Prognostic impact of alternative splicing-derived hMENA isoforms in resected, node-negative, non-small-cell lung cancer

Bria, Emilio; Modugno, Francesca Di; Sperduti, Isabella; Iapicca, Pierluigi; Visca, P.; Alessandrini, Gabriele; Antoniani, Barbara; Pilotto, Sara; Ludovini, Vienna; Vannucci, Jacopo; Bellezza, Guido; Sidoni, Angelo; Radisky, Derek C.; Crinò, Lucio; Cognetti, Francesco; Facciolo, Francesco; Mottolese, Marcella; Milella, Michèle; Nisticò, Paola

doi:10.18632/oncotarget.2609

Cited by 34 publications

(39 citation statements)

References 35 publications

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“…3A). As previously reported in different tumors, 10,14,19 WB with available antibodies (Fig. S3B) showed that Iso-11a (90 kDa protein) correlated with E-cadherin expression in HPDE, CFPAC and ASPC1.…”

Section: Resultssupporting

confidence: 84%

“…Our discovery that the pattern of hMENA isoforms may be a useful marker for early stage NSCLC, 10 suggested that this unique signature might also fill the lack of prognostic marker for pancreatic cancer. We explored the expression of hMENA isoforms in a series of surgically resected PDACs (n = 285), PanINs (n=15), chronic pancreatitis (n = 10), and normal pancreatic tissues from transplant donors (n = 3) (kindly provided by Lorenzo Piemonti, IRCCS San Raffaele Scientific Institute, Milan, Italy).…”

Section: Resultsmentioning

confidence: 99%

“…Cytoskeletal reorganization, 6 extracellular matrix (ECM) remodeling, and matrix metalloproteinase (MMPs) 7 contribute to PDAC aggressiveness in cooperation with soluble growth factor or cytokines, with TGF-β1 as a crucial player 8 . Alternative splicing is known to play a prominent role in tumor progression and the derived isoforms may represent powerful diagnostic and prognostic factors, 9 as we have recently shown for hMENA alternative splicing in early stage non-small cell lung cancer (NSCLC) 10 . hMENA belongs to the Ena/VASP family of actin regulatory proteins, which modulate cell adhesion and migration 11 and have been involved in axon guidance, 12 carcinogenesis, 13 and tumor invasiveness 14 .…”

Section: Introductionmentioning

confidence: 99%

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The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome

Melchionna¹,

Iapicca²,

Modugno³

et al. 2016

OncoImmunology

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease in need of prognostic markers to address therapeutic choices. We have previously shown that alternative splicing of the actin regulator, hMENA, generates hMENA11a, and hMENAΔv6 isoforms with opposite roles in cell invasion. We examined the expression pattern of hMENA isoforms by immunohistochemistry, using anti-pan hMENA and specific anti-hMENA11a antibodies, in 285 PDACs, 15 PanINs, 10 pancreatitis, and normal pancreas. Pan hMENA immunostaining, absent in normal pancreas and low-grade PanINs, was weak in PanIN-3 and had higher levels in virtually all PDACs with 64% of cases showing strong staining. Conversely, the anti-invasive hMENA11a isoform only showed strong staining in 26% of PDAC. The absence of hMENA11a in a subset (34%) of pan-hMENA-positive tumors significantly correlated with poor outcome. The functional effects of hMENA isoforms were analyzed by loss and gain of function experiments in TGF-β1-treated PDAC cell lines. hMENA11a knock-down in PDAC cell lines affected cell–cell adhesion but not invasion. TGF-β1 cooperated with β-catenin signaling to upregulate hMENA and hMENAΔv6 expression but not hMENA11a In the absence of hMENA11a, the hMENA/hMENAΔv6 up-regulation is crucial for SMAD2-mediated TGF-β1 signaling and TGF-β1-induced EMT. Since the hMENA isoform expression pattern correlates with patient outcome, the data suggest that hMENA splicing and related pathways are novel key players in pancreatic tumor microenvironment and may represent promising targets for the development of new prognostic and therapeutic tools in PDAC.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome

Melchionna¹,

Iapicca²,

Modugno³

et al. 2016

OncoImmunology

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“…Conversely, the overexpression of hMENAΔv6, in the absence of hMENA 11a , increases vimentin and fibronectin overexpression as well as matrix metalloproteinase (MMP)2 secretion [68] (and unpublished results), all mesenchymal markers belonging to an EMT signature across various human cancers, as explored in The Cancer Genome Atlas (TCGA) [70]. In agreement, we have suggested that the pattern of hMENA isoforms may represent a powerful prognostic factor in NSCLC and pancreatic ductal adenocarcinoma (PDAC), hMENA 11a being a good and hMENAΔv6 a poor prognostic factor [67,68].…”

Section: Tme-related Mechanisms Leading To Mesenchymal Traits and Ressupporting

confidence: 57%

“…The actin cytoskeleton regulator hMENA (ENAH gene) has been found among the ESRP1/2 targets [64,65]. We have shown that the tissue-specific splicing program of Mena, with the switch from hMENA 11a to hMENAΔv6 isoform expression, may represent a crucial node in the convergence of EMT-related signaling pathways [66][67][68]. Transforming growth factor The convergence of tumor-intrinsic and -extrinsic factors, as above schematically illustrated, generates mesenchymal traits with immune cell exclusion and/or dysfunction involved in resistance to ICB treatments.…”

Section: Tme-related Mechanisms Leading To Mesenchymal Traits and Resmentioning

confidence: 99%

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

Trono¹,

Sistigu

Palermo³

et al. 2017

Emerging Topics in Life Sciences

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Correspondence: Paola Nisticò ( paola.nistico@ifo.gov.it)Targeting of immune checkpoint blockers (ICBs), such as cytotoxic T-lymphocyte antigen-4 and programmed-death 1/programmed-death ligand 1, has dramatically changed the landscape of cancer treatment. Seeing patients who were refractory to conventional therapy recover after immunotherapy, with high rates of objective durable responses and increased overall survival, has raised great enthusiasm in cancer care and research. However, to date, only a restricted portion of patients benefit from these therapies, due to natural and acquired resistance relying on the ever-evolving cross-talk between tumor and stromal cells. Here, we review the convergence of tumor-intrinsic and -extrinsic cues, both affecting tumor plasticity and tumor stroma leading to an immunosuppressive tumor microenvironment, which may account for the heterogeneous responses and resistance to ICB therapies. A deeper knowledge of the mechanisms and fingerprints involved in natural and acquired resistance is likely to bring clinical benefit to the majority of patients, offering important clues for overcoming drug resistance and boosting the effectiveness of treatment. We discuss the need to define tumor subtypes based on the tumor, immune and stromal gene signature and propose that the better we understand tumor mesenchymal traits, the more we will be able to identify predictive biomarkers of response to ICB treatments.

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Alternative‐splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics

2018

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Defects in alternative splicing are frequently found in human tumors and result either from mutations in splicing-regulatory elements of specific cancer genes or from changes in the regulatory splicing machinery. RNA splicing regulators have emerged as a new class of oncoproteins and tumor suppressors, and contribute to disease progression by modulating RNA isoforms involved in the hallmark cancer pathways. Thus, dysregulation of alternative RNA splicing is fundamental to cancer and provides a potentially rich source of novel therapeutic targets. Here, we review the alterations in splicing regulatory factors detected in human tumors, as well as the resulting alternatively spliced isoforms that impact cancer hallmarks, and discuss how they contribute to disease pathogenesis. RNA splicing is a highly regulated process and, as such, the regulators are themselves tightly regulated. Differential transcriptional and posttranscriptional regulation of splicing factors modulates their levels and activities in tumor cells. Furthermore, the composition of the tumor microenvironment can also influence which isoforms are expressed in a given cell type and impact drug responses. Finally, we summarize current efforts in targeting alternative splicing, including global splicing inhibition using small molecules blocking the spliceosome or splicing-factor-modifying enzymes, as well as splice-switching RNA-based therapeutics to modulate cancer-specific splicing isoforms. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing.

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Prognostic impact of alternative splicing-derived hMENA isoforms in resected, node-negative, non-small-cell lung cancer

Cited by 34 publications

References 35 publications

The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome

The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

Alternative‐splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics

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