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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Functional Balance between TCF21-Slug defines phenotypic plasticity and sub-classes in high-grade serous ovarian cancer

Cellular plasticity and transitional phenotypes add to complexities of cancer metastasis initiated by single cell epithelial to mesenchymal transition or cooperative cell migration (CCM). We identified novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma. Live imaging discerned CCM as being achieved either through rapid cell proliferation or sheet migration. Transitional states were enriched over the rigid epithelial or mesenchymal phenotypes under conditions of environmental stresses. The Tcf21-Slug interplay identified in HGSC tumors through effective stratification of subtypes also contributed to class-switching in response to disease progression or therapy. Our study effectively provides a framework for understanding the relevance of cellular plasticity in situ as a function of two transcription factors.

cancer biology↗

bioRxiv2018

Cell-cell contact dictates life or death decisions following CD95 activation in cancer

Cancer cells react to CD95 activation with either apoptotic or tumorigenic responses. Yet, the determinants of these two antithetic reactions are fundamentally not understood. Here, we show that pre-confined CD95L molecules activate apoptosis of cancer cells in-vitro. For particular CD95L pre-confinement, apoptosis activation is most efficient. Surprisingly, in tumor models, the same pre-confinement yields enhanced proliferation of cancer cells. This shift is rooted in cell-cell interactions, as proliferation was also observed in tumorspheres in-vitro. Indeed, proliferation required death-domain tyrosine phosphorylation of CD95 that was facilitated by cell-cell contacts, whereas decreasing the levels of global tyrosine kinase activity favored apoptosis. Altogether, the response to CD95 activation is cell context-dependent and tunable by CD95L pre-confinement, thereby opening therapeutic opportunities in cancer.\n\nOne Sentence SummaryCell-cell contact tunes tyrosine-kinase activity thereby dictating life or death upon CD95 activation by pre-confined CD95L.

cancer biology↗

bioRxiv2018

Multi-omic profiling of TKI resistant K562 cells suggests metabolic reprogramming to promote cell survival

Resistance to chemotherapy can occur through a wide variety of mechanisms. Resistance to tyrosine kinase inhibitors (TKIs) often arises from kinase mutations-however, \"off-target\" resistance occurs but is poorly understood. Previously, we established cell line resistance models for three TKIs used in chronic myeloid leukemia treatment, and found that resistance was not attributed entirely to failure of kinase inhibition. Here, we performed global, integrated proteomic and transcriptomic profiling of these cell lines to describe mechanisms of resistance at the protein and gene expression level. We used whole transcriptome sequencing and SWATH-based data-independent acquisition mass spectrometry (DIA-MS), which does not require isotopic labels and provides quantitative measurements of proteins in a comprehensive, unbiased fashion. The proteomic and transcriptional data were correlated to generate an integrated understanding of the gene expression and protein alterations associated with TKI resistance. We defined mechanisms of resistance and two novel markers, CA1 and alpha-synuclein, that were common to all TKIs tested. Resistance to all of the TKIs was associated with oxidative stress responses, hypoxia signatures, and apparent metabolic reprogramming of the cells. Metabolite profiling and glucose-dependence experiments showed that resistant cells had routed their metabolism through glycolysis (particularly through the pentose phosphate pathway) and exhibited disruptions in mitochondrial metabolism. These experiments are the first to report a global, integrated proteomic, transcriptomic and metabolic analysis of TKI resistance. These data suggest that although the mechanisms are complex, targeting metabolic pathways along with TKI treatment may overcome pan-TKI resistance.\n\nKey PointsO_LIAlterations to metabolism are a common feature of target-mutation-independent resistance in CML cells across multiple clinically relevant TKIs.\nC_LIO_LICarbonic anhydrase 1 (CA1) and a-synuclein (SNCA) are novel markers of metabolic reprogramming in TKI resistant CML cells.\nC_LI

cancer biology↗

bioRxiv2018

B7-H1(PD-L1) confers chemoresistance through ERK and p38 MAPK pathway in tumor cells

Development of resistance to chemotherapy and immunotherapy is a major obstacle in extending the survival of patients with cancer. Although several molecular mechanisms have been identified that can contribute to chemoresistance, the role of immune checkpoint molecules in tumor chemoresistance remains underestimated. It has been recently observed that overexpression of B7-H1(PD-L1) confers chemoresistance in human cancers, however the underlying mechanisms are unclear. Here we show that the development of chemoresistance depends on the increased activation of ERK pathway in tumor cells overexpressing B7-H1. Conversely, B7-H1 deficiency renders tumor cells susceptible to chemotherapy in a cell-context dependent manner through activation of the p38 MAPK pathway. B7-H1 in tumor cells associates with the catalytic subunit of a DNA-dependent serine / threonine protein kinase (DNA-PKcs). DNA-PKcs is required for the activation of ERK or p38 MAPK in tumors expressing B7-H1, but not in B7-H1 negative or B7-H1 deficient tumors. Ligation of B7-H1 by anti-B7-H1 monoclonal antibody (H1A) increased the sensitivity of human triple negative breast tumor cells to cisplatin therapy in vivo. Our results suggest that B7-H1(PD-L1) expression in cancer cells modifies their chemosensitivity towards certain drugs and targeting B7-H1 intracellular signaling pathway is a new way to overcome cancer chemoresistance.

cancer biology↗

bioRxiv2018

Intron retention as a novel source of cancer neoantigens

Personalized cancer vaccine strategies directed at tumor neoantigens derived from somatic mutations in the DNA are currently under prospective evaluation1, 2. Alterations in tumor RNA, rather than DNA, may also represent a previously-unexplored source of neoantigens. Here, we show that intron retention, a widespread feature of cancer transcriptomes3, 4, represents a novel source of tumor neoantigens. We developed an in silico approach to identify retained intron neoantigens from RNA sequencing data and applied this methodology to tumor samples from patients with melanoma treated with immune checkpoint blockade5, 6, discovering that the retained intron neoantigen burden in these samples augments the DNA-derived, somatic neoantigen burden. We validated the existence of retained intron derived neoantigens by implementing this technique on cancer cell lines with mass spectrometry-derived immunopeptidome data7, 8, revealing that retained intron neoantigens were complexed with MHC I experimentally. Unexpectedly, we observed a trend toward lack of clinical benefit from immune checkpoint blockade in high retained intron load-tumors, which harbored transcriptional signatures consistent with cell cycle dysregulation and DNA damage repair. Our results demonstrate the contribution of transcriptional dysregulation to the overall burden of tumor neoantigens, provide a foundation for augmenting personalized cancer vaccine development with a new class of tumor neoantigens, and demonstrate how global transcriptional dysregulation may impact selective response to immune checkpoint blockade.\n\nStatement of significanceWe developed and experimentally validated a computational pipeline to identify a novel class of tumor neoantigens derived from RNA-based intron retention, which is prevalent throughout cancer transcriptomes. The discovery of transcriptionally-derived tumor neoantigens expands the tumor immunopeptidome and contributes potential substrates for personalized cancer vaccine development.

cancer biology↗

bioRxiv2018

Interaction of BIR2/3 of XIAP with E2F1/Sp1 Activates MMP2 and Bladder Cancer Invasion by Inhibiting Src Translation

Although X-linked inhibitor of apoptosis protein (XIAP) is associated with cancer cell behaviors, the structure-based function of XIAP in promotion human bladder cancer (BC) invasion is barely explored. Herein, we discovered that ectopic expression of the BIR domains of XIAP rescued the MMP2 activation and invasion in XIAP-deleted BC cells, while Src was further defined as a XIAP downstream negative regulator for MMP2 activation and BC invasion. The inhibition of Src expression by BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation resulting from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, consequently leading to fully activation of E2F1/Sp1. Our findings provide a novel insight into understanding of specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.

cancer biology↗

bioRxiv2018

Global immune fingerprinting in glioblastoma reveals immune-suppression signatures associated with prognosis

Abstract/SummaryGlioblastoma (GBM) remains uniformly lethal, and, despite a large accumulation of immune cells in the microenvironment, there is limited anti-tumor immune response, even with newly developed immune checkpoint therapies. To overcome these challenges and enhance the efficacy of immunotherapies, a comprehensive understanding of the immune system in GBM and changes during disease progression is required. Here, we integrated multi-parameter flow cytometry and mass cytometry time of flight (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing multi-parameter flow cytometry analysis in a cohort of over 250 patients with brain tumors ranging from benign to malignant primary and metastatic, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in blood, but not immunosuppressive T regulatory cells. We validated these findings in GBM patient tissue and found that increased numbers of MDSCs in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from a cohort of newly diagnosed GBM patients revealed that reduction in MDSC frequency over time is accompanied by a concomitant increase in dendritic cells and natural killer cells. This reduced MDSC profile was present in GBM patients with extended survival and was similar to that of low-grade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis, either by directly targeting or by shifting the immune profile to induce differentiation toward the immune profile of LGGs.

cancer biology↗

bioRxiv2018

Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients

In this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of non-invasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in two independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis and overall survival, revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential expression analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in both patient cohorts. Increasing levels of these miRNAs were also observed in serum from xenografted mice bearing human neuroblastoma tumors. Moreover, murine serum miRNA levels were strongly associated with tumor volume, suggesting this miRNA signature may be applied to monitor disease burden.

cancer biology↗

bioRxiv2018

Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and cell death

CDC25 phosphatases have a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors. Using a combination of computational approaches we defined a minimal common pharmacophore in established CDC25 inhibitors and performed a virtual screening of a proprietary library. Taking advantage of the availability of crystal structures for CDC25A and CDC25B and using a molecular docking strategy, we carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits. At the molecular level, the compounds acted through a mixed-type mechanism of inhibition of phosphatase activity, involving reversible oxidation of cysteine residues. In 2D cell cultures, the compounds caused arrest of the cell cycle at the G1/S or at the G2/M transition. Mitotic markers analysis and time-lapse microscopy confirmed that CDK1 activity was impaired and that mitotic arrest was followed by death. Finally, studies on 3D organoids derived from intestinal crypt stem cells of Apc/K-Ras mice revealed that the compounds caused arrest of proliferation.

cancer biology↗

bioRxiv2018

The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic

Esophageal Adenocarcinoma (EAC) is a poor prognosis cancer type with rapidly rising incidence. Our understanding of genetic events which drive EAC development is limited and there are few molecular biomarkers for prognostication or therapeutics. We have accumulated a cohort of 551 genomically characterised EACs (73% WGS and 27% WES) with clinical annotation and matched RNA-seq. Using a variety of driver gene detection methods, we discover 77 EAC driver genes (73% novel) and 21 non-coding driver elements (95% novel), and describe mutation and CNV types with specific functional impact. We identify a mean of 4.4 driver events per case derived from both copy number events and mutations. We compare driver mutation rates to the exome-wide mutational excess calculated using Non-synonymous vs Synonymous mutation rates (dNdS). We observe mutual exclusivity or co-occurrence of events within and between a number of EAC pathways (GATA factors, Core Cell cycle genes, TP53 regulators and the SWI/SNF complex) suggestive of important functional relationships. These driver variants correlate with tumour differentiation, sex and prognosis. Poor prognostic indicators (SMAD4, GATA4) are verified in independent cohorts with significant predictive value. Over 50% of EACs contain sensitising events for CDK4/6 inhibitors which are highly correlated with clinically relevant sensitivity in a panel EAC cell lines and organoids.

cancer biology↗

bioRxiv2018

Identification of the interaction of 2-aminosteroids with G-quadruplex in BCR/ABL gene promoter: An emerging potential target for treatment of human chronic myelogenous leukemia

Our preliminary studies have verified that the small molecules aminosteroid could inhibit the mRNA expression of bcr/abl fusion gene in CML (Chronic Myelogenous Leukemia) cells, which may be effective in treating CML and that may have dramatically different mechanism underlying the effects by tyrosine kinase inhibitors (TKI) binding to the BCR/ABL protein. Therefore, the exact mechanism of how the aminosteroid inhibited the CML growth should be clarified and we pay our attention to the promoter domain of BCR/ABL gene to see if any interaction between aminosteroid and the promoter. First, it should be verified if G-quadruplex could be formed in BCR/ABL promoter region. Secondly, it is highly desirable to verify if aminoteroid could be interacted with the G-quadruplex structure. Here, we reported a novel therapeutic strategy based on the targeting of the G-quadruplex which formed in the promoter regions of BCR/ABL gene by aminosteroid compounds KH and BH, verified by using bioinformatics and computer simulation, UV-Vis absorption spectra, circular dichrosism(CD), fluorescence absorption spectra, fluorescence emission lifetime expenditure experiments and polymerase chain stop assays. It showed that G-quadruplex structures can be folded in BCR/ABL promoter regions and aminosteroid inhibits the mRNA expression of BCR/ABL fusion gene by stabilizing the structure of G-quadruplex, and then inhibiting the DNA replication and transcription. This demonstrates the theory that is the so-called \"chemical gene therapy\" by aminosteroid in the interaction with G-quadruplex is an emerging therapeutic protocol in treatment of chronic myeloid leukemia.

cancer biology↗

bioRxiv2018

Silencing of the CSNK2β gene by siRNA inhibits invasiveness and growth of MDA-MB-231 cells

BackgroundBreast cancer is most common cancer and accounts for one-fourth of all cancer diagnoses worldwide. Treatment of triple-negative breast cancer is major challenge and identification of specific drivers is required for targeted therapies. The aim of our present study is to elucidate the therapeutic potential of CSNK2{beta} silencing in triple negative breast cancer MDA-MB-231 cell.\n\nMethodsCSNK2{beta} gene has been knockdown using siRNA and silencing was estimated by both real time and western blot. Cell Titer-Glo (CTG) and colony formation assay and wound healing assay, cell cycle analysis by flow cytometry was performed to assess the role of CSNK2{beta} in cell proliferation, migration, cell cycle, and oncogenesis. Morphological assessment of nuclear condensation, apoptosis by Hoechst staining and measurement of intracellular ROS production was examined using fluorescence microscopy. Real time PCR and western blot was done to study the expression of genes related to cell proliferation, survival, metastasis, apoptosis, and autophagy.\n\nResultsSilencing of CSNK2{beta} in MDA-MB-231 cells resulted in decreased cell viability, colony formation, and migratory potential. Cell cycle analysis showed that growth inhibitory effect was mediated by arresting the cells in G2/M phase. Furthermore, we demonstrated that silencing of CSNK2{beta} increased the nuclear condensation and intracellular ROS production. CSNK2{beta} regulates the expression of BAX, Bcl-xL, caspase 3, Beclin-1, LC3-I, p-ERK, p38-, c-Myc, MAPK, c-Jun, NF-B, {beta}-catenin, E2F1, PCNA. We have also shown the functional relationship between CSNK2{beta}, PIN1, and PTOV1 by western blotting. We have first time reported that silencing CSNK2{beta} using siRNA can inhibit invasiveness and proliferation of MDA-MB-213 cells.\n\nConclusionOur results suggested that CSNK2{beta} silencing may offer future therapeutic target in triple negative breast cancer.

cancer biology↗

bioRxiv2018

Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells

The oncogenic microRNA-155 (miR-155) is the most frequently upregulated miRNA in Epstein-Barr virus (EBV)-positive B cell malignancies and is upregulated in other non-viral lymphomas. Both the EBV nuclear antigen 2 (EBNA2), and B cell transcription factor, interferon regulatory factor 4 (IRF4) are known to activate transcription of the host cell gene from which miR-155 is processed (miR-155HG, BIC). EBNA2 also activates IRF4 transcription indicating that EBV may upregulate miR-155 through direct and indirect mechanisms. The mechanism of transcriptional regulation of IRF4 and miR-155HG by EBNA2 however has not been defined. We demonstrate that EBNA2 can activate IRF4 and miR-155HG expression through specific upstream enhancers that are dependent on the Notch signaling transcription factor RBPJ, a known binding partner of EBNA2. We demonstrate that in addition to activation of the miR-155HG promoter, IRF4 can also activate miR-155HG via the upstream enhancer also targeted by EBNA2. Gene editing to remove the EBNA2- and IRF4-responsive miR-155HG enhancer located 60 kb upstream of miR-155HG led to reduced miR155HG expression in EBV-infected cells. Our data therefore demonstrate that specific RBPJ-dependent enhancers regulate the IRF4-miR-155 expression network and play a key role in the maintenance of miR-155 expression in EBV-infected B cells. These findings provide important insights that will improve our understanding of miR-155 control in B cell malignancies.\n\nIMPORTANCEMicroRNA-155 (miR-155) is expressed at high level in many human cancers particularly lymphomas. Epstein-Barr virus (EBV) infects human B cells and drives the development of numerous lymphomas. Two EBV-encoded genes (LMP1 and EBNA2) upregulate miR-155 expression and miR-155 expression is required for the growth of EBV-infected B cells. We show that the EBV transcription factor EBNA2 upregulates miR-155 expression by activating an enhancer upstream from the miR-155 host gene (miR-155HG) from which miR-155 is derived. We show that EBNA2 also indirectly activates miR-155 expression through enhancer-mediated activation of IRF4. IRF4 then activates both the miR-155HG promoter and the upstream enhancer, independently of EBNA2. Gene editing to remove the miR-155HG enhancer leads to a reduction in miR-155HG expression. We therefore identify enhancer-mediated activation of miR-155HG as a critical step in promoting B cell growth and a likely driver of lymphoma development.

cancer biology↗

bioRxiv2018

Portraits of genetic intra-tumour heterogeneity and subclonal selection across cancer types

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin and drivers of ITH across cancer types are poorly understood. To address this question, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples, spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions, with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types, and identify cancer type specific subclonal patterns of driver gene mutations, fusions, structural variants and copy-number alterations, as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution, and provide an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

cancer biology↗

bioRxiv2018

Germline genomic landscapes of breast cancer patients significantly predict clinical outcomes

Germline genetic variants such as BRCA1/2 play an important role in tumorigenesis and clinical outcomes of cancer patients. However, only a small fraction (i.e., 5-10%) of inherited variants has been associated with clinical outcomes (e.g., BRCA1/2, APC, TP53, PTEN and so on). The challenge remains in using these inherited germline variants to predict clinical outcomes of cancer patient population. In an attempt to solve this issue, we applied our recently developed algorithm, eTumorMetastasis, which constructs predictive models, on exome sequencing data to ER+ breast (n=755) cancer patients. Gene signatures derived from the genes containing functionally germline genetic variants significantly distinguished recurred and non-recurred patients in two ER+ breast cancer independent cohorts (n=200 and 295, P=1.4x10-3). Furthermore, we found that recurred patients possessed a higher rate of germline genetic variants. In addition, the inherited germline variants from these gene signatures were predominately enriched in T cell function, antigen presentation and cytokine interactions, likely impairing the adaptive and innate immune response thus favoring a pro-tumorigenic environment. Hence, germline genomic information could be used for developing non-invasive genomic tests for predicting patients outcomes (or drug response) in breast cancer, other cancer types and even other complex diseases.

cancer biology↗

bioRxiv2018

S100A8/A9 mediate the reprograming of normal mammary epithelial cells induced by dynamic cell-cell interactions with adjacent breast cancer cells.

To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell-cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell-cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells.

cancer biology↗

bioRxiv2018

Two Isoforms of the Guanine Nucleotide Exchange Factor, Daple/CCDC88C Cooperate as Tumor Suppressors

Previously Aznar et al., showed that Daple enables Wnt/Frizzled receptors to transactivate trimeric G proteins during non-canonical Wnt signaling via a novel G-protein binding and activating (GBA) motif. By doing so, Daple serves as a double-edged sword; earlier during oncogenesis it suppresses neoplastic transformation and tumor growth, but later it triggers epithelial messenchymal transition (EMT). We have identified and characterized two isoforms of the human Daple/CCDC88c gene. While both isoforms cooperatively suppress tumor growth via their GBA motif, only the full-length transcript triggers EMT and invasion. Aspirin suppresses the full-length transcript and protein but upregulates the short isoform. Both isoforms are suppressed during colon cancer progression, and their reduced expression carries additive prognostic significance. These findings provide insights into the opposing roles of Daple during cancer progression and define the G protein regulatory GBA motif as one of the minimal modules essential for Daples role as a tumor suppressor.

cancer biology↗

bioRxiv2018

A mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling

Epithelial-mesenchymal transition (EMT) and cancer stem cell formation (CSCs) are two fundamental and well-studied processes contributing to cancer metastasis and tumor relapse. Cells can undergo a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype or a complete EMT to attain a mesenchymal one. Similarly, cells can reversibly gain or lose stemness. This plasticity in cell states is modulated by signaling pathways such as Notch. However, the interconnections among the cell states enabled by EMT, CSCs and Notch signaling remain elusive. Here, we devise a computational model to investigate the coupling among the core decision-making circuits for EMT, CSCs and the Notch pathway. Our model predicts that hybrid E/M cells are most likely to associate with stemness traits and exhibit enhanced Notch-Jagged signaling - a pathway that is implicated in therapeutic resistance. Further, we show that the position of the stemness window on the EMT axis is varied by altering the coupling strength between EMT and CSC circuits, and/or modulating Notch signaling. Finally, we analyze the gene expression profile of CSCs from several cancer types and observe a heterogeneous distribution along the EMT axis, suggesting that different subsets of CSCs may exist with varying phenotypes along the epithelial-mesenchymal plasticity axis. Our computational model offers insights into the complex EMT-stemness interplay and provides a platform to investigate the effects of therapeutic perturbations such as treatment with metformin, a common anti-diabetic drug that has been associated with decreased cancer incidence and increased lifespan of patients. Our mechanism-based model helps explain how metformin can both inhibit EMT and blunt the aggressive potential of CSCs simultaneously, by driving the cells out of a hybrid E/M stem-like state with enhanced Notch-Jagged signaling.

cancer biology↗