Alberto Villanueva

• Bellvitge Biomedical Research Institute

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the sam...

Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT 1 ) antagonist, alters UM cancer hallmarks in vitro, ex vivo a...

Double strand brakes (DSB) accumulate in cellular DNA as a result of deficiences in homologous recombination repair systems, such as mutations in BRCA genes, or upon antitumoral treatments. In the present study we show that the accumulation of DSB, regardless of its origins, leads to a shift towards oxidative metabolism. We have identified that DSB...

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heteroge...

Activation of the IκB kinase (IKK) complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF‐κB has remained elusive. Here, analysis of IKK‐dependent substrates in CRC cells after UV treatment revealed that phosphorylation of BRD4 by IKK‐α is required for...

Inflammatory signals are key in development and cell differentiation but their orchestration with pluripotency and stemness signals is poorly understood. Our previous work identified a chromatin function of IκBα, the NF-κB inhibitor, that is crucial for differentiation in different types of somatic stem cells. Here we demonstrate that deficiency of...

Activation of the IKK kinase complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-κB has remained elusive. Analysis of IKK-dependent substrates after UV-treatment revealed that BRD4 phosphorylation by IKKα is required for chromatin-binding dynamics u...

Cyclin-dependent kinases (CDKs), together with their cyclin partners, are the master cell cycle regulators. Remarkably, the cyclin family was extended to include atypical cyclins, characterized by distinctive structural features, but their partner CDKs remain elusive. Here, we conducted a yeast two-hybrid screen to identify new atypical cyclin-CDK...

Background RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. Methods Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cance...

Neurofibromas are benign peripheral nervous system tumors associated with neurofibromatosis type 1, which originate from NF1(-/-) Schwann cell precursors. We describe a protocol to generate neurofibromaspheres by differentiating NF1(-/-) Schwann cells from induced pluripotent stem cells and combining them with neurofibroma primary fibroblasts. We a...

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity of such aberrant signaling. While inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same p...

Background: Colorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-s...

Uveal melanoma (UM) is an intraocular cancer with propensity for liver metastases. The median overall survival (OS) for metastatic UM (MUM) is 1.07 years, with a reported range of 0.84–1.34. In primary UM, high cysteinyl leukotriene receptor 1 (CysLT1) expression associates with poor outcomes. CysLT1 antagonists, quininib and 1,4-dihydroxy quininib...

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer (EC), characterized by its high propensity for metastases. In fact, while endometrioid endometrial carcinoma (EEC), which accounts for 85% of EC, presents a good prognosis, USC is the most frequently fatal. Herein, we used for the first time a peptide‐based tyrosine‐kinase‐a...

Background: Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are s...

Clinical management of endometrial cancer (EC) is handicapped by the limited availability of second line treatments and bona fide molecular biomarkers to predict recurrence. These limitations have hampered the treatment of these patients, whose survival rates have not improved over the last four decades. The advent of coordinated studies such as Th...

Activation of the IKK kinase complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-kB has remained elusive. Analysis of IKK-dependent substrates after UV-treatment revealed that BRD4 phosphorylation by IKKa is required for chromatin-binding dynamics u...

Activation of the IKK kinase complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-kB has remained elusive. Analysis of IKK-dependent substrates after UV-treatment revealed that BRD4 phosphorylation by IKKa is required for chromatin-binding dynamics u...

BACKGROUND Colorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-spe...

Genetic inactivation in specific SWI/SNF complex members induce sensitivity to the inhibition of KDM6A/UTX and KDM6B/JMJD3 in cancer. Despite the genetic inactivation of the tumor suppressor SMARCA4 is frequently found in cancer, there are no therapies that effectively target SMARCA4-deficient tumors. In our previous work, we reported that unlike t...

Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy...

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas that are the leading cause of mortality in Neurofibromatosis type 1 (NF1) patients. Single chemotherapeutic agents have shown response rates ranging from 18-44% in clinical trials, so there is still a high medical need to identify chemotherapeutic combination treatments that...

Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than...

Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we use C. elegans to explore cisplatin effects on mitochondrial functions and investigate cispla...

Plexiform neurofibromas (pNFs) are developmental tumors that appear in neurofibromatosis type 1 individuals, constituting a major source of morbidity and potentially transforming into a highly metastatic sarcoma (MPNST). pNFs arise after NF1 inactivation in a cell of the neural crest (NC)-Schwann cell (SC) lineage. Here, we develop an iPSC-based NC...

Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) kn...

Despite the use of multimodal therapies, the treatment of high-risk neuroblastoma remains a major challenge. In our study, we aimed to target highly proliferative and aggressive tumor cells with a distinct inhibitor against KIF11, a mitotic-specific kinesin, which is essential for cell division. KIF11 has been proven to be a therapeutic target in m...

Recent technological advances and the application of high-throughput mutation and transcriptome analyses have improved our understanding of cancer diseases, including non-small cell lung cancer. For instance, genomic profiling has allowed the identification of mutational events which can be treated with specific agents. However, detection of DNA al...

There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. Based on publicly available transcriptomic data of MPM, patients with CDK4 or...

Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy in advanced stages. Chemotherapy has not demonstrated its efficacy in MM and current treatment for tumors carrying the most frequent BRAFV600E mutation consists of BRAF inhibitors alone or in combination with MAPK pathway inhibitors. We previously found that BRAF inhib...

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas with poor prognosis, developing either sporadically or in persons with neurofibromatosis type 1 (NF1). Loss of CDKN2A/B is an important early event in MPNST progression. However, many reported MPNSTs exhibit partial or no inactivation of CDKN2A/B, raising the quest...

Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading...

Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we take advantage of C. elegans to explore cisplatin effects on mitochondrial functions and inve...

Extramedullary multiple myeloma (EMM) has an overall survival of 6 months and occurs in 20% of multiple myeloma (MM) patients. Genetic and epigenetic mechanisms involved in EMM and the therapeutic role of new agents for MM are not well established. Besides, well characterized preclinical models for EMM are not available. Herein, a patient derived o...

Simple Summary Small-cell lung cancer accounts for approximately 13% of all new lung cancer diagnoses, but in contrast to non-small-cell lung cancer, the implementation of targeted treatments in small-cell lung cancer has been limited, with little improvement in the clinical outcome in the last several decades. Exploring new pathways for targeted t...

Current therapy against colorectal cancer is based on DNA-damaging agents that eradicate highly proliferative malignant cells. Whether sublethal chemotherapy affects tumor cell behavior and impacts on patient outcome is primarily unstudied. We now show that sublethal chemotherapy imposes a quiescent-like state to p53 wildtype human colorectal cance...

There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. Here, we investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK...

Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs)...

Purpose: Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with advanced and metastatic cSCC patients. Here, we analyze the molecular tr...

Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading...

Simple Summary This research investigates the disease relevance and therapeutic potential of cysteinyl leukotriene receptors in uveal melanoma (UM), a rare eye cancer that often spreads to the liver. Unfortunately, there are no therapies available to stop the spread of UM and patients are often faced with an extremely poor prognosis. We assess whet...

Background & Aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for pati...

Uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients...

p>Counteracting high failure rates in oncology drug development and improving therapeutic management of cancer patients requires preclinical models that can account for the complexity and heterogeneity of human tumors. Patient-derived cancer xenografts (PDXs) maintain histopathological features and genetic profiles of the original patient tumors an...

Significance Defects in transfer RNA (tRNA) modifications occur in human pathologies such as cancer; however, how these alterations contribute to the disease is poorly understood. One example is the tumor-specific hypomodification of position 37 of tRNA Phe , which was first described 45 y ago, although its cause and consequences have remained unkn...

Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading...

Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive biomarkers are needed for better patient stratification and for the identification of new therapeutic strategies,...

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers impairs the development of new therapies. Here, we utilize dynamic BH3 profiling (DBP), a functional predictive biomarker that measures net changes in...

Background The aim of this study was to test the feasibility and utility of developing patient-derived orthotopic xenograft (PDOX) models for patients with malignant peripheral nerve sheath tumors (MPNSTs) to aid therapeutic interventions in real time. Patient & Methods A sporadic relapsed MPNST developed in a 14-year-old boy was engrafted in mice...

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing...

Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidat...

Colorectal cancers (CRCs) are composed of an amalgam of cells with distinct genotypes and phenotypes. Here, we reveal a previously unappreciated heterogeneity in the biosynthetic capacities of CRC cells. We discover that the majority of ribosomal DNA transcription and protein synthesis in CRCs occurs in a limited subset of tumor cells that localize...

To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and LM for four clinically relevant CRC gene signatures. Twenty‐seven fresh and 55 formalin‐fixed paraffin‐embed...

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis, that combined with the lack of specific biomarkers difficult the development of new therapies. We here utilize dynamic BH3 Profiling (DBP), a functional predictive biomarker that measures net changes...

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RN...

Human tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost nothing is known about the contribution of distorte...

Retroviral gene transfer of interleukin-12 (IL-12) into T cells markedly enhances antitumor efficacy upon adoptive transfer but has clinically shown unacceptable severe side effects. To overcome the toxicity, we engineered tumor-specific CD8+ T cells to transiently express IL-12. Engineered T cells injected intratumorally, but not intravenously, le...

Targeted cancer drugs often elicit powerful initial responses, but generally fail to deliver long-term benefit due to the emergence of resistant cells. This is thought to be the consequence of strong selective pressure exerted on the cancer drug target by a Maximum Tolerated Dose (MTD) of a drug. We hypothesized that partial inhibition of multiple...

Background Resistance to androgen receptor signaling is arguably the principal hallmark of lethal prostate cancer. Several mechanisms account for this resistance, including mutations in the AR, restoration of signaling downstream of the pharmacological blocking and activation of alternative oncogenic pathways. Methods We used the Nkx3.1CreERT2/+;...

One largely unknown question in cell biology is the discrimination between inconsequential and functional transcriptional events with relevant regulatory functions. Here, we find that the oncofetal HMGA2 gene is aberrantly reexpressed in many tumor types together with its antisense transcribed pseudogene RPSAP52. RPSAP52 is abundantly present in th...

Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibito...

Phosphorylated IKKα(p45) is a nuclear active form of the IKKα kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-κB signaling. Insights into the sources of IKKα(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKα(p45) is rapidly act...

Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibito...

Purpose: The aim of the study is blocking the recruitment of a protective stroma by altering the crosstalk between normal stromal cells and tumor cells for stripping tumors of the protection conferred by the microenvironment. Methods: A transcriptomic analysis of cocultured normal colonic fibroblasts and colorectal tumor cells was performed. We foc...

The endoplasmic reticulum (ER) of cancer cells needs to adapt to the enhanced proteotoxic stress associated with the accumulation of unfolded, misfolded and transformation-associated proteins. One way by which tumors thrive in the context of ER stress is by promoting ER-Associated Degradation (ERAD), although the mechanisms are poorly understood. H...

Uveal melanoma is a rare, but deadly, form of eye cancer that arises from melanocytes within the uveal tract. Although advances have emerged in treatment of the primary tumour, patients are still faced with vision loss, eye enucleation and lethal metastatic spread of the disease. Approximately 50% of uveal melanoma patients develop metastases, whic...

Endometrial cancer (EC) is the most common malignancy of the genital tract among women in developed countries. Recently, a molecular classification of EC has been performed providing a system that, in conjunction with histological observations, reliably improves EC classification and enhances patient management. Patient-derived xenograft models (PD...

Colorectal cancer (CRC) is one of the most common cancers worldwide, with 8-10% of these tumours presenting a BRAF (V600E) mutation. Cyclins are known oncogenes deregulated in many cancers, but the role of the new subfamily of atypical cyclins remains elusive. Here we have performed a systematic analysis of the protein expression levels of eight at...

Delta ligands regulate Notch signaling in normal intestinal stem cells, while Jagged1 activates Notch in intestinal adenomas carrying active β-catenin. We used the ApcMin/+ mouse model, tumor spheroid cultures, and patient-derived orthoxenografts to address this divergent ligand-dependent Notch function and its implication in disease. We found that...

RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3. Inhibition of the RAS oncoproteins has proven difficult 4 , and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms 8 . It is also well established that KRAS-...

p>Counteracting high attrition rates in anticancer drug development and providing optimal therapeutic management of cancer patients require preclinical models that properly recapitulate the complexity and diversity of human tumours. Patient-derived cancer xenografts (PDXs), developed by transplanting human tumor fragments into immunodeficient mice,...

Dormant or slow-cycling tumour cells can form a residual chemoresistant reservoir responsible for relapse in patients, years after curative surgery and adjuvant therapy. We have adapted the pulse-chase expression of H2BeGFP for labelling and isolating slow-cycling cancer cells (SCCC). SCCC showed cancer-initiation potential and enhanced chemoresist...

Noncoding RNAs (ncRNAs), such as microRNAs and long noncoding RNAs (lncRNAs), participate in cellular transformation. Work done in the last decade has also demonstrated that ncRNAs with growth-inhibitory functions can undergo promoter CpG island hypermethylation-associated silencing in tumorigenesis. Herein, we wondered whether circular RNAs (circR...

Introduction Targeted cancer drugs elicit powerful initial responses but far less long-term benefits. The emergence of therapy resistance often involves the reactivation of the same pathway that is being blocked by the cancer drug. Our group and others have shown that inhibiting multiple nodes of the same activated signalling pathway provides longe...

Introduction NUP98 has numerous partner genes of which plant homeodomain (PHD) finger protein 23 (PHF23) fusion with NUP98 (NP23) can be detected by RT-PCR in patients with cytogenetically normal acute myelogenous leukaemia (AML). In this fusion transcript of NP23 plant homeodomain (PHD) of PHF23 is known to specifically bind H3K4me3 residues and a...