinum resistance was mediated by DGKA and its product, phosphatidic acid (PA), in ovarian cancer. Proteomic and genomic screens revealed that DGKA activates the transcription factor c-JUN and consequently enhances expression of a cell cycle regulator, WEE1. Mechanistically, PA facilitates JNK recruitment to c-JUN and its nuclear localization, leading to c-JUN activation upon cisplatin exposure. Pharmacological inhibition of DGKA sensitized ovarian cancer cells to cisplatin treatment and DGKA-c-JUN-WEE1 signaling positively correlated with platinum resistance in tumors derived from ovarian cancer patients.
    CONCLUSIONS: Our study demonstrates how the DGKA-derived lipid messenger, PA, contributes to cisplatin resistance by intertwining with kinase and transcription networks, and provides preclinical evidence for targeting DGKA as a new strategy in ovarian cancer treatment to battle cisplatin resistance.
  5. Nat Commun. 2020 May 01. 11(1): 2135
    Liu XD, Kong W, Peterson CB, McGrail DJ, Hoang A, Zhang X, Lam T, Pilie PG, Zhu H, Beckermann KE, Haake SM, Isgandrova S, Martinez-Moczygemba M, Sahni N, Tannir NM, Lin SY, Rathmell WK, Jonasch E.
      A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.
  6. Mol Cancer. 2020 Apr 27. 19(1): 79
    Lu Y, Chan YT, Tan HY, Li S, Wang N, Feng Y.
      Epigenetics is dynamic and heritable modifications to the genome that occur independently of DNA sequence. It requires interactions cohesively with various enzymes and other molecular components. Aberrant epigenetic alterations can lead to inappropriate onset of genetic expressions and promote tumorigenesis. As the epigenetic modifiers are susceptible to extrinsic factors and reversible, they are becoming promising targets in multiple cancer therapies. Recently, various epi-drugs have been developed and implicated in clinical use. The use of epi-drugs alone, or in combination with chemotherapy or immunotherapy, has shown compelling outcomes, including augmentation of anti-tumoral effects, overcoming drug resistance, and activation of host immune response.
    Keywords:  Cancer; Combination strategy; Epi-drugs; Epigenetic modification; Tumour microenvironment
  7. Mol Cancer Res. 2020 Apr 29. pii: molcanres.1162.2019. [Epub ahead of print]
    Dasari S, Pandhiri T, Grassi T, Visscher DW, Multinu F, Agarwal K, Mariani A, Sridhar V, Mitra AK.
      Treatment of ovarian cancer (OC) is limited by extensive metastasis and yet it remains poorly understood. We have studied the critical step of metastatic colonization in the context of the productive interactions with the metastatic microenvironment with a goal of identifying key regulators. By combining microRNA expression analysis using an organotypic 3D culture model of early OC metastasis with that of matched primary and metastatic tumors from 42 OC patients, we identified miR-4454 as a key regulator of both early colonization and advanced metastasis in OC patients. miR-4454 was downregulated in the metastasizing OC cells through paracrine signals from microenvironmental fibroblasts, which promoted migration, invasion, proliferation and clonogenic growth in OC cells as well as their ability to penetrate through the outer layers of the omentum. Stable overexpression of miR-4454 decreased metastasis in OC xenografts. Its mechanism of action was through the upregulation of its targets, secreted protein acidic and cysteine rich (SPARC) and BCL2 associated athanogene 5 (BAG5), which activated focal adhesion kinase (FAK) signaling, promoted mutant p53 gain of function by its stabilization and inhibited apoptosis. Since microenvironment-induced downregulation of miR-4454 is essential for early and advanced metastasis, targeting it could be a promising therapeutic approach. Implications: This study identifies a microRNA, miR-4454, which is downregulated by signals from the microenvironment and promotes early and advanced OC metastasis through its effects on FAK activation, mutant p53 stabilization and apoptosis inhibition.
  8. Cell Stem Cell. 2020 Apr 26. pii: S1934-5909(20)30142-9. [Epub ahead of print]
    Michels BE, Mosa MH, Streibl BI, Zhan T, Menche C, Abou-El-Ardat K, Darvishi T, Członka E, Wagner S, Winter J, Medyouf H, Boutros M, Farin HF.
      Colorectal cancer (CRC) is characterized by prominent genetic and phenotypic heterogeneity between patients. To facilitate high-throughput genetic testing and functional identification of tumor drivers, we developed a platform for pooled CRISPR-Cas9 screening in human colon organoids. Using transforming growth factor β (TGF-β) resistance as a paradigm to establish sensitivity and scalability in vitro, we identified optimal conditions and strict guide RNA (gRNA) requirements for screening in 3D organoids. We then screened a pan-cancer tumor suppressor gene (TSG) library in pre-malignant organoids with APC-/-;KRASG12D mutations, which were xenografted to study clonal advantages in context of a complex tumor microenvironment. We identified TGFBR2 as the most prevalent TSG, followed by known and previously uncharacterized mediators of CRC growth. gRNAs were validated in a secondary screen using unique molecular identifiers (UMIs) to adjust for clonal drift and to distinguish clone size and abundance. Together, these findings highlight a powerful organoid-based platform for pooled CRISPR-Cas9 screening for patient-specific functional genomics.
    Keywords:  clonal drift; colorectal cancer; human colonic stem cells; lentiviral barcoding; non-homologous end joining; patient-derived organoids; pooled-barcoded CRISPR-Cas9 screening; tumor microenvironment; tumor suppressor genes; unique molecular identifiers
  9. Trends Cancer. 2020 May;pii: S2405-8033(20)30057-1. [Epub ahead of print]6(5): 419-431
    Jiang MJ, Gu DN, Dai JJ, Huang Q, Tian L.
      Accelerated tumor repopulation following chemoradiation is often observed in the clinic, but the underlying mechanisms remain unclear. In recent years, dying cells caused by chemoradiation have attracted much attention, and they may manifest diverse forms of cell death and release complex factors and thus orchestrate tumor repopulation cascades. Dying cells potentiate the survival of residual living tumor cells, remodel the tumor microenvironment, boost cell proliferation, and accelerate cancer cell metastasis. Moreover, dying cells also mediate the side effects of chemoradiation. These findings suggest more caution when weighing the benefits of cytotoxic therapy and the need to accordingly develop new strategies for cancer treatment.
    Keywords:  cancer microenvironment; cell death; chemoradiation; dying cell; tumor repopulation
  10. Cancer Res. 2020 Apr 27. pii: canres.2549.2019. [Epub ahead of print]
    Wu H, You L, Li Y, Zhao Z, Shi G, Chen Z, Wang Z, Li X, Du S, Ye W, Gao X, Duan J, Cheng Y, Tao W, Bian J, Zhou JR, Zhu Q, Yang Y.
      In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide (ENZ) is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer (PCa) but decreased in CRPC compared to normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and ENZ resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated PCa progression and ENZ resistance in vitro and in vivo. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of ENZ in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in PCa pathogenesis and a potential alternative therapeutic option to overcome ENZ resistance.
  11. Trends Cancer. 2020 May;pii: S2405-8033(20)30060-1. [Epub ahead of print]6(5): 432-441
    Horn LA, Fousek K, Palena C.
      Tumor cell plasticity exhibited as an epithelial-mesenchymal transition (EMT) has been identified as a major obstacle for the effective treatment of many cancers. This process, which involves the dedifferentiation of epithelial tumor cells towards a motile, metastatic, and mesenchymal tumor phenotype, mediates resistance to conventional therapies and small-molecule targeted therapies. In this review, we highlight current research correlating the role of tumor plasticity with resistance to current immunotherapy approaches and discuss future and ongoing combination immunotherapy strategies to reduce tumor cell plasticity-driven resistance in cancer.
    Keywords:  EMT; IL-8; TGF-β; immunotherapy resistance; tumor plasticity
  12. Cell Rep. 2020 Apr 28. pii: S2211-1247(20)30517-9. [Epub ahead of print]31(4): 107568
    Volz C, Breid S, Selenz C, Zaplatina A, Golfmann K, Meder L, Dietlein F, Borchmann S, Chatterjee S, Siobal M, Schöttle J, Florin A, Koker M, Nill M, Ozretić L, Uhlenbrock N, Smith S, Büttner R, Miao H, Wang B, Reinhardt HC, Rauh D, Hallek M, Acker-Palmer A, Heukamp LC, Ullrich RT.
      Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF)-VEGFR2 signaling has shown limited efficacy in lung cancer patients. Here, we demonstrate that inhibition of VEGFR2 in tumor cells, expressed in ∼20% of non-squamous non-small cell lung cancer (NSCLC) patients, leads to a pro-invasive phenotype. Drug-induced inhibition of tumor VEGFR2 interferes with the formation of the EphA2/VEGFR2 heterocomplex, thereby allowing RSK to interact with Serine 897 of EphA2. Inhibition of RSK decreases phosphorylation of Serine 897 EphA2. Selective genetic modeling of Serine 897 of EphA2 or inhibition of EphA2 abrogates the formation of metastases in vivo upon VEGFR2 inhibition. In summary, these findings demonstrate that VEGFR2-targeted therapy conditions VEGFR2-positive NSCLC to Serine 897 EphA2-dependent aggressive tumor growth and metastasis. These data shed light on the molecular mechanisms explaining the limited efficacy of VEGFR2-targeted anti-angiogenic treatment in lung cancer patients.
    Keywords:  NSCLC; RSK; S897 EphA2; VEGFR2 inhibition; tumor cell invasion
  13. Clin Cancer Res. 2020 Apr 28. pii: clincanres.3925.2019. [Epub ahead of print]
    Lepletier A, Madore J, O'Donnell JS, Johnston RL, Li XY, McDonald E, Ahern E, Kuchel A, Eastgate M, Pearson SA, Mallardo D, Ascierto PA, Massi D, Merelli B, Mandala M, Wilmott JS, Menzies AM, Leduc C, Stagg J, Routy B, Long GV, Scolyer RA, Bald T, Waddell N, Dougall WC, Teng MWL, Smyth MJ.
      PURPOSE: Resistance to anti-PD1 based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. This observational study characterizes tumor CD155 ligand expression by metastatic melanoma tumors and correlates results with differences in immune cell features and response to ICB.EXPERIMENTAL DESIGN: Pre-treatment tumor specimens, from 155 metastatic melanoma patients treated with ICB and from 50 patients treated with BRAF/MEK-directed-targeted therapy, were assessed for CD155 expression by immunohistochemistry. Intratumor T cell features were analysed using multiplex-immunohistofluorescence for CD8, PD1 and SOX10. Correlations were made between CD155 tumor level and bulk tumor RNA-seq results, as well as clinical RECIST response and progression-free survival.
    RESULTS: High pretreatment CD155 tumor levels correlated with high parenchymal PD1+CD8+/CD8+ T cell ratios (PD1tR) and poor response to anti-PD1 therapy. In PD-L1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/CTLA4 therapy.
    CONCLUSIONS: Our findings are the first to suggest that tumor CD155 supports an increase in the fraction of PD1+CD8+ T cells in anti-PD1 refractory melanoma tumors and, further, that targeting the CD155 pathway might improve response to anti-PD1 therapy for metastatic melanoma patients.
  14. Nat Commun. 2020 Apr 27. 11(1): 2042
    Barbier V, Erbani J, Fiveash C, Davies JM, Tay J, Tallack MR, Lowe J, Magnani JL, Pattabiraman DR, Perkins AC, Lisle J, Rasko JEJ, Levesque JP, Winkler IG.
      The endothelial cell adhesion molecule E-selectin is a key component of the bone marrow hematopoietic stem cell (HSC) vascular niche regulating balance between HSC self-renewal and commitment. We now report in contrast, E-selectin directly triggers signaling pathways that promote malignant cell survival and regeneration. Using acute myeloid leukemia (AML) mouse models, we show AML blasts release inflammatory mediators that upregulate endothelial niche E-selectin expression. Alterations in cell-surface glycosylation associated with oncogenesis enhances AML blast binding to E-selectin and enable promotion of pro-survival signaling through AKT/NF-κB pathways. In vivo AML blasts with highest E-selectin binding potential are 12-fold more likely to survive chemotherapy and main contributors to disease relapse. Absence (in Sele-/- hosts) or therapeutic blockade of E-selectin using small molecule mimetic GMI-1271/Uproleselan effectively inhibits this niche-mediated pro-survival signaling, dampens AML blast regeneration, and strongly synergizes with chemotherapy, doubling the duration of mouse survival over chemotherapy alone, whilst protecting endogenous HSC.
  15. Cancer Res. 2020 Apr 27. pii: canres.0435.2020. [Epub ahead of print]
    Zhou H, Blevins MA, Hsu JY, Kong D, Galbraith MD, Goodspeed A, Culp-Hill R, Oliphant MU, Ramirez D, Zhang L, Pineiro JT, Mathews Griner L, King R, Barnaeva E, Hu X, Southall NT, Ferrer M, Gustafson DL, Regan DP, D'Alessandro A, Costello JC, Patnaik S, Marugan J, Zhao R, Ford HL.
      Metastasis is the major cause of mortality for cancer patients, and dysregulation of developmental signaling pathways can significantly contribute to the metastatic process. The SIX1/EYA transcriptional complex plays a critical role in the development of multiple organs and is typically downregulated after development is complete. In breast cancer, aberrant expression of SIX1 has been demonstrated to stimulate metastasis through activation of TGF-β signaling and subsequent induction of epithelial-mesenchymal transition (EMT). In addition, SIX1 can induce metastasis via non-cell autonomous means, including activation of GLI-signaling in neighboring tumor cells and activation of VEGF-C-induced lymphangiogenesis. Thus, targeting SIX1 would be expected to inhibit metastasis while conferring limited side effects. However, transcription factors are notoriously difficult to target, and thus novel approaches to inhibit their action must be taken. Here we identified a novel small molecule compound, NCGC00378430 (abbreviated as 8430), that reduces the SIX1/EYA2 interaction. 8430 partially reversed transcriptional and metabolic profiles mediated by SIX1 overexpression and reversed SIX1-induced TGF-β signaling and EMT. 8430 was well tolerated when delivered to mice and significantly suppressed breast cancer-associated metastasis in vivo without significantly altering primary tumor growth. Thus, we have demonstrated for the first time that pharmacological inhibition of the SIX1/EYA2 complex and associated phenotypes is sufficient to suppress breast cancer metastasis.
  16. PLoS One. 2020 ;15(4): e0227592
    Gisler S, Maia ARR, Chandrasekaran G, Kopparam J, van Lohuizen M.
      BMI1 is a core protein of the polycomb repressive complex 1 (PRC1) that is overexpressed in several cancer types, making it a promising target for cancer therapies. However, the underlying mechanisms and interactions associated with BMI1-induced tumorigenesis are often context-dependent and complex. Here, we performed a drug resistance screen on mutagenized human haploid HAP1 cells treated with BMI1 inhibitor PTC-318 to find new genetic and mechanistic features associated with BMI1-dependent cancer cell proliferation. Our screen identified NUMA1-mutations as the most significant inducer of PTC-318 cell death resistance. Independent validations on NUMA1-proficient HAP1 and non-small cell lung cancer cell lines exposed to BMI1 inhibition by PTC-318 or BMI1 knockdown resulted in cell death following mitotic arrest. Interestingly, cells with CRISPR-Cas9 derived NUMA1 knockout also showed a mitotic arrest phenotype following BMI1 inhibition but, contrary to cells with wildtype NUMA1, these cells were resistant to BMI1-dependent cell death. The current study brings new insights to BMI1 inhibition-induced mitotic lethality in cancer cells and presents a previously unknown role of NUMA1 in this process.
  17. Nat Rev Cancer. 2020 Apr 27.
    Clarke MA, Fisher J.
      Making decisions on how best to treat cancer patients requires the integration of different data sets, including genomic profiles, tumour histopathology, radiological images, proteomic analysis and more. This wealth of biological information calls for novel strategies to integrate such information in a meaningful, predictive and experimentally verifiable way. In this Perspective we explain how executable computational models meet this need. Such models provide a means for comprehensive data integration, can be experimentally validated, are readily interpreted both biologically and clinically, and have the potential to predict effective therapies for different cancer types and subtypes. We explain what executable models are and how they can be used to represent the dynamic biological behaviours inherent in cancer, and demonstrate how such models, when coupled with automated reasoning, facilitate our understanding of the mechanisms by which oncogenic signalling pathways regulate tumours. We explore how executable models have impacted the field of cancer research and argue that extending them to represent a tumour in a specific patient (that is, an avatar) will pave the way for improved personalized treatments and precision medicine. Finally, we highlight some of the ongoing challenges in developing executable models and stress that effective cross-disciplinary efforts are key to forward progress in the field.
  18. Oncogene. 2020 Apr 29.
    Sundqvist A, Vasilaki E, Voytyuk O, Bai Y, Morikawa M, Moustakas A, Miyazono K, Heldin CH, Ten Dijke P, van Dam H.
      Activator protein (AP)-1 transcription factors are essential elements of the pro-oncogenic functions of transforming growth factor-β (TGFβ)-SMAD signaling. Here we show that in multiple HER2+ and/or EGFR+ breast cancer cell lines these AP-1-dependent tumorigenic properties of TGFβ critically rely on epidermal growth factor receptor (EGFR) activation and expression of the ΔN isoform of transcriptional regulator p63. EGFR and ΔNp63 enabled and/or potentiated the activation of a subset of TGFβ-inducible invasion/migration-associated genes, e.g., ITGA2, LAMB3, and WNT7A/B, and enhanced the recruitment of SMAD2/3 to these genes. The TGFβ- and EGF-induced binding of SMAD2/3 and JUNB to these gene loci was accompanied by p63-SMAD2/3 and p63-JUNB complex formation. p63 and EGFR were also found to strongly potentiate TGFβ induction of AP-1 proteins and, in particular, FOS family members. Ectopic overexpression of FOS could counteract the decrease in TGFβ-induced gene activation after p63 depletion. p63 is also involved in the transcriptional regulation of heparin binding (HB)-EGF and EGFR genes, thereby establishing a self-amplification loop that facilitates and empowers the pro-invasive functions of TGFβ. These cooperative pro-oncogenic functions of EGFR, AP-1, p63, and TGFβ were efficiently inhibited by clinically relevant chemical inhibitors. Our findings may, therefore, be of importance for therapy of patients with breast cancers with an activated EGFR-RAS-RAF pathway.
  19. Nat Commun. 2020 Apr 29. 11(1): 2092
    Sung BH, von Lersner A, Guerrero J, Krystofiak ES, Inman D, Pelletier R, Zijlstra A, Ponik SM, Weaver AM.
      Small extracellular vesicles called exosomes affect multiple autocrine and paracrine cellular phenotypes. Understanding the function of exosomes requires a variety of tools, including live imaging. Our previous live-cell reporter, pHluorin-CD63, allows dynamic subcellular monitoring of exosome secretion in migrating and spreading cells. However, dim fluorescence and the inability to make stably-expressing cell lines limit its use. We incorporated a stabilizing mutation in the pHluorin moiety, M153R, which now exhibits higher, stable expression in cells and superior monitoring of exosome secretion. Using this improved construct, we visualize secreted exosomes in 3D culture and in vivo and identify a role for exosomes in promoting leader-follower behavior in 2D and 3D migration. Incorporating an additional non-pH-sensitive red fluorescent tag allows visualization of the exosome lifecycle, including multivesicular body (MVB) trafficking, MVB fusion, exosome uptake and endosome acidification. This reporter will be a useful tool for understanding both autocrine and paracrine roles of exosomes.
  20. Nat Commun. 2020 May 01. 11(1): 2142
    Cook DP, Vanderhyden BC.
      Epithelial-mesenchymal plasticity contributes to many biological processes, including tumor progression. Various epithelial-mesenchymal transition (EMT) responses have been reported and no common, EMT-defining gene expression program has been identified. Here, we have performed a comparative analysis of the EMT response, leveraging highly multiplexed single-cell RNA sequencing (scRNA-seq) to measure expression profiles of 103,999 cells from 960 samples, comprising 12 EMT time course experiments and independent kinase inhibitor screens for each. We demonstrate that the EMT is vastly context specific, with an average of only 22% of response genes being shared between any two conditions, and over half of all response genes were restricted to 1-2 time course experiments. Further, kinase inhibitor screens revealed signaling dependencies and modularity of these responses. These findings suggest that the EMT is not simply a single, linear process, but is highly variable and modular, warranting quantitative frameworks for understanding nuances of the transition.