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Results for “Cancer Biology”

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 901 records · Page 50Linked to original sources

bioRxiv2018

Lactate dehydrogenases amplify reactive oxygen species in cancer cells in response to oxidative stimuli

Previous studies have revealed that lactate dehydrogenase A (LDHA) exhibited an indirect antioxidative activity, which played a crucial role in preventing cancer cells from oxidative stress. Here we demonstrated that, apart from antioxidative activities, LDHA and LDHB displayed prooxidative activity in cancer cells. In aqueous phase, LDHA and B both exhibited ROS-generating activity and LDHB was more active than LDHA. In cancer cells, the dominant antioxidative activity of LDH can be switched to dominant prooxidative activity or vice versa, depending on the strength of oxidative stimuli, indicating that LDH were bifunctional. Moreover, we demonstrated that mitochondrial superoxide served as an initiator to trigger LDH-catalyzed amplification of ROS. The oxidative stimuli, such as modulators of electron transfer chain and anticancer agents that kill cancer cells via ROS induction, induced a ROS generation involving 2 phases, induction of mitochondrial superoxide and amplification of ROS by LDH.

cancer biology↗

bioRxiv2018

Cellular acidosis triggers MondoA transcriptional activity by driving mitochondrial ATP production

MondoA and its transcriptional target thioredoxin-interacting protein (TXNIP) constitute a regulatory loop that senses glycolytic flux and controls glucose availability. Cellular stress also triggers MondoA activity and TXNIP expression. To understand how MondoA integrates glucose and stress signals, we studied its activation by acidosis. We found that acidosis drives mitochondrial ATP (mtATP) synthesis. The subsequent export of mtATP from mitochondria via adenine-nucleotide transporter and voltage-dependent anion channel, and the enzymatic activity of mitochondria-bound hexokinase results in the production of glucose-6-phosphate (G6P), a known activator of MondoA transcriptional activity. MondoA localizes to the outer-mitochondrial membrane (OMM), and in response to G6P, shuttles to the nucleus and activates transcription. Our data suggests that MondoA is a required feature of a glucose- and mtATP-dependent, OMM-localized signaling center. We propose MondoA functions as a coincidence detector and its ability to sense glucose and cellular stress is coupled to the concerted production of G6P.

cancer biology↗

bioRxiv2018

The effects and mechanism of peiminine-induced apoptosis in human hepatocellular carcinoma HepG2 cells

Peiminine is a compound that is isolated from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae family), which has demonstrated antitumor activities. Its precise molecular mechanisms underlying antitumor activity remain elusive. In this study, peiminine-induced apoptosis towards human hepatocellular carcinoma and its molecular mechanisms were investigated. MTT assay was employed to assess anticancer effects of peiminine at concentrations of 2, 4, 6, 8, 10, 12, and 14 g/ml after 24, 48, or 72 h. Nuclear staining and flow cytometry were carried out to further assess apoptosis. Mitochondrial membrane potential evaluation and Western blot analysis were performed to investigate the mechanism of peiminine-induced apoptosis. Peiminine reduced the viability of HepG2 cells in a time- and dose-dependent manner and had an IC50 of 4.58 g/mL at 24h. Flow cytometry assessment indicated that peiminine markedly increased the cell number of apoptotic cells and the mitochondrial membrane potential dose-dependently in HepG2 cells. The results of Western blotting showed the expression of Bcl-2, procaspase-3, procaspase-8, procaspase-9, and PARP1 decreased in HepG2 cells treated with peiminine, while the expression of Bax, caspase-3, caspase-8, caspase-9, and cleaved PARP1 increased. The result suggest taht peiminine can induce apoptosis in human hepatocellular carcinoma HepG2 cells through both extrinsic and intrinsic apoptotic pathways.

cancer biology↗

bioRxiv2018

A draft single-cell atlas of human glioblastoma reveals a single axis of phenotype in tumor-propagating cells.

Tumor-propagating glioblastoma (GBM) stem-like cells (GSCs) of the proneural and mesenchymal molecular subtypes have been described. However, it is unknown if these two GSC populations are sufficient to generate the spectrum of cellular heterogeneity observed in GBM. The lineage relationships and niche interactions of GSCs have not been fully elucidated. We perform single-cell RNA-sequencing (scRNA-seq) and matched exome sequencing of human GBMs (12 patients; >37,000 cells) to identify recurrent hierarchies of GSCs and their progeny. We map sequenced cells to tumor-anatomical structures and identify microenvironment interactions using reference atlases and quantitative immunohistochemistry. We find that all GSCs can be described by a single axis of variation, ranging from proneural to mesenchymal. Increasing mesenchymal GSC (mGSC) content, but not proneural GSC (pGSC) content, correlates with significantly inferior survival. All clonal expressed mutations are found in the GSC populations, with a greater representation of mutations found in mGSCs. While pGSCs upregulate markers of cell-cycle progression, mGSCs are largely quiescent and overexpress cytokines mediating the chemotaxis of myeloid-derived suppressor cells. We find mGSCs enriched in hypoxic regions while pGSCs are enriched in the tumors invasive edge. We show that varying proportions of mGSCs, pGSCs, their progeny and stromal/immune cells are sufficient to explain the genetic and phenotypic heterogeneity observed in GBM. This study sheds light on a long-standing debate regarding the lineage relationships between GSCs and other glioma cell types.

cancer biology↗

bioRxiv2018

Modelling cancer immunomodulation using epithelial organoid cultures

Here we utilize organoid technology to study immune-cancer interactions and assess immunomodulation by colorectal cancer (CRC). Transcriptional profiling and flow cytometry revealed that organoids maintain differential expression of immunomodulatory molecules present in primary tumours. Finally, we established a method to model antigen-specific epithelial cell killing and cancer immunomodulation in vitro using CRC organoids co-cultured with cytotoxic T cells (CTLs).

cancer biology↗

bioRxiv2018

Targeting Wnt Signaling To Overcome PARP Inhibitor Resistance

Epithelial ovarian cancer (EOC) has one of the highest deaths to incidence ratios. High grade serous ovarian carcinoma (HGSOC) is the most common and deadliest EOC histotype because of the lack of secondary therapeutic options following debulking surgery and platinum/taxane-based chemotherapies. For recurrent chemosensitive HGSOC, poly(ADP)-ribose polymerase inhibitors (PARPi; olaparib, rucaparib, or niraparib) represent an emerging treatment strategy. While PARPi are most effective in homologous recombination DNA repair-deficient (HRD) HGSOCs, more recent studies have observed a significant clinical benefit in non-HRD HGSOCs. However, all HGSOC patients are likely to acquire resistance to PARPi. Therefore, there is an urgent clinical need to better understand PARPi resistance, and to introduce novel combinatorial therapies to overcome PARPi resistance and extend HGSOC disease-free intervals. Utilizing a two BRCA2-mutated and one BRCA-wildtype HGSOC cell lines that are olaparib sensitive, we established resistant cells. Transcriptome analysis of the matched olaparib-sensitive versus resistant cells did not detect BRCA2 reversion mutations, but revealed activation of Wnt/TCF signaling pathway, as TCF transcriptional activity was significantly increased in PARPi-resistant cells. In parallel, forced activation of Wnt signaling in PARPi-sensitive cells via WNT3A stimulation reduced response to PARPi. In a recurrent-HGSOC PARPi insensitive patient-derived xenograft model there was an increase in a Wnt/TCF transcriptional target. PARPi resistant cells were sensitive to inhibition of Wnt signaling using the FDA-approved compound, pyrvinium pamoate, which has been shown to inhibit Wnt signaling. We observed that combining pyrvinium pamoate with olaparib resulted in a significant decrease in tumor burden and number of tumor nodules. This study demonstrates that Wnt signaling can mediate PARPi resistance in HGSOC and provides a clinical rationale for combining PARPi and Wnt inhibitors.

cancer biology↗

bioRxiv2018

A novel enhancer RNA, Hmrhl, positively regulates its host gene, phkb, in Chronic Myelogenous Leukemia

Noncoding RNAs are increasingly being accredited with key roles in gene regulation during development and disease. Here we report the discovery and characterization of a novel long noncoding RNA, Hmrhl, which shares synteny and partial sequence similarity with the mouse lncRNA, Mrhl. The human homolog, Hmrhl, transcribed from intron 14 of phkb gene, is 5.5kb in size, expressed in all tissues examined and has acquired additional repeat elements. Analysis of Hmrhl locus using ENCODE database revealed that it is associated with hallmarks of enhancers like the open chromatin configuration, binding of transcription factors, enhancer specific histone signature etc. in the K562 Chronic Myelogenous Leukemia (CML) cells. We compared the expression of Hmrhl in the normal lymphoblast cell line, GM12878, with that of K562 cells and lymphoma samples and show that it is highly upregulated in leukemia as well as several cases of lymphoma. We validated the enhancer properties of Hmrhl locus in K562 cells with the help of Luciferase assay. Moreover, siRNA mediated down-regulation of Hmrhl in K562 cells leads to a concomitant down regulation of its parent gene, phkb, showing that Hmrhl functions as an enhancer RNA and positively regulates its host gene, phkb, in chronic myelogenous leukemia.

cancer biology↗

bioRxiv2018

Cryptic Promoter Activation Drives POU5F1 (OCT4) Expression in Renal Cell Carcinoma

Transcriptional dysregulation drives cancer formation but the underlying mechanisms are still poorly understood. As a model system, we used renal cell carcinoma (RCC), the most common malignant kidney tumor which canonically activates the hypoxia-inducible transcription factor (HIF) pathway. We performed genome-wide chromatin accessibility and transcriptome profiling on paired tumor/normal samples and found that numerous transcription factors with a RCC-selective expression pattern also demonstrated evidence of HIF binding in the vicinity of their gene body. Some of these transcription factors influenced the tumors regulatory landscape, notably the stem cell transcription factor POU5F1 (OCT4). Unexpectedly, we discovered a HIF-pathway-responsive cryptic promoter embedded within a human-specific retroviral repeat element that drives POU5F1 expression in RCC via a novel transcript. Elevat POU5F1 expression levels were correlated with advanced tumor stage and poorer overall survival in RCC patients. Thus, integrated transcriptomic and epigenomic analysis of even a small number of primary patient samples revealed remarkably convergent shared regulatory landscapes and a novel mechanism for dysregulated expression of POU5F1 in RCC.

cancer biology↗

bioRxiv2018

A Moonlighting Role for SPCA2 in E-cadherin Biogenesis and Suppression of Epithelial-Mesenchymal Transition

Progression of benign tumors to invasive, metastatic cancer requires loss of the cell-adhesion protein E-cadherin. Although intensive efforts have focused on gene repression and silencing mutations, much less is known about posttranslational control of E-cadherin expression in cancer. SPCA2 is a secretory pathway Ca2+-ATPase that is down-regulated in metastatic breast cancer. We show that SPCA2 is tightly co-expressed with epithelial signature genes and required for E-cadherin biogenesis and cell surface expression. Unexpectedly, this function is uncoupled from Ca2+ pumping and mediated by binding to E-cadherin. Loss of SPCA2 is sufficient to disrupt cell-cell adhesion in tumorspheres and elicit mesenchymal gene expression through Hippo-YAP signaling. These findings point to a causal link between low SPCA2 levels and the epithelial-mesenchymal transition required for breast cancer metastasis.\n\nHighlightsO_LISPCA2 is an epithelial marker transcriptionally linked to E-cadherin expression\nC_LIO_LILoss of SPCA2 impairs E-cadherin biogenesis independent of Ca2+ pump activity\nC_LIO_LISPCA2 is required for tumorsphere formation and Hippo-YAP signaling to antagonize epithelial-mesenchymal transition\nC_LIO_LIDown-regulation of SPCA2 in metastatic cancers may contribute to malignancy\nC_LI\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC=\"FIGDIR/small/379586_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@6b1e14org.highwire.dtl.DTLVardef@83edbborg.highwire.dtl.DTLVardef@16cbc5corg.highwire.dtl.DTLVardef@1c2752a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX-histone chaperone complex and that induced by MYCN-mediated metabolic reprogramming leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma.

cancer biology↗

bioRxiv2018

The tumor suppressor p53 promotes carcinoma invasion and collective cellular migration

SummaryLoss of function of the tumor suppressor p53 is generally thought to increase cell motility and invasiveness. Using 2-D confluent and 3-D spheroidal cell motility assays with bladder carcinoma cells and colorectal carcinoma cells, we report, to the contrary, that loss of p53 can decrease cell motility and invasion.\n\nAbstractFor migration of the single cell studied in isolation, loss of function of the tumor suppressor p53 is thought to increase cell motility. Here by contrast we used the 2-D confluent cell layer and the 3-D multicellular spheroid to investigate how p53 impacts dissemination and invasion of cellular collectives. We used two human carcinoma cell lines, the bladder carcinoma EJ and the colorectal carcinoma HCT116. We began by replicating single cell invasion in the traditional Boyden chamber assay, and found that the number of invading cells increased with loss of p53, as expected. In the confluent 2-D cell layer, however, for both EJ and HCT, speeds and effective diffusion coefficients for the p53 null types compared to their p53 expressing counterparts were significantly smaller. Compared to p53 expressers, p53 null cells exhibited more organized cortical actin rings together with reduced front-rear cell polarity. Furthermore, loss of p53 caused cells to exert smaller traction forces upon their substrates, and reduced formation of cryptic lamellipodia. In a 3-D collagen matrix, p53 consistently promoted invasion of the multicellular spheroids into surrounding matrix. Together, these results show that p53 expression in these carcinoma model systems increases collective cellular migration and invasion. As such, these studies point to paradoxical contributions of p53 in single cell versus collective cellular migration.

cancer biology↗

bioRxiv2018

SREBP1 drives KRT80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer

Approximately 30% of women diagnosed with ER breast cancer relapse with metastatic disease following adjuvant treatment with endocrine therapies1,2. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain (TAD)3 undergoes epigenetic reprogramming in cells that develop resistance to aromatase inhibitors (AI), leading to keratin 80 (KRT80) upregulation. In agreement, an increased number of KRT80-positive cells are observed at relapse in vivo while KRT80 expression associates with poor outcome using several clinical endpoints. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 14 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion maturation and cellular stiffening, which collectively promote cancer cell invasion. Shear-wave elasticity imaging of prospective patients shows that KRT80 levels correlate with stiffer tumors in vivo. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

cancer biology↗

bioRxiv2018

Modeling the MYC-driven normal-to-tumour switch in breast cancer.

The potent MYC oncoprotein is deregulated in many human cancers, including breast carcinoma, and is associated with aggressive disease. To understand the mechanisms and vulnerabilities of MYC-driven breast cancer, we have generated an in vivo model that mimics human disease in response to MYC deregulation. MCF10A cells ectopically expressing a common breast cancer mutation in the PI3 kinase pathway (PIK3CAH1047R) lead to the development of organized acinar structures in mice. However, expressing both PIK3CAH1047R and deregulated-MYC lead to the development of invasive ductal carcinoma, thus creating a model in which a MYC-dependent normal-to-tumour switch occurs in vivo. These MYC-driven tumors exhibit classic hallmarks of human breast cancer at both the pathological and molecular levels. Moreover, tumour growth is dependent upon sustained deregulated MYC expression, further demonstrating addiction to this potent oncogene and regulator of gene transcription. We therefore provide a MYC-dependent human model of breast cancer which can be assayed for in vivo tumour initiation, proliferation, and transformation from normal breast acini into invasive breast carcinoma. Taken together, we anticipate that this novel MYC-driven transformation model will be a useful research tool to both better understand MYCs oncogenic function and identify therapeutic vulnerabilities.

cancer biology↗

bioRxiv2018

Heterozygous mutations in p97 and resistance to p97 inhibitors

In recent years, multiple studies including ours have reported on the mechanism of resistance towards p97 inhibitors. While all these studies outline target alteration via mutations in p97 as the primary mechanism of resistance, discrepancies persist in the current literature due to the occurrence of both heterozygous and homozygous mutations when using HCT116 cells. Here, we report a pre-existing heterozygous frameshift mutation at codon 616 (N616fs*) in one of the p97 alleles in HCT116 cells and show that this mutant allele is subjected to nonsense-mediated decay. Furthermore, we independently generated p97 inhibitor (CB-5083) resistant HCT116 cells, and we observed a single heterozygous mutation at codon 526 (L526S) in genomic DNA sequencing but a homozygous L526S mutation in complementary DNA sequencing, indicating that the missense mutation (L526S) occurs in the allele that does not harbor the frameshift N616fs* mutation. Our results underscore the importance of performing simultaneous genomic and complementary DNA sequencing when confirming mutations in p97.

cancer biology↗

bioRxiv2018

Modelling bistable tumour population dynamics to design effective treatment strategies

Despite recent advances in targeted drugs and immunotherapy, cancer remains \"the emperor of all maladies\" due to inevitable emergence of resistance. Drug resistance is thought to be driven by mutations and/or dynamic plasticity that deregulate pathway activities and regulatory programs of a highly heterogeneous tumour. In this study, we propose a modelling framework to simulate population dynamics of heterogeneous tumour cells with reversible drug resistance. Drug sensitivity of a tumour cell is determined by its internal states, which are demarcated by coordinated activities of multiple interconnected oncogenic pathways. Transitions between cellular states depend on the effects of targeted drugs and regulatory relations between the pathways. Under this framework, we build a simple model to capture drug resistance characteristics of BRAF-mutant melanoma, where two cell states are described by two mutually inhibitory - main and alternative - pathways. We assume that cells with an activated main pathway are proliferative yet sensitive to the BRAF inhibitor, and cells with an activated alternative pathway are quiescent but resistant to the drug. We describe a dynamical process of tumour growth under various drug regimens using the explicit solution of mean-field equations. Based on these solutions, we compare efficacy of three treatment strategies: static treatments with continuous and constant dosages, periodic treatments with regular intermittent phases and drug holidays, and treatments derived from optimal control theory (OCT). Based on these analysis, periodic treatments outperform static treatments with a considerable margin, while treatments based on OCT outperform the best periodic treatment. Our results provide insights regarding optimal cancer treatment modalities for heterogeneous tumours, and may guide the development of optimal therapeutic strategies to circumvent drug resistance and due to tumour plasticity.

cancer biology↗

bioRxiv2018

Genome-wide silencing screen in mesothelioma cells reveals that loss of function of BAP1 induces chemoresistance to ribonucleotide reductase inhibition: implication for therapy

IntroductionLoss of function of BRCA1 associated protein 1 (BAP1) is observed in about 50% of malignant pleural mesothelioma (MPM) cases. The aim of this study was to investigate whether this aspect could be exploited for targeted therapy.\n\nMethodsA genetically engineered model was established expressing either functional or nonfunctional BAP1 and whole-genome siRNA screens were performed assessing impaired survival between the two cell lines. Cytotoxity induced by gemcitabine and hydroxyurea were assessed in a panel of BAP1-WT and BAP1-mut/del cell lines. Functional studies were carried out in BAP1 mut/del cell line reconstituted with BAP1 WT or BAP1 C91A (catalytically dead mutant) and in BAP1 WT cell line upon siRNA-mediated knock-down of BAP1.\n\nResultsThe whole-genome siRNA screen unexpectedly revealed 11 hits (FDR<0.05) more cytotoxic for BAP1-proficient cells. Two actionable targets, RRM1 and RRM2, were validated and their inhibition mediated by gemcitabine or hydroxyurea respectively, was more cytotoxic in BAP1-proficient cell lines. Upregulation of RRM2 upon gemcitabine and hydroxyurea was more profound in BAP1 mut/del cell lines. Increased lethality mediated by gemcitabine and hydroxyurea was observed in NCI-H2452 cells reconstituted with BAP1 WT but not with C91A mutant and upregulation of RRM2 in NCI-H2452-BAP1 WT spheroids was modest compared to control or C91A mutant. Finally, the opposite was observed after BAP1 knockdown in BAP1-proficient SPC111 cell line.\n\nConclusionWe found that BAP1 is involved in the regulation of RRM2 levels during replication stress. These observations reveal a potential therapeutic approach where MPM patients to be stratified depending on BAP status for gemcitabine treatment.

cancer biology↗

bioRxiv2018

High-throughput Automated Single Cell Imaging Analysis Reveals Dynamics Of Glioblastoma Stem Cell Population During State Transition

Cancer stem cells (CSCs) are a heterogeneous and dynamic population that stands at the top of tumor cellular hierarchy and is responsible for maintenance of the tumor microenvironment. As methods of CSC isolation and functional interrogation advance, there is a need for a reliable and accessible quantitative approach to assess heterogeneity and state transition dynamics in CSCs. We developed a High-throughput Automated Single Cell Imaging Analysis (HASCIA) approach for quantitative assessment of protein expression with single cell resolution and applied the method to investigate spatiotemporal factors that influence CSC state transition using glioblastoma (GBM) CSC as a model system. We were able to validate the quantitative nature of this approach through comparison of the protein expression levels determined by HASCIA to those determined by immunoblotting. A virtue of HASCIA was exemplified by detection of a subpopulation of SOX2-low cells, which expanded in fraction size during state transition. HASCIA also revealed that CSCs were committed to loose stem cell state at an earlier time point than the average SOX2 level decreased. Functional assessment of stem cell frequency in combination with quantification of SOX2 expression by HASCIA defined a stable cut-off of SOX2 expression level for stem cell state. We also developed an approach to assess local cell density and found that denser monolayer areas possess higher average levels of SOX2, higher cell diversity and a presence of a sub-population of slowly proliferating SOX2-low CSCs. HASCIA is an open source software that facilitates understanding the dynamics of heterogeneous cell population such as that of CSCs and their progeny. It is a powerful and easy-to-use image analysis and statistical analysis tool available at https://hascia.lerner.ccf.org.

cancer biology↗

bioRxiv2018

Rho-mediated MRTF and YAP1 activation contributes to BRAF inhibitor resistance in Sox9High/Sox10Low melanoma cells.

Over half of cutaneous melanoma tumors have BRAFV600E/K mutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that approximately 50-60% of melanoma cell lines with acquired vemurafenib resistance activate the RhoA family signaling pathway. RhoAHigh BRAFi-resistant cells are sensitive to the combination of ROCK inhibitors and vemurafenib. Further, these RhoAHigh cells have >100-fold increase in Sox9 expression and >100-fold decrease in Sox10 expression. Two transcriptional co-activators downstream of RhoA, MRTF and YAP1, are activated in Sox9High/Sox10Low BRAFi-resistant cells. Pharmacological inhibition of these transcriptional mechanisms re-sensitizes the cells to vemurafenib. Analysis of human BRAFi-resistant tumors reveals that many resistant tumors show gene expression signatures consistent with increased RhoA activation or activation of the transcriptional co-activators MRTF and YAP1. A subset of melanoma tumors in the TCGA dataset with low Sox10 expression also have elevated RhoA, MRTF, and YAP1 activation signatures. Taken together, these results support the concept of targeting RhoA-regulated gene transcription pathways as a promising approach for treating or preventing BRAFi-resistance in melanoma.

cancer biology↗