MYB is a novel regulator of pancreatic tumour growth and metastasis

Srivastava, Sanjeev K.; Bhardwaj, Arun; Arora, Sumit; Singh, Seema; Azim, Shafquat; Tyagi, Nidhi; Carter, James E.; Wang, Bin; Singh, Ajay P.

doi:10.1038/bjc.2015.400

Cited by 44 publications

(55 citation statements)

References 39 publications

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“…We recently identified MYB as an important regulator of pancreatic cancer pathogenesis which modulates tumor growth, aggressiveness as well as metastasis6. The analysis of the RNA-seq data of MYB-silenced MiaPaCa PC cells identified known MYB-target genes, e.g., ADM, BRCA1, CBFB, KLF4, LDHA, PCNA etc 6171819,.…”

Section: Discussionmentioning

confidence: 99%

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Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer

Azim

Zubair

Srivastava

et al. 2016

Sci Rep

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We have recently demonstrated that the transcription factor MYB can modulate several cancer-associated phenotypes in pancreatic cancer. In order to understand the molecular basis of these MYB-associated changes, we conducted deep-sequencing of transcriptome of MYB-overexpressing and -silenced pancreatic cancer cells, followed by in silico pathway analysis. We identified significant modulation of 774 genes upon MYB-silencing (p < 0.05) that were assigned to 25 gene networks by in silico analysis. Further analyses placed genes in our RNA sequencing-generated dataset to several canonical signalling pathways, such as cell-cycle control, DNA-damage and -repair responses, p53 and HIF1α. Importantly, we observed downregulation of the pancreatic adenocarcinoma signaling pathway in MYB-silenced pancreatic cancer cells exhibiting suppression of EGFR and NF-κB. Decreased expression of EGFR and RELA was validated by both qPCR and immunoblotting and they were both shown to be under direct transcriptional control of MYB. These observations were further confirmed in a converse approach wherein MYB was overexpressed ectopically in a MYB-null pancreatic cancer cell line. Our findings thus suggest that MYB potentially regulates growth and genomic stability of pancreatic cancer cells via targeting complex gene networks and signaling pathways. Further in-depth functional studies are warranted to fully understand MYB signaling in pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

“…The analysis of the RNA-seq data of MYB-silenced MiaPaCa PC cells identified known MYB-target genes, e.g., ADM, BRCA1, CBFB, KLF4, LDHA, PCNA etc 6171819,. along with several novel direct/indirect targets.…”

Section: Discussionmentioning

confidence: 99%

Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer

Azim

Zubair

Srivastava

et al. 2016

Sci Rep

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“…Soft-agar assay was performed as described previously by us (19). Briefly, equal volumes of agarose (1.6%) and regular growth medium were mixed and plated to form bottom layer (0.8% agar growth medium) in six-well plates.…”

Section: Soft-agar Assaymentioning

confidence: 99%

“…injection of ketamine (100 mg/kg) and xylazine (15 mg/kg). Luciferase-tagged MiaPaCa cells (1 × 10 6 /50 μl) were injected into the pancreas of immunocompromised mice as described previously (19). Once tumor became palpable (~7 days after injection), the animals were randomly divided into two groups (six mice per group …”

Section: Orthotopic Xenograft Studymentioning

confidence: 99%

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Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor–stromal cross-talk

Averett

Bhardwaj

Arora

et al. 2016

CARCIN

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The poor clinical outcome of pancreatic cancer (PC) is largely attributed to its aggressive nature and refractoriness to currently available therapeutic modalities. We previously reported antitumor efficacy of honokiol (HNK), a phytochemical isolated from various parts of Magnolia plant, against PC cells in short-term in vitro growth assays. Here, we report that HNK reduces plating efficiency and anchorage-independent growth of PC cells and suppresses their migration and invasiveness. Furthermore, significant inhibition of pancreatic tumor growth by HNK is observed in orthotopic mouse model along with complete-blockage of distant metastases. Histological examination suggests reduced desmoplasia in tumors from HNK-treated mice, later confirmed by immunohistochemical analyses of myofibroblast and extracellular matrix marker proteins (α-SMA and collagen I, respectively). At the molecular level, HNK treatment leads to decreased expression of sonic hedgehog (SHH) and CXCR4, two established mediators of bidirectional tumor-stromal cross-talk, both in vitro and in vivo. We also show that the conditioned media (CM) from HNK-treated PC cells have little growth-inducing effect on pancreatic stellate cells (PSCs) that could be regained by the addition of exogenous recombinant SHH. Moreover, pretreatment of CM of vehicle-treated PC cells with SHH-neutralizing antibody abolishes their growth-inducing potential on PSCs. Likewise, HNK-treated PC cells respond poorly to CM from PSCs due to decreased CXCR4 expression. Lastly, we show that the transfection of PC cells with constitutively active IKKβ mutant reverses the suppressive effect of HNK on nuclear factorkappaB activation and partially restores CXCR4 and SHH expression. Taken together, these findings suggest that HNK interferes with tumor-stromal cross-talk via downregulation of CXCR4 and SHH and decreases pancreatic tumor growth and metastasis.

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Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T‐cell lymphoblastic leukemia

Almeida,

T'Sas,

Pagliaro

et al. 2024

HemaSphere

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T‐lineage acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological malignancy that accounts for 10%–15% of pediatric and 25% of adult ALL cases. Although the prognosis of T‐ALL has improved over time, the outcome of T‐ALL patients with primary resistant or relapsed leukemia remains poor. Therefore, further progress in the treatment of T‐ALL requires a better understanding of its biology and the development of more effective precision oncologic therapies. The proto‐oncogene MYB is highly expressed in diverse hematologic malignancies, including T‐ALLs with genomic aberrations that further potentiate its expression and activity. Previous studies have associated MYB with a malignant role in the pathogenesis of several cancers. However, its role in the induction and maintenance of T‐ALL remains relatively poorly understood. In this study, we found that an increased copy number of MYB is associated with higher MYB expression levels, and might be associated with inferior event‐free survival of pediatric T‐ALL patients. Using our previously described conditional Myb overexpression mice, we generated two distinct MYB‐driven T‐ALL mouse models. We demonstrated that the overexpression of Myb synergizes with Pten deletion but not with the overexpression of Lmo2 to accelerate the development of T‐cell lymphoblastic leukemias. We also showed that MYB is a dependency factor in T‐ALL since RNA interference of Myb blocked cell cycle progression and induced apoptosis in both human and murine T‐ALL cell lines. Finally, we provide preclinical evidence that targeting the transcriptional activity of MYB can be a useful therapeutic strategy for the treatment of T‐ALL.

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MYB is a novel regulator of pancreatic tumour growth and metastasis

Cited by 44 publications

References 39 publications

Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer

Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer

Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor–stromal cross-talk

Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T‐cell lymphoblastic leukemia

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