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bioRxiv2018

KPNA2 promotes cellular proliferation and inhibits apoptosis in the Saos-2 osteosarcoma cell line

Karyopherin 2 plays a critical role in tumorigenesis and tumor progression. However, nothing is currently known about the effects of KPNA2 on osteosarcomas. This study aimed to investigate differential KPNA2 protein and mRNA expression in human osteosarcoma tumor cells and normal bone tissue. We also sought to determine whether KPNA2 can influence the proliferation and apoptosis of the Saos-2 osteosarcoma cell line. Immunohistochemistry (IHC) was used to investigate KPNA2 protein expression. Real-time quantitative PCR (qPCR) was used to detect levels of KPNA2 mRNA expression, and lentivirus-mediated short-hairpin RNAs (shRNAs) were used to knock down KPNA2 expression in Saos-2 cells. The MTT assay and multiparametric high-content screening (HCS) were used to measure cell proliferation and growth, respectively. Flow cytometry was conducted to detect cell cycle distribution and apoptosis. The results revealed significantly higher KPNA2 expression levels in osteosarcoma tissues than in normal bone tissues; furthermore, KPNA2 mRNA was also highly expressed in three osteosarcoma cell lines. After transducing Saos-2 cells with KPNA2-shRNA lentivirus, the proliferative rate was notably decreased compared to that of the negative control (NC) lentivirus group (P<0.05). Flow cytometry results indicated that KPNA2 may arrest cell cycle progression and regulate the growth of these cells. The results for apoptosis indicated an apoptotic rate of 13.38{+/-}0.48% in KPNA2-shRNA cells, which was significantly higher than the rate for cells in the control group (5.13 {+/-}0.33%). Therefore, this study showed that KPNA2 is highly expressed in osteosarcoma tissues and that reduced KPNA2mRNA levels inhibited proliferation and promoted apoptosis in an osteosarcoma cell line.

cancer biology↗

bioRxiv2018

Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

Nimbolide, a terpenoid natural product derived from the Neem tree, impairs cancer pathogenicity across many types of human cancers; however, the direct targets and mechanisms by which nimbolide exerts its effects are poorly understood. Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. Nimbolide impairs breast cancer cell proliferation by disrupting RNF114 substrate recognition, leading to inhibition of ubiquitination and degradation of the tumor-suppressor p21, resulting in its rapid stabilization. We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Our study highlights the utility of ABPP platforms in uncovering unique druggable modalities accessed by natural products for cancer therapy and drug discovery applications.

cancer biology↗

bioRxiv2018

Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses - implications for the management of irAEs

Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high doses of corticosteroids or, in refractory cases, with tumor necrosis factor (TNF) antagonists, are the mainstay of treatment for irAEs. It is currently unknown what is the impact of corticosteroids and anti-TNF on the activity of antitumor T cells. In this study, the influences of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10 to 125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing ability of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high dose impaired the activation (respectively -46% and -62%) and tumor-killing ability (respectively -48% and -53%) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (-20%) and tumor killing (-10%). A brief resting following exposure to dexamethasone was sufficient to rescue the in vitro activity of TILs. In conclusion, clinically-relevant doses of infliximab only influenced to a lesser extent the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. These data support steroid-sparing strategies and early initiation of anti-TNF for the treatment of irAEs in immuno-oncology.

cancer biology↗

bioRxiv2018

The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, in clinically relevant models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor and antimetastatic activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for effective treatment of patients with primary/metastatic TNBC.

cancer biology↗

bioRxiv2018

MTHFD1 is a genetic interactor of BRD4 and links folate metabolism to transcriptional regulation

The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression.

cancer biology↗

bioRxiv2018

Dietary sulfate-driven and gut dysbiosis-triggered breast cancer-related gene upregulation

By gut microbiota metagenomic analysis, we found that the abundance of sulfatase-secreting bacteria (SSB) in the gut of mice fed chondroitin sulfate (CS) increases with significant individual difference. The fluctuation of lipopolysaccharide (LPS) and pro-inflammatory indicators with significant individual and tissue variations was also observed. After mice were fed mixed with CS or injected separately with LPS, the breast cancer-related transcriptional factor genes, BCL11A and RUNX1, were upregulated, whereas the tumor suppressor gene, TP53BP1, were downregulated. Further, the mammary myopithelium marker CK5/6, the mammary hyperplasia marker Ki-67, and other tumor markers were also upregulated. While the exogenous estradiol does not induce the expression of BCL11A, RUNX1, and TP53BP1, the estrogen receptor (ER) agonist Fulvestrant that mimics estradiol action not only elevates estradiol concentrations, but also upregulates tumor marker expression levels, revealing that ER inflammatory inactivation and hyperestrogenemia induction might be the etiological cues of breast cancer origin. This study has preliminarily established a possible correlation of gut microbiota dysbiosis and chronic low-grade inflammation with the early-phase onset of breast cancer in mice. The statistical insignificance of test data was attributed to the individual difference of gut microbiota compositions, which determining the individual and tissue variations of systemic inflammation.

cancer biology↗

bioRxiv2018

Calotropis gigantea extract induces apoptosis through extrinsic/intrinsic pathways and upregulation of reactive oxygen species in non-small-cell lung cancer cells

BackgroundCalotropis gigantea (CG) plant grows in Asia and tropical Africa. However, the precise mechanisms of its anticancer effects have not yet been examined in human non-small cell lung cancer (NSCLC) cells, A549 and NCI-H1299 cells.\n\nPurposeThis study was focused on the anti-cancer effects of CG extract on non-small cell lung cancer (NSCLC) cells.\n\nMethodsThe cytotoxic effects of CG extract on NSCLC, A549 and NCI-H1299 cells, were detected by MTS assay, microscope and DAPI staining. Apoptosis was determined by annexin V-FITC/PI staining, cell cycle analysis, western blotting, quantitative polymerase chain reaction, and JC-1 staining.\n\nResultsFirst, CG showed significant dose-dependent cytotoxicity in NSCLC, A549, and NCI-H1299 cells. In addition to induction of caspase-8 processing, CG induced apoptosis by upregulating mRNA expression levels of extrinsic pathway molecules such as Fas, Fas ligand (FasL), Fas-associated protein with death domain (FADD) and death receptor 5 (DR5). Also, mitochondrial membrane potential (MMP) was collapsed, and intrinsic pathway molecules such as poly (ADP-ribose) polymerase (PARP), caspase-3, and caspase-9 were processed by CG. Moreover, reactive oxygen species (ROS) were generated in a CG dose-dependent manner, and inhibition of ROS by NAC, ROS scavenger, recovered A549 and NCI-H1299 cell viability.\n\nConclusionThese results indicate that CG causes apoptosis by activating the extrinsic and intrinsic pathways and generating ROS in NSCLC cells. These results suggest that CG can be used as a lung cancer therapeutic agent.

cancer biology↗

bioRxiv2018

The mouse HP1 proteins are not required for cell viability but are essential for preventing liver tumorigenesis

Chromatin organization plays essential roles in cell identity and functions. Here, we demonstrated by hepatocyte-specific inactivation of the genes encoding the three Heterochromatin Protein 1 (HP1, {beta} and {gamma}) in mice (HP1-TKO) that these proteins are dispensable for hepatocyte activity and survival. Conversely, the chronic absence of these proteins led to a drastic increased incidence of liver tumor development. Molecular characterization of HP1-TKO hepatocytes revealed that HP1 proteins are required for maintenance of histone marks associated with heterochromatin, and for the appropriate expression of large number of genes involved in liver-specific functions as well as in genes encoding for transcriptional repressors of the KRAB-ZFP family. Moreover, several specific endogenous retrovirus families were upregulated in HP1-TKO hepatocytes, leading to the deregulated expression of genes in their vicinity. Our findings indicate that HP1 proteins act as guardians of liver homeostasis to prevent tumor development through the modulation of multiple chromatin-associated events.

cancer biology↗

bioRxiv2018

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

PTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NF{kappa};B activating protein (NKAP) and limits NF{kappa}B activation to suppress expression of PDHK1, a NF{kappa}B target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.\n\nSIGNIFICANCEThe tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. PTEN antagonizes PI3K/AKT signaling via its lipid phosphatase activity. The modest success of PI3K/AKT inhibition in PTEN-deficient cancer patients provides rationale for identifying other vulnerabilities in PTEN-deficient cancers to improve clinical outcomes. We show that PTEN-deficient cells are uniquely sensitive to PDHK1 inhibition. PTEN and PDHK1 co-suppression reduced colony formation and induced cell death in vitro and tumor regression in vivo. PDHK1 levels were high in PTEN-deficient patient tumors and associated with inferior patient survival, establishing clinical relevance. Our study identifies a PTEN-regulated signaling pathway linking the PTEN protein phosphatase to the metabolic regulator PDHK1 and provides a mechanistic basis for PDHK1 targeting in PTEN-deficient cancers.

cancer biology↗

bioRxiv2018

Elevated de novo fatty acid biosynthesis gene expression promotes melanoma cell survival and drug resistance

Elevated de novo fatty acid biosynthesis (DNFA) is a hallmark adaptation in many cancers that supports survival, proliferation, and metastasis. Here we elucidate previously unexplored aspects of transcription regulation and clinical relevance of DNFA in melanomas. We show that elevated expression of DNFA genes is characteristic of many tumor types and correlates with poor prognosis. Elevated DNFA gene expression depends on transcription factor SREBP1 in multiple melanoma cell lines. SREBP1 predominantly binds to the transcription start sites of DNFA genes, directly regulating transcription via RNA polymerase II recruitment and productive elongation. We find that SREBP1-regulated DNFA represents an intrinsic survival mechanism in melanoma cells, regardless of proliferative state and oncogenic mutation status. Indeed, malignant melanoma cells exhibit elevated DNFA gene expression after pro-survival signaling pathways are blocked (e.g. by the BRAF inhibitor vemurafenib). Altogether, these results implicate SREBP1 and DNFA enzymes as enticing therapeutic targets in melanomas.

cancer biology↗

bioRxiv2018

Unraveling Tumor-Immune Heterogeneity in Advanced Ovarian Cancer Uncovers Immunogenic Effect of Chemotherapy

In metastatic cancer, the role of heterogeneity at the tumor-immune microenvironment, its molecular underpinnings and clinical relevance remain largely unexplored. To understand tumor-immune dynamics at baseline and upon chemotherapy treatment, we performed unbiased pathway and cell type-specific immunogenomics analysis of treatment-naive (38 samples from 8 patients) and paired chemotherapy treated (80 paired samples from 40 patients) high-grade serous ovarian cancer (HGSOC) samples. Whole transcriptome analysis and image-based quantification of T cells from treatment-naive tumors revealed ubiquitous variability in immune signaling and distinct immune microenvironments co-existing within the same individuals and within tumor deposits at diagnosis. To systematically explore cell type composition of the tumor microenvironment using bulk mRNA, we derived consensus immune and stromal cell gene signatures by intersecting state-of-the-art deconvolution methods, providing improved accuracy and sensitivity when compared to HGSOC immunostaining and leukocyte methylation data sets. Cell-type deconvolution and pathway analyses revealed that Myc and Wnt signaling associate with immune cell exclusion in untreated HGSOC. To evaluate the effect of chemotherapy on the intrinsic tumor-immune heterogeneity, we compared site-matched and site-unmatched tumors before and after neoadjuvant chemotherapy. Transcriptomic and T-cell receptor sequencing analyses showed that site-matched samples had increased cytotoxic immune activation and oligoclonal expansion of T cells after chemotherapy, which was not seen in site-unmatched samples where heterogeneity could not be accounted for. These results demonstrate that the tumor-immune interface in advanced HGSOC is intrinsically heterogeneous, and thus requires site-specific analysis to reliably unmask the impact of therapy on the tumor-immune microenvironment.

cancer biology↗

bioRxiv2018

Galectin-1 promotes the invasion of bladder cancer urothelia through their matrix milieu

The progression of carcinoma of the urinary bladder involves migration of cancer epithelia through their surrounding tissue matrix microenvironment. This was experimentally confirmed when a gender- and grade-diverse set of bladder cancer cell lines were cultured in pathomimetic three-dimensional laminin-rich environments. The high-grade cells, particularly female, formed multicellular invasive morphologies in 3D. In comparison, low- and intermediate-grade counterparts showed growth-restricted phenotypes. A proteomic approach combining mass spectrometry and bioinformatics analysis identified the estrogen-driven lactose-binding lectin Galectin-1 (GAL-1) as a putative candidate that could drive this invasion. Expression of LGALS1, the gene encoding GAL-1 showed an association with tumor grade progression in bladder cell lines. Immunohisto- and cyto-chemical experiments suggested greater extracellular levels of GAL-1 in 3D cultures of high-grade bladder cells and cancer tissues. High levels of GAL-1 associated with increased proliferation- and adhesion- of bladder cancer cells when grown on laminin-rich matrices. Pharmacological inhibition and Gal-1 knockdown in high-grade female cells decreased their adhesion to, and viability on, laminin-rich substrata. Higher GAL-1 also correlated with reduced E-cadherin and increased N-cadherin levels in consonance with a mesenchymal-like phenotype that we observed in 3D culture. The inhibition of GAL-1 reversed the stellate invasive phenotype to a more growth-restricted one in high-grade cells embedded within both basement-membrane-like and stromal collagenous matrix scaffolds. Finally, inhibition of GAL-1 specifically altered cell surface sialic acids, suggesting the mechanism by which the levels of GAL-1 may underlie the aggression and poor prognosis of invasive bladder cancer, especially in women.

cancer biology↗

bioRxiv2018

Tumor pre-conditioning of draining lymph node stroma by lactic acid

Communication between tumors and the stroma of tumor draining lymph nodes (TDLNs) exists before metastasis arises, altering structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRCs), the dominant stromal population of the LN, revealed reprogramming of these cells in immune related pathways, but also in fibroblast activation and mitochondrial function. However, tumor derived factors driving the changes in FRCs remained to be identified. Taking an unbiased approach, we show that lactate, a metabolite released by cancer cells, elicits upregulation of Pdpn and Thy1 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we show that tumor-derived lactate alters mitochondrial function of FRCs of TDLNs. Thus, our results demonstrate a novel mechanism by which a tumor-derived metabolite modulates the function of fibroblasts in TDLNs.

cancer biology↗

bioRxiv2018

High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma

We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating the highest-resolution 3D genome maps to-date for this cancer. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including individual physical interactions between regulatory regions and their target genes. Residing in structurally conserved regions in GSCs was CD276, a gene known to play a role in immuno-modulation. We show that, unexpectedly, CD276 is part of a stemness network in GSCs and can be targeted with an antibody-drug conjugate to curb self-renewal, a key stemness property. Our results demonstrate that integrated structural genomics datasets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.\n\nSIGNIFICANCEIn adult GBM, GSCs act as therapy-resistant reservoirs to nucleate tumor recurrence. New therapeutic approaches that target these cell populations hold the potential of significantly improving patient care and overall prognosis for this always-lethal cancer. Our work describes new links between 3D genome architecture and stemness properties in GSCs. In particular, through integration of multiple genomics and structural genomics datasets, we found an unexpected connection between immune-related genes and self-renewal programs in GBM. Among these, we show that targeting CD276 with knockdown strategies or specific antibody-drug conjugates achieve suppression of self-renewal. Strategies to target CD276+ cells are currently in clinical trials for solid tumors. Our results indicate that CD276-targeting agents could be deployed in GBM to specifically target GSC populations.\n\nHIGHLIGHTSO_LIWe generated high (sub-5 kb) resolution Hi-C maps for stem-like cells from GBM patients.\nC_LIO_LIIntegration of Hi-C and genomics datasets dissects mechanisms of gene regulation.\nC_LIO_LI3D genomes poise immune-related genes, including CD276, for expression.\nC_LIO_LITargeting CD276 curbs self-renewal properties of GBM cells.\nC_LI

cancer biology↗

bioRxiv2018

Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

The NRL-PRL murine model, defined by mammary-selective transgenic rat prolactin ligand rPrl expression, establishes spontaneous ER+ mammary tumors, mimicking the association between elevated prolactin (PRL) and risk for development of ER+ breast cancer in postmenopausal women. Whole genome and exome sequencing in a discovery cohort (n=5) of end stage tumors revealed canonical activating mutations and copy number amplifications of Kras. The frequent mutations in this pathway were validated in an extension cohort, identifying activating Ras alterations in 79% (23/29) of tumors. Transcriptome analyses over the course of oncogenesis revealed marked alterations associated with Ras activity in established tumors, compared to preneoplastic tissues, in cell-intrinsic processes associated with mitosis, cell adhesion and invasion, as well as in the tumor microenvironment, including immune activity. These genomic analyses suggest that PRL induces a selective bottleneck for spontaneous Ras-driven tumors which may model a subset of aggressive clinical ER+ breast cancers.

cancer biology↗

bioRxiv2018

A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers

BackgroundDespite much progress in cancer research, its incidence and mortality continue to rise. A robust biomarker that would predict tumor behavior is highly desirable and could improve patient treatment and prognosis.\n\nMethodsIn a retrospective bioinformatics analysis involving patients with liver cancer (n=839), we developed a prognostic signature consisting of 45 genes associated with tumor-infiltrating lymphocytes and cellular responses to hypoxia. From this gene set, we were able to identify a second prognostic signature comprised of 8 genes. Its performance was further validated in five other cancers: head and neck (n=520), renal papillary cell (n=290), lung (n=515), pancreas (n=178) and endometrial (n=370).\n\nFindingsThe 45-gene signature predicted overall survival in three liver cancer cohorts: hazard ratio (HR)=1.82, P=0.006; HR=1.84, P=0.008 and HR=2.67, P=0.003. Additionally, the reduced 8-gene signature was sufficient and effective in predicting survival in liver and five other cancers: liver (HR=2.36, P=0.0003; HR=2.43, P=0.0002 and HR=3.45, P=0.0007), head and neck (HR=1.64, P=0.004), renal papillary cell (HR=2.31, P=0.04), lung (HR=1.45, P=0.03), pancreas (HR=1.96, P=0.006) and endometrial (HR=2.33, P=0.003). Receiver operating characteristic analyses demonstrated both signatures superior performance over current tumor staging parameters. Multivariate Cox regression analyses revealed that both 45-gene and 8-gene signatures were independent of other clinicopathological features in these cancers. Combining the gene signatures with somatic mutation profiles increased their prognostic ability.\n\nConclusionsThis study, to our knowledge, is the first to identify a gene signature uniting both tumor hypoxia and lymphocytic infiltration as a prognostic determinant in six cancer types (n=2,712). The 8-gene signature can be used for patient risk stratification by incorporating hypoxia information to aid clinical decision making.

cancer biology↗

bioRxiv2018

Prognostic signatures of oxygen-sensing genes predict patient survival in ten cancers including those of the liver, pancreas and stomach

ObjectivesTumor hypoxia is associated with metastasis and resistance to chemotherapy and radiotherapy. Genes involved in oxygen-sensing are clinically relevant and have significant implications on prognosis.\n\nMethodsWe identified of two signatures, signature 1 (good prognosis) and signature 2 (adverse prognosis), each consisting of 5 genes using three pancreatic cancer cohorts (n=681). We validated the signatures performance in predicting survival in ten cancers using Cox regression and receiver operating characteristic (ROC) analyses.\n\nResultsSignature 1 and signature 2 were associated with good and poor overall survival respectively. Prognosis of signature 1 in 8 cohorts representing 6 cancers (n=2,627): bladder (hazard ratio [HR]=0.68, P=0.039), papillary renal cell (HR=0.35, P=0.013), liver (HR=0.64, P=0.033 and HR=0.49, P=0.025), lung (HR=0.66, P=0.014) and pancreatic (HR=0.42, P<0.001 and HR=0.64, P=0.04) and endometrial (HR=0.40, P<0.001). Prognosis of signature 2 in 12 cohorts representing 9 cancers (n=4,134): bladder (HR=1.46, P=0.039), cervical (HR=1.97, P=0.035), head and neck (HR=1.39, P=0.038), renal clear cell (HR=1.47, P=0.012), papillary renal cell (HR=3.89, P=0.0015), liver (HR=5.10, P<0.0001 and HR=2.26, P<0.001), lung (HR=1.54, P=0.011), pancreatic (HR=2.09, P=0.002, HR=1.46, P=0.018, and HR=1.99, P<0.0001) and stomach (HR=1.78, P=0.004). Multivariate Cox regression confirmed independent clinical relevance of signatures in these cancers. ROC analyses confirmed superior performance of signatures to current tumor staging benchmarks. KDM8 is a potential tumor suppressor downregulated in liver and pancreatic cancers and is an independent prognostic factor. KDM8 expression negatively correlated with cell cycle regulators. Low KDM8 in tumors was associated with loss of cell adhesion phenotype through HNF4A signaling.\n\nConclusionsPan-cancer signatures of oxygen-sensing genes used for risk assessment in 10 cancers (n=6,761) could guide individualized treatment plans.

cancer biology↗

bioRxiv2018

Intravascular arrest of circulating tumor cells is a two-step process exploiting their adhesion repertoire.

Cancer metastasis is a process whereby a primary tumor spreads to distant organs. We have previously demonstrated that blood flow controls the intravascular arrest of circulating tumor cells (CTCs), through stable adhesion to endothelial cells. We now aim at defining the contribution of cell adhesive potential and at identifying adhesion receptors at play. Early arrest is mediated by the formation of weak adhesion depending on CD44 and integrin v{beta}3. Stabilization of this arrest uses integrin 5{beta}1-dependent adhesions with higher adhesion strength, which allows CTCs to stop in vascular regions with lower shear forces. Moreover, blood flow favors luminal deposition of fibronectin on endothelial cells, an integrin 5{beta}1 ligand. Finally, we show that only receptors involved in stable adhesion are required for subsequent extravasation and metastasis. In conclusion, we identified the molecular partners that are sequentially exploited by CTCs to arrest and extravasate in vascular regions with permissive flow regimes.

cancer biology↗