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Mycoplasma Hyorhinis Infection Promotes NF-κB–Dependent Migration of Gastric Cancer Cells | Cancer Research
Note - activation of EGFR and NFKB signaling

Chronic infection of Mycoplasma hyorhinis (M. hyorhinis) has been postulated to be associated with several types of cancer, but its effect on patients' survival and host factors mediating its infection remain unclear. Herein, we demonstrated that M. hyorhinis p37 protein expression in gastric cancer tissues predicts poor survival and associates with metastasis. M. hyorhinis infects mammalian cells and promotes gastric cancer cell invasiveness via its membrane protein p37. Synthesized peptide corresponding to the N-terminus of p37 prevents M. hyorhinis infection. Host Annexin A2 (ANXA2) interacts with the N-terminus of p37. In addition, EGFR forms a complex with p37 and ANXA2, and is required for M. hyorhinis–induced phosphorylation and membrane recruitment of ANXA2. M. hyorhinis infection is inhibited by siRNA-mediated knockdown of ANXA2 or EGFR, but is enhanced by expression of ectopic ANXA2 or EGFR. Downstream of ANXA2 and EGFR, the NF-κB pathway is activated and mediates M. hyorhinis–driven cell migration. In conclusion, our study unveils the effect of M. hyorhinis infection on gastric cancer survival and uncovers the mechanisms by which M. hyorhinis infects mammalian cells and promotes cancer cell migration. Cancer Res; 74(20); 5782–94. ©2014 AACR.
mycoplasma  prostate_cancer  Cancer  nfkb  EGFR  anxa2 
24 days ago by Segalllab
Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells | Oncogene
Interesting concept that transmembrane TNFA may reverse signal through ERK/nfkb and GST to increase resistance to dox. 231 has more than MCF7. Not sure they really ruled out regular TNF signaling but perhaps tm TNFA could be on TNTs?


Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-α (sTNF-α) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-α (tmTNF-α) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-α at high levels in breast cancer tissues and tmTNF-α expression positively correlated with resistance to anthracycline chemotherapy. Alteration of tmTNF-α expression changed the sensitivity of primary human breast cancer cells and breast cancer cell lines to doxorubicin (DOX). Overexpression of N-terminal fragment (NTF) of tmTNF-α, a mutant form with intact intracellular domain of tmTNF-α to transmit reverse signals, induced DOX-resistance. Mechanistically, the tmTNF-α/NTF-ERK-GST-π axis and tmTNF-α/NTF-NF-κB-mediated anti-apoptotic functions were required for tmTNF-α-induced DOX-resistance. In a xenograft mouse model, the combination of tmTNF-α suppression with chemotherapy significantly enhanced the efficacy of DOX. Our data indicate that tmTNF-α mediates DOX-resistance through reverse signaling and targeting tmTNF-α may be beneficial for the treatment of DOX-resistant breast cancer.
tnfa  doxorubicin  chemoresistance  nfkb  gst  transmembrane_TNF 
25 days ago by Segalllab
Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis | Cancer Research
MTDH/AEG1 contributes to NFKB activation in macrophages...

Chronic inflammation is a known hallmark of cancer and is central to the onset and progression of hepatocellular carcinoma (HCC). Hepatic macrophages play a critical role in the inflammatory process leading to HCC. The oncogene Astrocyte elevated gene-1 (AEG-1) regulates NFκB activation, and germline knockout of AEG-1 in mice (AEG-1−/−) results in resistance to inflammation and experimental HCC. In this study, we developed conditional hepatocyte- and myeloid cell–specific AEG-1−/− mice (AEG-1ΔHEP and AEG-1ΔMAC, respectively) and induced HCC by treatment with N-nitrosodiethylamine (DEN) and phenobarbital (PB). AEG-1ΔHEP mice exhibited a significant reduction in disease severity compared with control littermates, while AEG-1ΔMAC mice were profoundly resistant. In vitro, AEG-1−/− hepatocytes exhibited increased sensitivity to stress and senescence. Notably, AEG-1−/− macrophages were resistant to either M1 or M2 differentiation with significant inhibition in migration, endothelial adhesion, and efferocytosis activity, indicating that AEG-1 ablation renders macrophages functionally anergic. These results unravel a central role of AEG-1 in regulating macrophage activation and indicate that AEG-1 is required in both tumor cells and tumor microenvironment to stimulate hepatocarcinogenesis.
MTDH  nfkb  Macrophages  macrophage_polarization 
5 weeks ago by Segalllab
Cross-talk between EGFR and IL-6 drives oncogenic signaling and offers therapeutic opportunities in cancer - ScienceDirect
Though EGFR promotes cell proliferation and metabolism primarily through the PI3K/AKT and MAPK pathways, its activation of the NF-kB pathway in cancer is not well-defined. In advanced-stage epithelial ovarian cancer, ligand-dependent EGFR signaling was found to promote an inflammatory microenvironment with enhanced secretion of IL-6 via activation of the NF-kB pathway [84]. One of the mediators of this activation is mucosa-associated lymphoid tissue 1 (MALT1), which also mediates the cross-talk between NF-kB and STAT3 transcription factors in lung cancer via IL-6 [85]. The NF-kB transcription factor was also implicated in Erlotinib resistance in EGFR-mutant NSCLC cells, and using NF-kB inhibitors restored drug sensitivity [86]. Hence, the crosstalk between EGFR and IL-6 via NF-kB and STAT3 could be blocked using IL-6 blockade therapies, which could be used as a means of overcoming resistance and reducing cancer-related inflammation.
EGFR  IL6  nfkb  STAT3 
6 weeks ago by Segalllab
Proinvasive extracellular matrix remodeling in tumor microenvironment in response to radiation | Oncogene
I wonder if macrophages could provide the IL1A to trigger HA to stimulate CD44...

Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.
radiation  il1alpha  nfkb  hyaluronic_acid  U87 
6 weeks ago by Segalllab
Suppression of PMA-induced tumor cell invasion by dihydroartemisinin via inhibition of PKCα/Raf/MAPKs and NF-κB/AP-1-dependent mechanisms - ScienceDirect
artemisinin inhibits PMA induced phosphorylation of Raf/JNK and reduces NFKB and AP1 activation


Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently been shown to possess antitumor activity in various cancer cells. However, the effects of DHA in preventing the invasion of cancer cells have not been studied. In the present study, we investigated the inhibitory effects of DHA on tumor invasion and migration and the possible mechanisms involved using human fibrosarcoma HT-1080 cells. DHA reduced PMA-induced activation of MMP-9 and MMP-2 and further inhibited cell invasion and migration. DHA suppressed PMA-enhanced expression of MMP-9 protein, mRNA, and transcriptional activity through suppressing NF-κB and AP-1 activation without changing the level of tissue inhibitor of metalloproteinase (TIMP)-1. DHA also reduced PMA-enhanced MMP-2 expression by suppressing membrane-type 1 MMP (MT1-MMP), but did not alter TIMP-2 levels. DHA-inhibited PMA-induced NF-κB and c-Jun nuclear translocation, which are upstream of PMA-induced MMP-9 expression and invasion. Furthermore, DHA strongly repressed the PMA-induced phosphorylation of Raf/ERK and JNK, which are dependent on the PKCα pathway. In conclusion, we demonstrated that the anti-invasive effects of DHA may occur through inhibition of PKCα/Raf/ERK and JNK phosphorylation and reduction of NF-κB and AP-1 activation, leading to down-regulation of MMP-9 expression. The data presented show that DHA is an effective anti-metastatic agent that functions by down-regulating MMP-9 gene expression
artemisinin  nfkb  pma  phosphorylation 
november 2018 by Segalllab
VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma | Science
Possible connection to GPX2 and nfkb?

"Many clear cell renal cell carcinomas (ccRCCs) have alterations to the gene encoding the von Hippel-Lindau protein (VHL). VHL is a ubiquitin ligase that degrades target proteins when they are prolyl-hydroxylated. Zhang et al. performed a genome-wide search for VHL target (see the Perspective by Sanchez and Simon). They identified ZHX2, a protein with structural motifs that indicate DNA binding. ZHX2 has been implicated in tumor suppression. Loss of ZHX2 inhibited signaling through the transcription factor NF-κB, and ZHX2 bound to many NF-κB target genes. Depletion of ZHX2 slowed growth of ccRCC cells in vitro and in a mouse model.
nfkb  vhl  gpx2 
october 2018 by Segalllab
CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness - ScienceDirect
Mention IL1B activation of nfkb also in discussion

"Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.
cafs  cancer_stem_cells  niche  IL1B  nfkb 
october 2018 by Segalllab
Exosome-mediated miR-222 transferring: An insight into NF-κB-mediated breast cancer metastasis - ScienceDirect
231 cells secrete exosomes with mir222 that downregulate PDLIM2, leading to increased relA/B and NFKB activity and migration/metatsasis. Maybe also activates NFKB in macrophages?

"This study demonstrates that exosomal miR-222 signatures are associated with BCa metastatic progression. Exosome-mediated miR-222 intercellular transferring promotes tumorigenicity of the recipient BCa cells through enhancing NF-κB by repressing PDLIM2 expression.
231_cells  nfkb  mir-222  exosomes 
september 2018 by Segalllab
Attenuated TRAF3 Fosters Activation of Alternative NF-κB and Reduced Expression of Antiviral Interferon, TP53, and RB to Promote HPV-Positive Head and Neck Cancers | Cancer Research
combine tnfa with cisplatin for chemotherapy ?


Human papilloma viruses (HPV) are linked to an epidemic increase in oropharyngeal head and neck squamous cell carcinomas (HNSCC), which display viral inactivation of tumor suppressors TP53 and RB1 and rapid regional spread. However, the role of genomic alterations in enabling the modulation of pathways that promote the aggressive phenotype of these cancers is unclear. Recently, a subset of HPV+ HNSCC has been shown to harbor novel genetic defects or decreased expression of TNF receptor–associated factor 3 (TRAF3). TRAF3 has been implicated as a negative regulator of alternative NF-κB pathway activation and activator of antiviral type I IFN response to other DNA viruses. How TRAF3 alterations affect pathogenesis of HPV+ HNSCC has not been extensively investigated. Here, we report that TRAF3-deficient HPV+ tumors and cell lines exhibit increased expression of alternative NF-κB pathway components and transcription factors NF-κB2/RELB. Overexpression of TRAF3 in HPV+ cell lines with decreased endogenous TRAF3 inhibited NF-κB2/RELB expression, nuclear localization, and NF-κB reporter activity, while increasing the expression of IFNA1 mRNA and protein and sensitizing cells to its growth inhibition. Overexpression of TRAF3 also enhanced TP53 and RB tumor suppressor proteins and decreased HPV E6 oncoprotein in HPV+ cells. Correspondingly, TRAF3 inhibited cell growth, colony formation, migration, and resistance to TNFα and cisplatin-induced cell death. Conversely, TRAF3 knockout enhanced colony formation and proliferation of an HPV+ HNSCC line expressing higher TRAF3 levels. Together, these findings support a functional role of TRAF3 as a tumor suppressor modulating established cancer hallmarks in HPV+ HNSCC.

Significance: These findings report the functional role of TRAF3 as a tumor suppressor that modulates the malignant phenotype of HPV+ head and neck cancers. Cancer Res; 78(16);
HPV  HNSCC  chemotherapy  nfkb 
august 2018 by Segalllab
Oncotarget | Canonical NF-κB signaling in myeloid cells promotes lung metastasis in a mouse breast cancer model
See macrophage changes in both primary and lung but argue primary growth is not altered so effect is on lung. They look at circulating PyMT which may not be the best measure of intravasation

"In the present study, the role of canonical NF-κB signaling in myeloid cells in metastatic breast cancer was addressed by myeloid-specific deletion of Ikkβ in the MMTV polyoma middle T (PyMT) mouse model. Ikkβ deletion in myeloid cells did not affect primary mammary tumor growth but significantly reduced lung metastasis. While dissemination from the primary tumor was unaltered, myeloid-specific Ikkβ loss resulted in a strong up-regulation of pro-inflammatory genes and changes in immune cell populations in the lung, creating a tumor-suppressive microenvironment at the distant site. Thus, canonical NF-κB signaling in myeloid cells creates a permissive lung microenvironment that supports breast to lung metastasis.
PyMT-MMTV  nfkb  Macrophages  metastases  lung_colonization  macrophage_polarization  inflammation 
august 2018 by Segalllab
Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype | Nature Communications
Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca2+ release via the lysosomal Ca2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca2+ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.
macrophage_polarization  chloroquine  nfkb  p38  ca  glycolysis 
july 2018 by Segalllab
Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells | Cell Death & Disease
I wonder if TNFA from NRG1 stimulated macrophages could induced CXCL1 in tumor cells?

The damage-associated molecular pattern molecules (DAMPs) released by necrotic cells can trigger inflammatory response, which will facilitate the clearance of these dead cells. Neutrophil mobilization is a very important step for the dead cell clearance, however the detailed mechanisms for DAMPs induce neutrophil mobilization remains largely elusive. In this study, by using a necrotic cell-induced neutrophil mobilization mice model, we found that both neutrophil number and percentage rapidly (as early as 30 min) increased with necrotic cells but not live cell treatment. CXCL1 was rapidly increased in the serum and was responsible for the neutrophil mobilization when treated with necrotic cells. We further demonstrated that the hepatocytes in the liver were the main source of CXCL1 production in response to necrotic cells challenge. However, the hepatocytes did not express CXCL1 when incubating with necrotic cells alone. When Kupffer cells were ablated, the increased CXCL1 levels as well as neutrophil mobilization were abolished with necrotic cells challenge. Moreover, we clarified Kupffer cells-derived TNF-α activates the NF-κB pathway in hepatocytes and promote hepatocytes to express CXCL1. In summary, we showed that the liver is the main source for necrotic cell-induced CXCL1 production and neutrophil mobilization. Kupffer cells in the liver sense DAMPs and release TNF-α to activate the NF-κB pathway in hepatocytes. The interaction between Kupffer cells and hepatocytes is critical for CXCL1 production.
tnfalpha  CXCL1  Macrophage  nfkb  damps 
july 2018 by Segalllab
Proteolytic release of the p75NTR intracellular domain by ADAM10 promotes metastasis and resistance to anoikis | Cancer Research
Looking at HNSCC cells - interesting point that EGFR is activated upon cell detachment..

"Resistance to anoikis allows cancer cells to survive during systemic circulation, however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75NTR) and subsequent generation of the p75NTR intracellular domain (ICD) endows cancer cells with resistance to anoikis. p75NTR ICD promoted expression of TNF receptor associated factor 6 (TRAF6), a critical intermediary in p75NTR ICD-mediated signal transduction, at the translational level. Cell detachment-induced activation of epidermal growth factor receptor (EGFR) triggered auto-ubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NF-κB, and eventually led to anoikis resistance. ADAM10 and p75NTR ICD also promoted tumor metastasis formation in vivo. Together, our findings uncover a previously unknown function for the ADAM10-p75NTR ICD-TRAF6-NF-κB axis in preventing anoikis and suggest ADAM10 and p75NTR ICD as potential cancer therapeutic targets."
anoikis  EGFR  cell_detachment  chemoresistance  nfkb  adam10  p75NTR 
july 2018 by Segalllab
SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer | Oncogene
Kras to NFKB to SOX9 in pancreatic cancer - maybe also in bc? Though no correlation of SOX9 with outcome in pancreatic cancer

"SRY (sex determining region Y)-box 9 (SOX9) is required for oncogenic Kras-mediated acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasias (PanINs) and ultimately pancreatic ductal adenocarcinoma (PDAC). However, how oncogenic Kras affects SOX9 activity is not yet understood, and SOX9-associated genes in PDAC are also unknown at all. Here, we investigated the mechanistic link between SOX9 and oncogenic Kras, studied biological function of SOX9, and identified SOX9-related genes and their clinical significance in patients with PDAC. Our studies reveal that oncogenic Kras induces SOX9 mRNA and protein expression as well as phosphorylated SOX9 expression in human pancreatic ductal progenitor cells (HPNE) and pancreatic ductal cells (HPDE). Moreover, oncogenic Kras promoted nuclear translocation and transcriptional activity of SOX9 in these cells. TAK1/IκBα/NF-κB pathway contributed to induction of SOX9 by oncogenic Kras, and SOX9 in turn enhanced NF-κB activation. SOX9 promoted the proliferation of HPNE and PDAC cells, and correlated with minichromosome maintenance complex components (MCMs) and mediator of DNA damage checkpoint 1 (MDC1) expression. The overexpressive MDC1 was associated with less perineural and lymph node invasion of tumors and early TNM-stage of patients. Our results indicate that oncogenic Kras induces constitutive activation of SOX9 in HPNE and HPDE cells, and Kras/TAK1/IκBα/NF-κB pathway and a positive feedback between SOX9 and NF-κB are involved in this inducing process. SOX9 accelerates proliferation of cells and affects MCMs and MDC1 expression. MDC1 is associated negatively with invasion and metastasis of PDAC.
sox9  kras  nfkb 
july 2018 by Segalllab
Twitter
Link between TGFβ signalling (->receptor type I levels on lymphocytes) and T cell quiescence vs activation.
NFkB  from twitter_favs
april 2018 by maverickny
CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness: Cell
Though need to check if TNFA could do it, this could be a way to bring in CAFs for a 3 cell system: TC NRG1 to Mac TNFA to CAF Cta/IL6

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors
stem_cells  cancer_stem_cells  cafs  nfkb  IL6  c5a 
march 2018 by Segalllab
Coactivation of Estrogen Receptor and IKKβ Induces a Dormant Metastatic Phenotype in ER-Positive Breast Cancer | Cancer Research
Most of the work was with an MCF7 line overexpressing a CA ikkb, so unclear how easily TNFA could do this but still an interesting possibility. NRG1 to macrophages which make TNFA to put the ER positive tumor cells in a more invasive metastatic but dormant state?

A growing body of evidence suggests that the inflammatory NFκB pathway is associated with the progression of ER+ tumors to more aggressive stages. However, it is unknown whether NFκB is a driver or a consequence of aggressive ER+ disease. To investigate this question, we developed breast cancer cell lines expressing an inducible, constitutively active form of IκB kinase β (CA-IKKβ), a key kinase in the canonical NFκB pathway. We found that CA-IKKβ blocked E2-dependent cell proliferation in vitro and tumor growth in vivo in a reversible manner, suggesting that IKKβ may contribute to tumor dormancy and recurrence of ER+ disease. Moreover, coactivation of ER and IKKβ promoted cell migration and invasion in vitro and drove experimental metastasis in vivo. Gene expression profiling revealed a strong association between ER and CA-IKKβ–driven gene expression and clinically relevant invasion and metastasis gene signatures. Mechanistically, the invasive phenotype appeared to be driven by an expansion of a basal/stem-like cell population rather than EMT. Taken together, our findings suggest that coactivation of ER and the canonical NFκB pathway promotes a dormant, metastatic phenotype in ER+ breast cancer and implicates IKKβ as a driver of certain features of aggressive ER+ breast cancer.

Significance: The canonical NFκB pathway promotes expansion of stem/basal-like cells and a dormant, metastatic phenotype in ER+ breast cancer cells
MCF7  tnfa  nfkb  invasion  Metastasis  dormancy 
march 2018 by Segalllab
Downregulating Neuropilin-2 Triggers a Novel Mechanism Enabling EGFR-Dependent Resistance to Oncogene-Targeted Therapies | Cancer Research
EGFR signaling is upregulated by NFKB, NRP2 hurts 231 proliferation



Neuropilins are a class of cell surface proteins implicated in cell migration and angiogenesis, with aberrant expression in human tumors. Here, we show that the expression of Neuropilin-2 (NRP2) controls EGFR protein levels, thereby impinging on intracellular signaling, viability, and response to targeted therapies of oncogene-addicted cells. Notably, increased NRP2 expression in EGFR-addicted tumor cells led to downregulation of EGFR protein and tumor cell growth inhibition. NRP2 also blunted upregulation of an EGFR "rescue" pathway induced by targeted therapy in Met-addicted carcinoma cells. Cancer cells acquiring resistance to MET oncogene-targeted drugs invariably underwent NRP2 loss, a step required for EGFR upregulation. Mechanistic investigations revealed that NRP2 loss activated NFkB and upregulated the EGFR-associated protein KIAA1199/CEMIP, which is known to oppose the degradation of activated EGFR kinase. Notably, KIAA1199 silencing in oncogene-addicted tumor cells improved therapeutic responses and counteracted acquired drug resistance. Our findings define NRP2 as the pivotal switch of a novel broad-acting and actionable pathway controlling EGFR signaling, and driving resistance to therapies targeting oncogene-addiction.

Significance: These important findings identify the cell surface molecule Nrp2 as the pivotal switch of a novel, actionable pathway driving EGFR upregulation and resistance to oncogene- targeted therapies
231  EGFR  nfkb  nrp2 
march 2018 by Segalllab

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