Molecular Mechanisms of Cancer Program

Our research focuses on understanding how GTPase-driven signaling networks contribute to cancer initiation and progression, as well as on identifying novel therapeutic targets using integrated computational and experimental approaches.

During this period, we have made significant advances in defining R-RAS2, a RAS-related GTPase, as a clinically relevant oncogenic driver. We demonstrated its role across multiple tumor types, including aggressive settings such as triple-negative breast cancer. Importantly, we also showed that wild-type R-RAS2 can drive tumorigenesis, revealing non-mutational mechanisms of oncogenic activation with important conceptual and therapeutic implications.

We have also uncovered previously unrecognized regulatory mechanisms controlling R-RAS2 activity, including its direct activation by antigen receptor complexes. In addition, we demonstrated that active R-RAS2 can functionally substitute for canonical RAS proteins, reshaping current models of RAS pathway organization.

In parallel, we identified new metabolic dependencies in cancer, such as the role of the mevalonate pathway in breast cancer growth and metastasis. We demonstrated that this pathway is regulated in this cancer cell subtype through a novel mechanism involving the VAV–RAC1 signaling axis. At the systems level, our pan-cancer analyses revealed new oncogenic drivers and actionable vulnerabilities within the RHO GTPase signaling landscape. These findings have been complemented by mechanistic studies on VAV proteins, linking signaling, proliferation, and ribosome biogenesis.

Our work has strong translational potential, providing a framework for the development of targeted therapies against RAS and RHO pathway components. This effort is reinforced by active collaborations and participation in multidisciplinary initiatives.

Total publications

10

Mean IF

12

% Q1

90

% D1

40

% CA/MA

50

% OA

100

The group is interested in understanding the main mechanisms that drive or block ribosome synthesis in mammalian cells under both normal and pathological conditions. In the past two years we have been working on several projects whose results have been already publsied or will soon be published. In one study we deciphered the oncogenic signalling pathways that activate ribosome production in oral squamous cell carcinoma (Scientific Reports, 2024); in another one we unveiled how different ribosome biogenesis defects selectively affect the ATF4-mediated stress responses that might contribute to the variable penetrance and phenotypes in the ribosomopathy Diamond-Blackfan anemia (iScience, 2025), and in another study we have demonstrated that very different lesions that lead to defects in 40 ribosomal subunit maturation converge in the accumulations of aberrant subnucleolar condensates that cause major alterations of nuclear proteostasis, a common moelcular alteration to ribosompathies not previously accounted for (manuscript to be published in 2026). We have also participated, as collaborators, in one published studies about R-RAS2, a transforming GTPase that regulates protein translation.

Total publications

2

Mean IF

4

% Q1

100

% D1

0

% CA/MA

100

% OA

100

Our laboratory focuses on the identification of novel therapeutic vulnerabilities for KRAS-mutant lung adenocarcinoma to improve current targeted strategies that often result in resistance. To this end, we interrogate the extended KRAS signaling network to define bypass mechanisms that sustain oncogenic signaling independently of canonical KRAS pathway inhibition, and to leverage these insights for the development of rational combination therapies. We have now uncovered in mouse models that lung tumor initiation driven by Kras mutations also requires copy number gains to potentiate the activaty of downstream signaling pathways in order to facilitate efficient functional inactivation of the transcriptional repressor Capicua (CIC). Notably, absence of CIC abrogated the requirement for Kras copy number gains, demonstrating that CIC inactivation plays a key role in lung adenocarcinoma formation.

We have also demonstrated that absence of CIC confers resistance to pharmacological inhibition of the KRAS/MAPK axis through constitutive derepression of its downstream target genes ETV4 and ETV5. Functional suppression of ETV4 and ETV5 was sufficient to restore therapeutic sensitivity, indicating that these transcription factors are promising candidate targets for combination therapies. Furthermore, our work also revealed that CIC-deficient tumor cells acquire distinct dependencies, rendering them for instance selectively vulnerable to inhibition of the glycolytic regulator PFKFB3. Collectively, our work has established CIC as a central node within the expanded KRAS signaling network that modulates both tumor initiation and therapeutic response. Our ongoing studies are focused on delineating additional resistance mechanism and context-specific vulnerabilities to expand the repertoire of actionable targets for combination therapies in KRAS-mutant lung adenocarcinoma.

Total publications

7

Mean IF

14

% Q1

86

% D1

43

% CA/MA

57

% OA

86

Our research focuses on the regulation of cell signaling by the small GTPase Rap1 and its contribution to human disease. C3G (RapGEF1) is a guanine nucleotide exchange factor that activates Rap1. In collaboration with the group of Carmen Guerrero, we investigated the consequences of C3G deregulation—caused by a lymphoma-associated missense mutation—in B-cell lymphoma. Using CRISPR/Cas9-engineered murine models, we demonstrated that sustained activation of the C3G–Rap1 axis profoundly reshapes lymphoma cell behavior. C3G hyperactivation impaired proliferation and promoted apoptosis through reduced ERK1/2 signaling, supporting a tumor suppressor function. Strikingly, however, the cells exhibited enhanced migration, invasion, and metastatic dissemination in vivo. Mechanistic analyses revealed that this phenotypic switch is linked to decreased Rac2 activity and altered adhesion, uncovering a previously unrecognized interplay between Rap1- and Rac2-dependent pathways. Transcriptomic profiling further identified extensive rewiring of gene networks controlling cytoskeletal dynamics and cell motility. These findings establish C3G as a dual regulator of tumor growth and dissemination, providing new insight into how small GTPase signaling balances proliferation versus metastasis, with potential implications for therapeutic targeting in hematologic malignancies.

We have also collaborated with the group of Coert Margadant (Leiden University, NL) to characterize the molecular basis of antibody-mediated pathology in fetal and neonatal alloimmune thrombocytopenia (FNAIT). We characterized maternal alloantibodies against human platelet antigen-1a (HPA-1a) in the integrin β3 subunit and demonstrated that these antibodies do not discriminate between αIIbβ3 and αvβ3 integrins. Instead, antibody binding is strongly modulated by integrin conformational state, with higher affinity for inactive forms. Structural analyses indicate that epitope accessibility is reduced in active conformations. These findings suggest that integrin conformation, rather than receptor subtype selectivity, contributes to the clinical outcome in FNAIT, and have potential implications for diagnosis and therapeutic intervention.

Total publications

2

Mean IF

13.85

% Q1

100

% D1

50

% CA/MA

0

% OA

50

C3G is a guanine nucleotide exchange factor that activates Rap1 GTPases and participates in key cellular processes including adhesion, migration, and development. Our research group has identified an important role for C3G in megakaryocyte (MK) and platelet biology, including the promotion of platelet activation, aggregation, α-granule secretion, and clot retraction. C3G also facilitates platelet-mediated angiogenesis and metastasis and supports megakaryopoiesis under stress conditions such as thrombopoietin stimulation or chemotherapy-induced myeloablation.

C3G overexpression in MKs increases megakaryopoiesis and thrombopoiesis after myeloablation. This effect is associated with enhanced secretion of Fgf1 by MKs, which stimulates adipogenesis and contributes to improved hematopoietic regeneration. Consistently, female C3G transgenic mice show higher survival rates than control females after repeated chemotherapy treatments.

In addition, deletion of C3G in MKs (C3GPf4-KO mice) protects against Dextran Sulfate Sodium (DSS)–induced colitis, whereas MK-specific C3G overexpression worsens disease severity. DSS-treated C3GPf4-KO mice display increased numbers of natural killer cells, suggesting that C3G expression in MKs may influence immune responses during inflammatory conditions.

C3G also plays a role in the hematopoietic stem cell (HSC) compartment. Deletion of C3G in hematopoietic stem and progenitor cells (HSPCs) enhances their proliferation and differentiation in response to stress, with a bias toward lymphopoiesis, consistent with C3G role in promoting myelopoiesis. Moreover, loss of C3G in HSPCs induces a phenotype resembling polycythemia vera (PV), characterized by increased erythroid parameters and enhanced coagulation. Reduced C3G expression is associated with increased phosphorylated JAK2 levels in JAK2V617F-mutant HEL cells, and C3G expression is downregulated in PV patient datasets. These findings suggest that C3G may protect against PV development by regulating JAK2 activity.

Finally, C3G ablation in HSPCs delays chronic myeloid leukemia (CML) onset and alters JAK2-STAT signaling in BCR:ABL1-expressing cells. These findings will be validated using patient samples from CML and PV.

Total publications

6

Mean IF

12.52

% Q1

100

% D1

33

% CA/MA

67

% OA

100

Dr. Lorenzo-Martín's research unit is dedicated to the implementation of cutting-edge biotechnological tools for the establishment and characterization of ex vivo cancer models with enhanced pathophysiological relevance. They utilize miniature organ-mimicking 3D cellular models in combination with high-throughput genomic technologies as the primary systems for their research. Their main objective is to uncover the complex molecular interactions between cancer cells and their tumor microenvironment that drive cancer pathobiology.

To achieve this goal, they are currently focusing on the following research lines: the characterization of the molecular crosstalk between colorectal cancer cells, cancer-associated fibroblasts, tumor-infiltrating lymphocytes, and tumor vasculature; the development of functional immune ecosystems capable of capturing key steps of the cancer-immunity cycle; the reconstruction of the microbiomal tumor microenvironment in colorectal cancer models; and the integration of multi-omic approaches (genomics, transcriptomics, proteomics) for the identification of key molecular regulators of tumor initiation, progression, and therapy response.

Beyond contributing to a better understanding of key genetic and cellular principles governing cancer biology, this research program opens up exciting prospects for drug discovery and personalized medicine.

Total publications

7/16

Mean IF

6.94

% Q1

86

% D1

29

% CA/MA

14

% OA

100

• During this period, LFLM contributed to 16 peer-reviewed publications available online before 31 December 2025. Of these, 7 were affiliated with the CIC and are considered for the metrics and elaboration of this report; the remaining 9 were produced during his previous position and are therefore excluded from the institutional analysis.

We employ murine and cellular genetic models to investigate novel signalling pathways and oncogenic functions that drive the initiation and progression of lung adenocarcinoma (LUAD). Emerging evidence indicates that membrane-bound RAS molecules organize into multimers known as nanoclusters, whose formation is shaped by protein–protein and protein–lipid interactions. However, the molecular principles governing the assembly and function of these membrane-associated structures remain poorly understood. KRAS nano-aggregation involves the formation of KRAS membrane dimers. Whether those act as bona fide signalling entities or serve as transient intermediates during nanocluster formation remains an open and intriguing question.

Our current efforts aim to elucidate the molecular determinants underlying this phenomenon and to identify novel protein factors essential for the assembly of KRAS-dependent signalling platforms. We are also investigating how these complexes quantitatively modulate downstream signalling — particularly the initiation, amplitude, and duration of RAS-ERK pathway activation — which is a central regulator of tumour onset, progression, and therapeutic resistance.

Recently, we have also evaluated the therapeutic efficacy of inducing targeted protein degradation of the KRAS oncogene in lung adenocarcinoma. We have also characterized both the cancer cell autonomous as well as the tumour microenvironment consequences upon acute elimination of the oncogene. We are currently dissecting the phenotypes of a rare population of persister cells that survive and provide a reservoir from which acquired resistance mechanisms eventually unfold.

By dissecting these molecular mechanisms, our research seeks to uncover new determinants of cancer susceptibility and to identify therapeutic vulnerabilities with low toxicity and clinical relevance in LUAD.

Total publications

10

Mean IF

16.55

% Q1

60

% D1

50

% CA/MA

20

% OA

100

Our research focuses on analyzing the mechanisms of activation of cellular RAS proteins by guanine nucleotide exchange factors (GEF) and ascertaining the functional specificity or redundancy of various RAS and GEF isoforms in physiological and pathological (tumoral) contexts. Our findings have been instrumental in identifying and characterizing novel mechanisms, biomarkers, therapeutic targets, and antitumor drugs that may be relevant for RAS-driven malignancies.

Regarding the functional specificity of RAS proteins, our recent work has contributed to further detailing the mechanistic specificity of the different RAS family members in synaptic plasticity and myeloid cell homeostasis. Additionally, we reported the emergence of a novel RASopathy-like phenotype resulting from the concomitant genetic ablation of HRAS and NRAS.

Our studies of GRF family members continued to demonstrate the differential functionalities of GRF1 and GRF2 across diverse biological settings ranging from pancreatic beta cells to neurosensory and neuronal cells. Specifically, we reported during this period that GRF2 is essential for cone photoreceptor viability and ribbon synapse formation in the mouse retina.

Finally, our functional analyses of the two members of the SOS family of GEFs have confirmed them as the most ubiquitously expressed and functionally relevant activators of RAS proteins in eukaryotic cells and have also characterized their specific functionalities in different physiological and pathological settings. Importantly, our work using various mouse tumor models has demonstrated that SOS1 is critically required for DMBA/TPA-induced skin carcinogenesis, BCR/ABL-driven chronic myeloid leukemia (CML), and KRAS-driven lung adenocarcinoma (LUAD). These findings —coupled with our recent discovery of the markedly synergistic therapeutic behavior exhibited by SOS1 pharmacological inhibitors when combined with other RAS pathway antitumoral drugs— validate SOS1 as a novel, actionable and bona fide therapeutic target for different RAS-dependent cancers.

Total publications

7

Mean IF

9.46

% Q1

100

% D1

43

% CA/MA

43

% OA

100

Our lab delves into the role of oncogenic RAS proteins in driving lung cancer. Focusing on the interplay between tumor cells and their microenvironment, crucial for tumor growth, we explore how RAS signaling modulates the stroma to support cancer progression. Despite RAS oncogenes being central to cancer initiation, their specific impact on tumor-stroma crosstalk remains unclear. Identifying key molecules in this interaction is vital for a deeper understanding of RAS-driven lung cancer biology, offering potential targets for therapeutic interventions in the intricate network sustaining tumor progression.

Over the past two years, our research has extended to investigate the role of the RAS-PI3K signaling pathway in Cancer-Associated Fibroblasts (CAFs). Specifically, we've focused on understanding how this signaling pathway regulates CAFs' ability to acquire a myoCAF phenotype, influencing the formation of a permissive extracellular matrix crucial for the progression and proliferation of lung cancer cells with RAS mutations. Our findings suggest that PI3K activation through RAS in CAFs impacts the production of various extracellular matrix components, particularly altering the composition of glycoproteins. This, in turn, affects the physicochemical properties of the matrix and, consequently, the mechanotransductive properties of tumor cells.

We started a new research avenue investigating how distinct mutations within tumor cells influence their interaction with the microenvironment, fostering the creation of microenvironments with unique characteristics. This aims to pave the way for developing mutation-specific therapies. Specifically, in alignment with our focus on lung cancer, we are delving into how mutations in KRAS or EGFR (the two most prevalent mutations in lung cancer, constituting 50% of cases) induce distinct transcriptional activation patterns in CAFs. This may lead to the formation of extracellular matrices with diverse properties, consequently impacting other recruited cellular populations within tumors, and creating vulnerabilities that can be used to develop new therapeutic strategies.

In conclusion, our ongoing research aims not only to unravel the complexities of tumor-stroma interactions but also to inform the development of tailored therapies, emphasizing the potential for precision medicine in addressing the diverse landscape of lung cancer mutation.

Total publications

3

Mean IF

6.03

% Q1

67

% D1

33

% CA/MA

33

% OA

100

As Leonard Hayflick described in the 60s, the proliferative potential of normal cells is not unlimited. After a few dozen divisions, telomere attrition triggers a DNA-damage response and drives entry into an essentially irreversible cell cycle arrest known as cellular senescence. Senescent cells appear and persist naturally during aging and can be induced by several types of cellular damage. Interestingly, most anti-cancer therapies induce cellular senescence in a subset of cells within solid tumors.

Damaged cells secrete a complex mixture of soluble factors (cytokines, chemokines, growth factors…) that influence the surrounding tissue in a context- and time-dependent manner. Cellular senescence has been linked to age-related diseases, and, in the context of cancer, it has been shown to contribute to cellular division and migration. Elimination of damaged cells has shown promise in the treatment of some age-related diseases and, in combination with genotoxic chemotherapy, in preclinical models of cancer.

Importantly, a rich and still poorly understood dialogue takes place between damaged cells and the immune system, both in aging and in post-therapy tumors. How do these secreted factors, often overlapping with those of myeloid cells, regulate immunity? Damaged cells upregulate both their antigen presentation machinery and some immune checkpoint inhibitory ligands. Which mechanism predominates and why? Which immune cells are responsible for clearance of these cells? How can we find and target these cells in human tumors?

The answer to these questions will provide valuable information on cancer biology but also for our societal quest for extended healthy years of life.

Total publications

2

Mean IF

4.95

% Q1

50

% D1

0

% CA/MA

0

% OA

100

• During this period, JALD contributed to 4 peer-reviewed publications available online before 31 December 2025. Of these, 2 were affiliated with the CIC and are considered for the metrics and elaboration of this report; the remaining 2 were produced during his previous position and are therefore excluded from the institutional analysis.

Our research aims at unraveling the molecular mechanisms by which cells generate forces and mechanical work, particularly in tumor metastasis and immune cell migration. To this end, we combine biophysical techniques such as traction force microscopy with molecular biology and advanced superresolution microscopy. Over the last 12 years, we have generated several key contributions to the field that have led to the following findings (all first, last and/or corresponding author): the specific consequences of force generation by the two major myosin II isoforms (Vicente-Manzanares, J Cell Biol 2007, 2008, 2011); a novel mode of regulation of tensile control and cell polarization in living cells based on phosphorylation of myosin IIB (Juanes-García, J Cell Biol 2015); a novel mode of regulation of myosin II assembly and protrusion in migrating cells based on the phosphorylation of the RLC (Aguilar-Cuenca et al, Curr Biol 2020); the structural study of myosin II function based on mutational analysis and its impact in human disease (Llorente-González et al., Cell Mol Life Sci 2026); the molecular determinants of cellular shape during T cell activation, which are crucial for migration, mechanosensation, proliferation and immune responses (Millán-Salanova, under revision); and the effect of taxanes in cellular contraction and long-term mechanically-determined resistance to chemotherapy (Asensio-Juárez, under revision).

We are currently focusing on the role of microtubule-binding proteins in the cellular response to taxanes and the mechanical effects of K/N-Ras mutations in lung cancer and hematologic cancers, respectively. We are also interested in the role of flavivirus proteins in controlling the mechanics of macrophages and endothelial cells in severe dengue. Besides primary research articles, increasing recognition in the field is evidenced by several reviews in top journals (for example, Garrido-Casado, Annu. Rev. Cell. Dev. Biol. 2021). I have obtained four uninterrupted grants from Plan Nacional and grants from FBBVA and F. Ramón Areces. Since 2021, I participate in a large-scale consortium that obtained an Accelerator Award to study the mechanics of monoclonal B lymphocytosis, and I am a founding member and current coordinator of the Spanish Network of Excellence in Mechanobiology.

Total publications

4

Mean IF

5.75

% Q1

75

% D1

0

% CA/MA

75

% OA

100

Most solid tumours exhibit aneuploidy, accompanied by increased chromosome instability (CIN) rates, emphasising the urgent need to elucidate the mechanisms driving chromosome missegregation in cancer cell biology. Mitotic errors can lead to micronuclei (MN) formation, making them vulnerable to nuclear envelope rupture and resulting in extensive genomic rearrangements leading to chromothripsis. While considerable attention has been directed towards studying spindle mechanics for accurate genome segregation during cell division, less focus has been placed on other intracellular structures, including endomembranes such as the nuclear envelope (NE), Golgi remnants, endoplasmic reticulum (ER), and vesicles. Recent research, including studies from our laboratory, has highlighted the significant role of endomembranes, particularly the ER, in modulating chromosome dynamics, promoting aneuploidy, and facilitating MN formation.

Our research vision is to understand the organisation, remodelling, and reassembly of endomembranes during cell division, elucidating their pivotal role in maintaining genome integrity throughout metazoan cell division. To achieve these objectives, we have designed two interconnected aims: (1) Characterizing nuclear envelope organization during cell division; and (2) Determining how the endoplasmic reticulum is reorganized and partitioned during cell division. This research holds significant promise in identifying novel therapeutic targets for treating cancer and other related diseases.

Total publications

1

Mean IF

7.2

% Q1

100

% D1

100

% CA/MA

0

% OA

100

Our research investigates how meiotic chromosome dynamics safeguard genome stability and how their failure leads to human disease. We combine genetically engineered mouse models with functional genomics to dissect the proteins and pathways that control meiotic recombination, chromosome structure, and segregation in vivo, with direct relevance to infertility, miscarriage, congenital disorders, cancer, and aging.

We have shown that the meiotic cohesin RAD21L is a key organizer of 3D genome architecture and transcription in the male germline, linking chromosome structure to stage-specific gene expression programs. We also uncovered that genome-wide transcriptional silencing coupled to mRNA stabilization ensures the coordinated execution of the meiotic program in mice. Building on our long-standing expertise in generating and analyzing meiotic mouse mutants, we recently identified the E3 ligase RNF212B as an essential factor for crossover designation and maturation in both male and female meiosis, thereby securing accurate reductional chromosome segregation. Together, these studies define a cohesive research line aimed at understanding how meiotic cohesins, recombination factors, and the synaptonemal complex integrate to preserve genome integrity across generations. The deciphering of the intricate mechanisms underlying meiotic recombination and chromosome segregation holds the potential to illuminate the evolutionary equilibrium between the advantages conferred by sexual reproduction and, significantly, the potential drawbacks associated with its mutational risk and its direct involvement in human genetic diseases.

Total publications

5

Mean IF

10.28

% Q1

100

% D1

75

% CA/MA

40

% OA

100

• The Methods in Molecular Biology series has no JCR Impact Factor or quartile. It is included in the table but excluded from the calculation of mean IF, % quartiles and % OA. The main metrics are calculated on the 4 publications with an assigned IF.

Our research group investigates the molecular mechanisms that govern DNA replication and genome stability, with a particular focus on the regulation of Proliferating Cell Nuclear Antigen (PCNA), a central coordinator of DNA metabolism. PCNA functions as a sliding clamp that organizes the assembly and activity of replication and repair factors on chromatin. Its regulation by ubiquitin-dependent post-translational modifications is critical for coordinating DNA damage tolerance pathways and ensuring efficient lagging-strand synthesis through the proper maturation of Okazaki fragments.

In recent years, our work has significantly advanced the understanding of ubiquitin-mediated control of PCNA dynamics. We have provided novel evidence supporting an asymmetric organization of DNA damage tolerance pathways at replication forks and identified key roles for PCNA deubiquitylases in modulating these processes. Our findings further support a model in which PCNA undergoes dynamic cycles of ubiquitylation and deubiquitylation during unperturbed S phase, contributing to the fine regulation of replication progression and genome-wide clamp turnover.

More recently, we have focused on the mechanisms of PCNA unloading from chromatin, a critical step for the completion of lagging-strand synthesis and the restoration of chromatin structure. While the Elg1 replication factor C-like complex (Elg1/RLC) has been established as the primary PCNA unloader, our research has uncovered the existence of parallel pathways that ensure the robustness of this process. In particular, we have identified the deubiquitylase Ubp10 as a central component of an alternative unloading mechanism that operates independently of Elg1. Ubp10 associates with the lagging-strand maturation machinery and promotes PCNA release through targeted deubiquitylation, thereby facilitating efficient Okazaki fragment processing.

Our results demonstrate that this alternative pathway becomes especially relevant under conditions where canonical unloading is compromised, highlighting its role in maintaining replication efficiency and genome stability. Collectively, our work establishes a bifurcated network of PCNA unloading mechanisms that provides both robustness and adaptability to the replication machinery.

Total publications

2

Mean IF

14.40

% Q1

100

% D1

100

% CA/MA

100

% OA

100

Our research focuses on the study of the epitranscriptome, a new layer of biological complexity involving chemical modifications in RNA, with a particular interest in cancer. We explore how these modifications affect fundamental processes such as self-renewal, differentiation, and survival in both normal and cancerous cells. Using advanced sequencing techniques and diverse experimental models, we have discovered that RNA modifications like methylation regulate gene expression and key cellular processes.

Our goals include characterizing the role of RNA modifications and their regulators in tissue homeostasis, identifying the impact of epitranscriptomic alterations in cancer, and understanding how these modifications influence cancer dynamics, including metastasis and immune resistance. Additionally, we aim to develop new technologies for detecting RNA modifications and assess the therapeutic potential of manipulating the epitranscriptome in cancer cells. This innovative approach offers new insights into cancer biology and the development of targeted therapeutic strategies.

Total publications

4

Mean IF

6.48

% Q1

25

% D1

25

% CA/MA

75

% OA

100