Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumors.

Pancreatic ductal adenocarcinoma (PDAC) shows limited response to chemotherapy, partly due to the absence of effective biomarkers for personalized treatment. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 90% of PDAC cases, and tumors dependent on KRAS (dKRAS) can be identified using gene expression signature scores. Previous research indicates that dKRAS-PDAC cells are sensitive to decitabine (DEC), an FDA-approved drug for hematological cancers, though its use in solid tumors is limited by side effects.

Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancer.

Background: Tertiary Lymphoid Structures (TLS) correlate with positive outcomes in patients with NSCLC and the efficacy of immune checkpoint blockade (ICB) in cancer. The actin regulatory protein hMENA undergoes tissue-specific splicing, producing the epithelial hMENA linked to favorable prognosis in early NSCLC, and the mesenchymal hMENAΔv6 found in invasive cancer cells and pro-tumoral cancer-associated fibroblasts (CAFs). This study investigates how hMENA isoforms in tumor cells and CAFs relate to TLS presence, localization and impact on patient outcomes and ICB response.

Transcription factors in fibroblast plasticity and CAF heterogeneity.

In recent years, research focused on the multifaceted landscape and functions of cancer-associated fibroblasts (CAFs) aimed to reveal their heterogeneity and identify commonalities across diverse tumors for more effective therapeutic targeting of pro-tumoral stromal microenvironment. However, a unified functional categorization of CAF subsets remains elusive, posing challenges for the development of targeted CAF therapies in clinical settings.The CAF phenotype arises from a complex interplay of signals within the tumor microenvironment, where transcription factors serve as central mediators of various cellular pathways.

Upregulated expression of miR-4443 and miR-4488 in drug resistant melanomas promotes migratory and invasive phenotypes through downregulation of intermediate filament nestin.

Background: BRAF-mutant melanoma patients benefit from the combinatorial treatments with BRAF and MEK inhibitors. However, acquired drug resistance strongly limits the efficacy of these targeted therapies in time. Recently, many findings have underscored the involvement of microRNAs as main drivers of drug resistance.

hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC.

Background: Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN) pathway that may be both detrimental and beneficial. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance.

Strategies for Efficient Targeting of Tumor Collagen for Cancer Therapy.

The tumor stroma, which comprises stromal cells and non-cellular elements, is a critical component of the tumor microenvironment (TME). The dynamic interactions between the tumor cells and the stroma may promote tumor progression and metastasis and dictate resistance to established cancer therapies. Therefore, novel antitumor approaches should combine anticancer and anti-stroma strategies targeting dysregulated tumor extracellular matrix (ECM).

Fibronectin as a multiregulatory molecule crucial in tumor matrisome: from structural and functional features to clinical practice in oncology.

Deciphering extracellular matrix (ECM) composition and architecture may represent a novel approach to identify diagnostic and therapeutic targets in cancer. Among the ECM components, fibronectin and its fibrillary assembly represent the scaffold to build up the entire ECM structure, deeply affecting its features. Herein we focus on this extraordinary protein starting from its complex structure and defining its role in cancer as prognostic and theranostic marker.

The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation.

The dynamic interplay between cancer cells and cancer-associated fibroblasts (CAFs) is regulated by multiple signaling pathways, which can lead to cancer progression and therapy resistance. We have previously demonstrated that hMENA, a member of the actin regulatory protein of Ena/VASP family, and its tissue-specific isoforms influence a number of intracellular signaling pathways related to cancer progression. Here, we report a novel function of hMENA/hMENAΔv6 isoforms in tumor-promoting CAFs and in the modulation of pro-tumoral cancer cell/CAF crosstalk via GAS6/AXL axis regulation.

3D models in the new era of immune oncology: focus on T cells, CAF and ECM.

Immune checkpoint inhibitor therapy has changed clinical practice for patients with different cancers, since these agents have demonstrated a significant improvement of overall survival and are effective in many patients. However, an intrinsic or acquired resistance frequently occur and biomarkers predictive of responsiveness should help in patient selection and in defining the adequate treatment options. A deep analysis of the complexity of the tumor microenvironment is likely to further advance the field and hopefully identify more effective combined immunotherapeutic strategies.

hMENA isoforms impact NSCLC patient outcome through fibronectin/β1 integrin axis.

We demonstrated previously that the splicing of the actin regulator, hMENA, generates two alternatively expressed isoforms, hMENA and hMENAΔv6, which have opposite functions in cell invasiveness. Their mechanisms of action have remained unclear. Here we report two major findings: (i) hMENA regulates β1 integrin expression.

hMENA is a key regulator in endothelin-1/β-arrestin1-induced invadopodial function and metastatic process.

Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by β-arrestin1 (β-arr1)-driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of β-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression.

Deciphering the loop of epithelial-mesenchymal transition, inflammatory cytokines and cancer immunoediting.

Tumorigenesis and tumor progression relies on the dialectics between tumor cells, the extracellular matrix and its remodelling enzymes, neighbouring cells and soluble cues. The host immune response is crucial in eliminating or promoting tumor growth and the reciprocal coevolution of tumor and immune cells, during disease progression and in response to therapy, shapes tumor fate by activating innate and adaptive mechanisms. The phenotypic plasticity is a common feature of epithelial and immune cells and epithelial-mesenchymal transition (EMT) is a dynamic process, governed by microenvironmental stimuli, critical in tumor cell shaping, increased tumor cell heterogeneity and stemness.

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

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 hMENA, 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-hMENA antibodies, in 285 PDACs, 15 PanINs, 10 pancreatitis, and normal pancreas.

Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis.

Background: We have previously shown that in pancreatic ductal adenocarcinoma (PDA) cells, the glycolytic enzyme alpha-enolase (ENO1) also acts as a plasminogen receptor and promotes invasion and metastasis formation. Moreover, ENO1 silencing in PDA cells induces oxidative stress, senescence and profoundly modifies PDA cell metabolism. Although anti-ENO1 antibody inhibits PDA cell migration and invasion, little is known about the role of ENO1 in regulating cell-cell and cell-matrix contacts.

hMENA(11a), a hMENA isoform sending survival signals.

Human MENA(11a) (hMENA(11a)), an epithelial-associated isoform of the actin binding protein enabled homolog (ENAH, also known as mammalian ENA [MENA]), is upregulated and phosphorylated following the activation of human epidermal growth factor receptor (HER) 1, HER2, and HER3. Here, we reveal a novel role of this isoform in sustaining cell survival and propose hMENA(11a) as a marker of HER3 activation and resistance to phosphatidylinositol-3-kinase inhibition therapies.

β1 and β4 integrins: from breast development to clinical practice.

Following a highly dynamic and complex dialogue between the epithelium and the surrounding microenvironment, the mammary gland develops into a branching structure during puberty, buds during pregnancy, forms intricate polar acini during lactation and, once the babies are weaned, remodels and involutes. At every stage of menstrual and pregnancy cycles, interactions between the cells and the extracellular matrix (ECM) and homotypic and heterotypic cell–cell interactions give rise to the architecture and function of the gland at that junction. These orchestrated programs would not be possible without the important role of the ECM receptors, integrins being the prime examples.

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

Risk assessment and treatment choice remain a challenge in early non-small-cell lung cancer (NSCLC). Alternative splicing is an emerging source for diagnostic, prognostic and therapeutic tools. Here, we investigated the prognostic value of the actin cytoskeleton regulator hMENA and its isoforms, hMENA11a and hMENAΔv6, in early NSCLC.

Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors.

Human mena (hMENA), a member of the actin cytoskeleton regulators Ena/VASP, is overexpressed in high-risk preneoplastic lesions and in primary breast tumors and has been identified as playing a role in invasiveness and poor prognosis in breast cancers that express HER2. Here we identify a unique isoform, hMENAΔv6, derived from the hMENA alternative splicing program. In an isogenic model of human breast cancer progression, we show that hMENA(11a) is expressed in premalignant cells, whereas hMENAΔv6 expression is restricted to invasive cancer cells.

Molecular and genetic bases of pancreatic cancer.

Pancreatic cancer remains a formidable challenge for oncologists and patients alike. Despite intensive efforts, attempts at improving survival in the past 15 years, particularly in advanced disease, have failed. This is true even with the introduction of molecularly targeted agents, chosen on the basis of their action on pathways that were supposedly important in pancreatic cancer development and progression: indeed, with the notable exception of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, that has provided a minimal survival improvement when added to gemcitabine, other agents targeting EGFR, matrix metallo-proteases, farnesyl transferase, or vascular endothelial growth factor have not succeeded in improving outcomes over standard gemcitabine monotherapy for a variety of different reasons.

The cooperation between hMena overexpression and HER2 signalling in breast cancer.

hMena and the epithelial specific isoform hMena(11a) are actin cytoskeleton regulatory proteins belonging to the Ena/VASP family. EGF treatment of breast cancer cell lines upregulates hMena/hMena(11a) expression and phosphorylates hMena(11a), suggesting cross-talk between the ErbB receptor family and hMena/hMena(11a) in breast cancer. The aim of this study was to determine whether the hMena/hMena(11a) overexpression cooperates with HER-2 signalling, thereby affecting the HER2 mitogenic activity in breast cancer.

Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo.

We have studied the gene expression pattern of invasive primary mammary tumor cells using a unique in vivo invasion assay that isolates the invasive tumor cells by chemotaxis. One of the genes upregulated in the invasive tumor cells is Mena, an actin binding protein involved in the regulation of cell motility. There are multiple known splice variants of Mena accounted for by four alternatively included exons, +, ++, +++ and 11a.

Human Mena+11a isoform serves as a marker of epithelial phenotype and sensitivity to epidermal growth factor receptor inhibition in human pancreatic cancer cell lines.

Purpose: hMena, member of the enabled/vasodilator-stimulated phosphoprotein family, is a cytoskeletal protein that is involved in the regulation of cell motility and adhesion. The aim of this study was to determine whether or not the expression of hMena isoforms correlated with sensitivity to EGFR tyrosine kinase inhibitors and could serve as markers with potential clinical use.

Experimental Design: Human pancreatic ductal adenocarcinoma cell lines were characterized for in vitro sensitivity to erlotinib, expression of HER family receptors, markers of epithelial to mesenchymal transition, and expression of hMena and its isoform hMena(+11a).

Molecular cloning of hMena (ENAH) and its splice variant hMena+11a: epidermal growth factor increases their expression and stimulates hMena+11a phosphorylation in breast cancer cell lines.

hMena (ENAH), an actin regulatory protein involved in the control of cell motility and adhesion, is modulated during human breast carcinogenesis. In fact, whereas undetectable in normal mammary epithelium, hMena becomes overexpressed in high-risk benign lesions and primary and metastatic tumors. In vivo, hMena overexpression correlates with the HER-2(+)/ER(-)/Ki67(+) unfavorable prognostic phenotype.

The cytoskeleton regulatory protein hMena (ENAH) is overexpressed in human benign breast lesions with high risk of transformation and human epidermal growth factor receptor-2-positive/hormonal receptor-negative tumors.

Purpose: hMena (ENAH), a cytoskeleton regulatory protein involved in the regulation of cell motility and adhesion, is overexpressed in breast cancer. The aim of this study was to define at what stage of breast carcinogenesis hMena is overexpressed and to correlate hMena overexpression with established prognostic factors in breast cancer, focusing on human epidermal growth factor receptor-2 (HER-2).

Experimental Design: hMena expression was assessed immunohistochemically in a prospective cohort of cases (n = 360) encompassing a highly representative spectrum of benign breast diseases associated with different risk of transformation, in situ, invasive, and metastatic tumors.

Human Mena protein, a serex-defined antigen overexpressed in breast cancer eliciting both humoral and CD8+ T-cell immune response.

Screening of a cDNA expression library from a primary breast tumor with the autologous patient serum led to the isolation of 6 cDNA clones corresponding to 3 different genes, including a novel gene that maps to chromosome 1 and encodes the human homologue of mouse Mena (hMena, cDNA clone RMNY-BR-55), a protein of the Ena/VASP family involved in the regulation of cell motility and adhesion. A cancer-restricted antibody response against hMena was demonstrated, since 18/93 cancer patient sera, the majority (10/52) from breast cancer, showed anti-hMena-specific IgG, while no antibodies were present in healthy donors. When hMena protein expression was analyzed by Western blot and immunohistochemistry, the antigen was overexpressed in the majority of breast cancer cell lines and in 75% of primary breast tumor lesions evaluated.