Our lab focuses on the basic mechanisms that control cell differentiation and proliferation, and their implications in pathology. We are interested in deciphering the mechanisms that drive tumour cell proliferation, with a patient-focused perspective, and the therapeutic opportunities of inhibiting the activity of critical cell cycle regulators in cancer.
Over the last two decades, advances in cancer research have led to the approval of inhibitors of specific cell cycle regulators (cyclin-dependent kinases 4 and 6; CDK4/6) in breast cancer therapy. CDK4/6 blockade, along with hormonotherapy, is the current standard of care in advanced estrogen receptor-positive breast cancer. However, most metastatic tumors develop resistance, and these inhibitors are not effective in the treatment of other tumor types. Intriguingly, despite extensive cell cycle analysis in the last few years, we still do not understand how cells drive the cell cycle in the absence of CDK4/6 activity.
CDK4/6 inhibitors exemplify the use of cell cycle-targeted therapies in the clinic. But what is next? First, we are interested in understanding the mechanisms of resistance to CDK4/6-targeted therapies, or in other words, how cells manage to continue proliferating in the absence of these kinases. Investigating the differences between these two kinases, CDK4 and CDK6, may also be critical in improving the use of these inhibitors in other tumor types. Next, there are 20 members of the CDK family and the relative dependence of tumor cells on most of the other family members remains unclear. Cell cycle control involves many other enzymatic activities beyond CDKs, offering many additional possibilities in several pathologies including breast, gynecological, lung, colorectal and pedriatic cancers for detailed investigation in the future.
In addition to generating knowledge and evaluating novel therapeutic strategies, our group is interested in advancing the use of novel technologies to monitor tumor evolution, especially in response to clinical treatments. We are currently exploring the use of single-cell genomic and transcriptomic studies to better understand mechanisms of sensitivity and resistance to available therapies. Performing these studies in liquid biopsies and circulating tumor molecules and tumor cells will facilitate the identification of key therapeutically actionable mechanisms, taking advantage of the accumulated insights generated by basic science and discovery.
- Understand how the balance between proliferation and quiescence or senescence is controlled in physiological conditions.
- Advance insights into the mechanisms of resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors: biomarkers and combinatorial therapies.
- Evaluate novel therapeutic approaches based on unconventional CDKs.
- Assess core cell cycle and DNA damage-targeted therapies for patients in progression to current standard-of-care treatments.
- Develop pipelines for monitoring how tumor and immune cells co-evolve in real time in response to cancer treatments.
Group Leader
Marcos Malumbres
Senior Scientist
Begoña Hurtado
Postdoctoral scientists
Isabel García Cao
Alexis Pérez
Research Assistants
María Catalán
Sandra Díez Ribas
Lab Manager
Lidia Pérez
Graduate Students
Gloria C. Bonel
Mariona Cubells
Fátima Guerra
Luis R. López
Enrique Nogueira
Bioinformatician
Agustín Sánchez Belmonte
Most relevant publications 2023
- Villarroya-Beltri C, Martins AFB, García A, Giménez D, Zarzuela E, Novo M, Del Álamo C, González-Martínez J, Bonel-Pérez GC, Díaz I, Guillamot M, Chiesa M, Losada A, Graña-Castro O, Rovira M, Muñoz J, Salazar-Roa M, Malumbres M. Mammalian CDC14 phosphatases control exit from stemness in pluripotent cells. EMBO J. 2023 Jan 4;42(1):e111251.
- Sanz-Castillo B, Hurtado B, Vara-Ciruelos D, El Bakkali A, Hermida D, Salvador-Barbero B, Martínez-Alonso D, González-Martínez J, Santiveri C, Campos-Olivas R, Ximénez-Embún P, Muñoz J, Álvarez-Fernández M, Malumbres M. The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner. EMBO J. 2023 Jan 16;42(2):e110833.
- Olivera-Salguero R, Seguí E, Cejalvo JM, Oliveira M, Tolosa P, Vidal M, Malumbres M, Gavilá J, Saura C, Pernas S, López R, Margelí M, Balmaña J, Muñoz M, Blancas I, Boni V, Ciruelos E, Galve E, Perelló A, Sánchez-Bayona R, de la Cruz S, de la Hoya M, Galván P, Sanfeliu E, Gonzalez-Farre B, Sirenko V, Blanch-Torras A, Canes J, Masanas H, Olmos R, Forns M, Prat A, Casas A, Pascual T. HOPE (SOLTI-1903) breast cancer study: real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer. Front Oncol. 2023 Apr 28;13:1151496.
- Martínez-Illescas NG, Leal S, González P, Graña-Castro O, Muñoz-Oliveira JJ, Cortés-Peña A, Gómez-Gil M, Vega Z, Neva V, Romero A, Quintela-Fandino M, Ciruelos E, Sanz C, Aragón S, Sotolongo L, Jiménez S, Caleiras E, Mulero F, Sánchez C, Malumbres M, Salazar-Roa M. miR-203 drives breast cancer cell differentiation. Breast Cancer Res. 2023 Aug 4;25(1):91.
All Publications
- Villarroya-Beltri C, Martins AFB, García A, Giménez D, Zarzuela E, Novo M, Del Álamo C, González-Martínez J, Bonel-Pérez GC, Díaz I, Guillamot M, Chiesa M, Losada A, Graña-Castro O, Rovira M, Muñoz J, Salazar-Roa M, Malumbres M. (2023) Mammalian CDC14 phosphatases control exit from stemness in pluripotent cells. EMBO J. 42, e111251. doi: 10.15252/embj.2022111251. [PMID: 36326833]
- Sanz-Castillo B, Hurtado B, Vara-Ciruelos D, El Bakkali A, Hermida D, Salvador-Barbero B, Martínez-Alonso D, González-Martínez J, Santiveri C, Campos-Olivas R, Ximénez-Embún P, Muñoz J, Álvarez-Fernández M, Malumbres M. (2023) The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner. EMBO J. 42, e110833. doi: 10.15252/embj.2022110833. [PMID: 36354735]
- Olivera-Salguero R, Seguí E, Cejalvo JM, Oliveira M, Tolosa P, Vidal M, Malumbres M, Gavilá J, Saura C, Pernas S, López R, Margelí M, Balmaña J, Muñoz M, Blancas I, Boni V, Ciruelos E, Galve E, Perelló A, Sánchez-Bayona R, de la Cruz S, de la Hoya M, Galván P, Sanfeliu E, Gonzalez-Farre B, Sirenko V, Blanch-Torras A, Canes J, Masanas H, Olmos R, Forns M, Prat A, Casas A*, Pascual T* (2023) HOPE (SOLTI-1903) Breast Cancer Study: Real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer. Front Oncol 13:1151496. [PMID: 37188177]
- Martínez-Illescas NG, Leal S, González P, Graña-Castro O, Muñoz-Oliveira JJ, Cortés-Peña A, Gómez-Gil M, Vega Z, Neva V, Romero A, Quintela-Fandino M, Ciruelos E, Sanz C, Aragón S, Sotolongo L, Jiménez S, Caleiras E, Mulero F, Sánchez C*, Malumbres M*, Salazar-Roa M*. (2023) miR-203 drives breast cancer cell differentiation. Breast Cancer Res 25:91. doi: 10.1186/s13058-023-01690-9. [PMID: 37542268]
- Frontiñán-Rubio J, Llanos-González E, García-Carpintero S, Peinado JR, Ballesteros-Yáñez I, Rayo MV, de la Fuente J, Pérez-García VM, Perez-Romasanta LA, Malumbres M, Alcaín FJ, Durán-Prado M. (2023) CoQ10 reduces glioblastoma growth and infiltration through proteome remodeling and inhibition of angiogenesis and inflammation. Cell Oncol 46, 65-77. doi: 10.1007/s13402-022-00734-0. [PMID: 36319818]
- Dhital B, Santasusagna S, Kirthika P, Xu M, Li P, Carceles-Cordon M, Soni RK, Li Z, Hendrickson RC, Schiewer MJ, Kelly WK, Sternberg CN, Luo J, Lujambio A, Cordon-Cardo C, Alvarez-Fernandez M, Malumbres M, Huang H, Ertel A, Domingo-Domenech J, Rodriguez-Bravo V. (2023) Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer. Cell Rep Med. 4, 100937. doi: 10.1016/j.xcrm.2023.100937. [PMID: 36787737]
- Mouron S, Bueno MJ, Muñoz M, Torres R, Rodríguez S, Apala JV, Silva J, Sánchez-Bayona R, Manso L, Guerra J, Rodriguez-Lajusticia L, Malon D, Malumbres M, Quintela-Fandino M. (2023) p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer. JNCI Cancer Spectr. Feb 20:pkad014. doi: 10.1093/jncics/pkad014. [PMID: 36806942]
- Sayago C, Sánchez-Wandelmer J, García F, Hurtado B, Lafarga V, Prieto P, Zarzuela E, Ximénez-Embún P, Ortega S, Megías D, Fernández-Capetillo O, Malumbres M, Munoz J. (2023) Decoding protein methylation function with thermal stability analysis. Nat Commun. 14, 3016. [PMID: 37230995] doi: 10.1038/s41467-023-38863-1.
- Baldrighi, M., Doreth, C., Li, Y., Zhao, X., Warner, E., Chenoweth, H., Kishore, K., Umrania, Y., Minde, D.P., Thome, S., Yu, X., Lu, Y., Knapton, A., Harrison, J., Clarke, M., Latz, E., de Carcer, G., Malumbres, M., Ryffel, B., Bryant, C., Liu, J., Lilley, K.S., Mallat, Z., Li, X. (2023) PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models. J Clin Invest 133, e162129. [PMID: 37698938]
HOPE (SOLTI-1903) breast cancer study: real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer. Olivera-Salguero R, Seguí E, Cejalvo JM, Oliveira M, Tolosa P, Vidal M, Malumbres M, Gavilá J, Saura C, Pernas S, López R, Margelí M, Balmaña J, Muñoz M, Blancas I, Boni V, Ciruelos E, Galve E, Perelló A, Sánchez-Bayona R, de la Cruz S, de la Hoya M, Galván P, Sanfeliu E, Gonzalez-Farre B, Sirenko V, Blanch-Torras A, Canes J, Masanas H, Olmos R, Forns M, Prat A, Casas A, Pascual T. Front Oncol. 2023 Apr 28;13:1151496. doi: 10.3389/fonc.2023.1151496. eCollection 2023.https://pubmed.ncbi.nlm.nih.gov/37188177/
Decoding protein methylation function with thermal stability analysis.Sayago C, Sánchez-Wandelmer J, García F, Hurtado B, Lafarga V, Prieto P, Zarzuela E, Ximénez-Embún P, Ortega S, Megías D, Fernández-Capetillo O, Malumbres M, Munoz J. Nat Commun. 2023 May 25;14(1):3016. doi: 10.1038/s41467-023-38863-1.https://pubmed.ncbi.nlm.nih.gov/37230995/
(2023) Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer. Cell Rep Med. Feb 7:100937. [Pubmed]
Mouron S, Bueno MJ, Muñoz M, Torres R, Rodríguez S, Apala JV, Silva J, Sánchez-Bayona R, Manso L, Guerra J, Rodriguez-Lajusticia L, Malon D, Malumbres M, Quintela-Fandino M. p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer. JNCI Cancer Spectr. 2023 Mar 1;7(2):pkad014. doi: 10.1093/jncics/pkad014. PMID: 36806942; PMCID: PMC10035773.
(all of them are also here: https://malumbreslab.org/publications/)
Targeting CDK16-18 as a novel strategy against aggressive cancers (neoCDK)
PI: M. Malumbres.
A new platform to predict response to CDK4/6 inhibitors in metastatic breast cancer patients
Reference: DTS21/00132
Ministerio de Ciencia e Innovación
Award Period: 01/2022-12/2023.
PI: M. Malumbres.
Therapeutic evaluation of the Cdk14-18 subfamily in advanced breast cancer (breastCDKS)
Reference: PID2021-128726OB-I00
Ministerio de Ciencia, Innov. y Univ.
Award Period: 1/2022-31/2024
IP: M. Malumbres.
Implementing CDK16-18 targeted therapies for cancer treatment
PDC2022-133408-I00
Ministerio de Ciencia, Innov. y Univ.
Award Period: 1/2023-31/2024
IP: M. Malumbres.
Balancing cell proliferation and differentiation: mechanisms and relevance in human disease
Títle: Predictive spatial transcriptomics to identify minimal residual in ER+ HER2 – breast cancer
Grantor: Asociación de Cancer de Mama Metastásico.
Duration: 1/12/2023-30/11/2025
PI: Marcos Malumbres
