Staff member


Joan Montero Boronat

Senior Researcher
Nanobioengineering
jmontero@ibecbarcelona.eu
+34 934 039 956
Staff member publications

Watt, April C., Cejas, Paloma, DeCristo, Molly J., Metzger-Filho, Otto, Lam, Enid Y. N., Qiu, Xintao, BrinJones, Haley, Kesten, Nikolas, Coulson, Rhiannon, Font-Tello, Alba, Lim, Klothilda, Vadhi, Raga, Daniels, Veerle W., Montero, Joan, Taing, Len, Meyer, Clifford A., Gilan, Omer, Bell, Charles C., Korthauer, Keegan D., Giambartolomei, Claudia, Pasaniuc, Bogdan, Seo, Ji-Heui, Freedman, Matthew L., Ma, Cynthia, Ellis, Matthew J., Krop, Ian, Winer, Eric, Letai, Anthony, Brown, Myles, Dawson, Mark A., Long, Henry W., Zhao, Jean J., Goel, Shom, (2021). CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity Nature Cancer 2, 34-48

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that are enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several activator protein-1 transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.

Keywords: Breast cancer, Cancer, Cancer therapy, Epigenetics


Alcon, Clara, Manzano-Muñoz, Albert, Montero, Joan, (2020). A new CDK9 inhibitor on the block to treat hematologic malignancies Clinical Cancer Research 26, (4), 761-763

CDK9-specific inhibition with AZD4573 impairs cancer-promoting gene expression such as MCL-1 and has been proven effective in hematologic malignancies preclinical models. This new clinical candidate should be further explored in the clinic not only as a monotherapy but also in combination with BH3 mimetics to prevent treatment resistance.


Serrat, Neus, Guerrero-Hernández, Martina, Matas-Céspedes, Alba, Yahiaoui, Anella, Valero, Juan G., Nadeu, Ferran, Clot, Guillem, Di Re, Miriam, Corbera-Bellalta, Marc, Magnano, Laura, Rivas-Delgado, Alfredo, Enjuanes, Anna, Beà , Silvia, Cid, Maria C., Campo, ElÃas, Montero, Joan, Hodson, Daniel J., López-Guillermo, Armando, Colomer, Dolors, Tannheimer, Stacey, Pérez-Galán, Patricia, (2020). PI3Kδ inhibition reshapes follicular lymphoma–immune microenvironment cross talk and unleashes the activity of venetoclax Blood Advances 4, (17), 4217-4231

Despite idelalisib approval in relapsed follicular lymphoma (FL), a complete characterization of the immunomodulatory consequences of phosphatidylinositol 3-kinase δ (PI3Kδ) inhibition, biomarkers of response, and potential combinatorial therapies in FL remain to be established. Using ex vivo cocultures of FL patient biopsies and follicular dendritic cells (FDCs) to mimic the germinal center (n = 42), we uncovered that PI3Kδ inhibition interferes with FDC-induced genes related to angiogenesis, extracellular matrix formation, and transendothelial migration in a subset of FL samples, defining an 18-gene signature fingerprint of idelalisib sensitivity. A common hallmark of idelalisib found in all FL cases was its interference with the CD40/CD40L pathway and induced proliferation, together with the downregulation of proteins crucial for B–T-cell synapses, leading to an inefficient cross talk between FL cells and the supportive T-follicular helper cells (TFH). Moreover, idelalisib downmodulates the chemokine CCL22, hampering the recruitment of TFH and immunosupressive T-regulatory cells to the FL niche, leading to a less supportive and tolerogenic immune microenvironment. Finally, using BH3 profiling, we uncovered that FL–FDC and FL–macrophage cocultures augment tumor addiction to BCL-XL and MCL-1 or BFL-1, respectively, limiting the cytotoxic activity of the BCL-2 inhibitor venetoclax. Idelalisib restored FL dependence on BCL-2 and venetoclax activity. In summary, idelalisib exhibits a patient-dependent activity toward angiogenesis and lymphoma dissemination. In all FL cases, idelalisib exerts a general reshaping of the FL immune microenvironment and restores dependence on BCL-2, predisposing FL to cell death, providing a mechanistic rationale for investigating the combination of PI3Kδ inhibitors and venetoclax in clinical trials.


Alcon, Clara, Manzano-Muñoz, Albert, Prada, Estela, Mora, Jaume, Soriano, Aroa, Guillén, Gabriela, Gallego, Soledad, Roma, Josep, Samitier, Josep, Villanueva, Alberto, Montero, Joan, (2020). Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance Cell Death & Disease 11, (8), 634

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 mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We employ this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 pro-survival proteins, defeat resistance and avoid relapse. Indeed, we found that BH3 mimetics that selectively target anti-apoptotic BCL-xL and MCL-1, synergistically enhance the effect of clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft model and observed a reduction in tumor growth with a tendency to stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. We identified the molecular mechanism by which RMS cells acquire resistance to vincristine: an enhanced binding of BID and BAK to MCL-1 after drug exposure, which is suppressed by subsequently adding S63845. Our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for combining BH3 mimetics with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency, and decrease undesired secondary effects.


Almici, Enrico, Caballero, David, Montero, Joan, Samitier, Josep, (2020). 3D neuroblastoma in vitro models using engineered cell-derived matrices Biomaterials for 3D Tumor Modeling (ed. Kundu, Subhas C., Reis, Rui L.), Elsevier (Amsterdam, Netherlands) , 107-130

Neuroblastoma (NB) is a malignant tumor that affects the peripheral nervous system and represents one of the most frequent cancers in infants. Its prognosis is poor in older patients and the presence of genetic abnormalities. Metastasis is often present at the time of diagnosis, making treatment more intensive and unsuccessful. Poor prognosis and variable treatment efficacy require a better understanding of the underlying biology. Evidence has shown that the tumor microenvironment is the characteristic of tumor malignancy and progression. A more highly differentiated tissue phenotype represents a positive prognostic marker, while the tumoral tissue is characterized by a distinct composition and morphology of the extracellular matrix (ECM). In this chapter, we discuss the application of decellularized cell-derived matrices (CDMs) to model in vitro the morphology of the ECM encountered in histological hallmarks of NB patients. This technique allows for the in vitro reproduction of the fine structure and composition of native microenvironments. Because of recent advances in culture systems and decellularization techniques, it is possible to engineer CDM composition and microarchitecture to produce differentiated models of tissue niches. The final goal is to repopulate the “scaffold” with malignant NB cells for drug screening and target discovery applications, studying the impact of patient-inspired tissues on signaling, migration, and tissue remodeling.

Keywords: Neuroblastoma, Cancer, Bioengineering, Tumor microenvironment, Cell-derived matrices, Decellularization


Almici, Enrico, Caballero, David, Montero, Joan, Samitier, Josep, (2020). Engineering cell-derived matrices with controlled 3D architectures for pathophysiological studies Methods in Cell Biology (ed. Caballero, David, Kundu, Subhas C., Reis, Rui Luís), Academic Press (Cambridge, USA) 156, 161-183

The composition and architecture of the extracellular matrix (ECM) and their dynamic alterations, play an important regulatory role on numerous cellular processes. Cells embedded in 3D scaffolds show phenotypes and morphodynamics reminiscent of the native scenario. This is in contrast to flat environments, where cells display artificial phenotypes. The structural and biomolecular properties of the ECM are critical in regulating cell behavior via mechanical, chemical and topological cues, which induce cytoskeleton rearrangement and gene expression. Indeed, distinct ECM architectures are encountered in the native stroma, which depend on tissue type and function. For instance, anisotropic geometries are associated with ECM degradation and remodeling during tumor progression, favoring tumor cell invasion. Overall, the development of innovative in vitro ECM models of the ECM that reproduce the structural and physicochemical properties of the native scenario is of upmost importance to investigate the mechanistic determinants of tumor dissemination. In this chapter, we describe an extremely versatile technique to engineer three-dimensional (3D) matrices with controlled architectures for the study of pathophysiological processes in vitro. To this aim, a confluent culture of “sacrificial” fibroblasts was seeded on top of microfabricated guiding templates to induce the 3D ECM growth with specific isotropic or anisotropic architectures. The resulting matrices, and cells seeded on them, recapitulated the structure, composition, phenotypes and morphodynamics typically found in the native scenario. Overall, this method paves the way for the development of in vitro ECMs for pathophysiological studies with potential clinical relevance.

Keywords: Extracellular matrix, Cell-derived matrix, 3D model, Biomimicry, Anisotropy


Montero, Joan, (2019). The attack of the “seeding” clones Science Translational Medicine 11, (483), eaax0872

Tumor clone tracking in breast cancer xenografts identifies a small subset of circulating tumor cells as “seeders” associated with metastasis.


Montero, J., (2019). Dual oncogene excision is greater than the sum of its parts Science Translational Medicine 11, (491), eaax4876

Ablation of EGFR and c-RAF in combination is effective against aggressive pancreatic tumors.


Montero, J., (2019). Ingestible macromolecule injectors Science Translational Medicine 11, (515), eaaz3720

A next-generation ingestible device uses microneedles for macromolecule administration in the small intestine to avoid subcutaneous injections.


Montero, J., (2019). Modeling endometrial disease using organoids Science Translational Medicine 11, (507), eaaz0304

Organoids generated from patient-derived endometrial tissue model the pathophysiology of endometrial disease and can be used for drug screening.


Montero, J., (2019). P21: One protein to rule cell fate Science Translational Medicine 11, (499), eaay3568

Early p21 expression controls cells’ proliferation/senescence fate after chemotherapy.


Montero, Joan, Gstalder, Cécile, Kim, Daniel J., Sadowicz, Dorota, Miles, Wayne, Manos, Michael, Cidado, Justin R., Paul Secrist, J., Tron, Adriana E., Flaherty, Keith, Stephen Hodi, F., Yoon, Charles H., Letai, Anthony, Fisher, David E., Haq, Rizwan, (2019). Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies Nature Communications 10, (1), 5157

Most targeted cancer therapies fail to achieve complete tumor regressions or attain durable remissions. To understand why these treatments fail to induce robust cytotoxic responses despite appropriately targeting oncogenic drivers, here we systematically interrogated the dependence of cancer cells on the BCL-2 family of apoptotic proteins after drug treatment. We observe that multiple targeted therapies, including BRAF or EGFR inhibitors, rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL-1. This adaptation requires a pathway leading to destabilization of the NOXA mRNA transcript. We find that interruption of this mechanism of anti-apoptotic adaptive resistance dramatically increases cytotoxic responses in cell lines and a murine melanoma model. These results identify NOXA mRNA destabilization/MCL-1 adaptation as a non-genomic mechanism that limits apoptotic responses, suggesting that sequencing of MCL-1 inhibitors with targeted therapies could overcome such widespread and clinically important resistance.

Keywords: Cancer therapeutic resistance, Melanoma, Targeted therapies


Park, D. E., Cheng, J., Berrios, C., Montero, J., Cortés-Cros, M., Ferretti, S., Arora, R., Tillgren, M. L., Gokhale, P. C., DeCaprio, J. A., (2019). Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response Proceedings of the National Academy of Sciences of the United States of America 116, (3), 1027-1032

Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative MCC contains inactivating mutations in TP53 and RB1. While the MCV-truncated LT can bind and inhibit RB, it does not bind p53. We report here that MCV LT binds to RB, leading to increased levels of ARF, an inhibitor of MDM2, and activation of p53. However, coexpression of ST reduced p53 activation. MCV ST recruits the MYC homologue MYCL (L-Myc) to the EP400 chromatin remodeler complex and transactivates specific target genes. We observed that depletion of EP400 in MCV-positive MCC cell lines led to increased p53 target gene expression. We suspected that the MCV ST–MYCL–EP400 complex could functionally inactivate p53, but the underlying mechanism was not known. Integrated ChIP and RNA-sequencing analysis following EP400 depletion identified MDM2 as well as CK1α, an activator of MDM4, as target genes of the ST–MYCL–EP400 complex. In addition, MCV-positive MCC cells expressed high levels of MDM4. Combining MDM2 inhibitors with lenalidomide targeting CK1α or an MDM4 inhibitor caused synergistic activation of p53, leading to an apoptotic response in MCV-positive MCC cells and MCC-derived xenografts in mice. These results support dual targeting of MDM2 and MDM4 in virus-positive MCC and other p53 wild-type tumors.

Keywords: Casein kinase 1 alpha, Lenalidomide, MDM2-MDM4, Merkel cell carcinoma, P53


Stover, Elizabeth H., Baco, Maria B., Cohen, Ofir, Li, Yvonne Y., Christie, Elizabeth L., Bagul, Mukta, Goodale, Amy, Lee, Yenarae, Pantel, Sasha, Rees, Matthew G., Wei, Guo, Presser, Adam G., Gelbard, Maya K., Zhang, Weiqun, Zervantonakis, Ioannis K., Bhola, Patrick D., Ryan, Jeremy, Guerriero, Jennifer L., Montero, Joan, Liang, Felice J., Cherniack, Andrew D., Piccioni, Federica, Matulonis, Ursula A., Bowtell, David D. L., Sarosiek, Kristopher A., Letai, Anthony, Garraway, Levi A., Johannessen, Cory M., Meyerson, Matthew, (2019). Pooled genomic screens identify anti-apoptotic genes as targetable mediators of chemotherapy resistance in ovarian cancer Molecular Cancer Research 17, (11), 2281-2293

High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including BCL2L1 (BCL-XL) and BCL2L2 (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of BCL2L1 decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC.Implications: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.