Molecular Thoracic Oncology

Our Research

The image displays fluorescent signals representing genetic markers related to Eml4-Alk fusion in cells. Colored dots indicate different genetic sequences: orange for 5' Eml4, green for 3' Alk, and red for 5' Alk. The inset highlights clustered signals, suggesting potential gene fusion activity.

Our research is focused on understanding the genetic and molecular basis of lung and breast cancers by studying various oncogenic drivers and specific genetic alterations that drive cancer progression. Using advanced genetically engineered mouse models, we examine how distinct gene expression profiles influence tumor aggressiveness and responsiveness to treatment. A key part of our research involves identifying biomarkers predictive of poor therapeutic outcomes, aiming to develop more precise cancer therapies.

Methods and technologies
Our research leverage several cutting-edge technologies:

Genetically engineered mouse models to closely mimic human cancer.
CRISPR/Cas9 technology for precise genetic modifications to study the impact of specific genes on cancer.
Lineage tracing, this technique traces the evolution and differentiation of cancer cells, offering insights into tumor development.
Epigenome and single-cell transcriptome analysis, help us explore gene expression and regulatory changes at the single-cell level, enhancing our understanding of cancer cell behavior.
3D in vitro culture systems that allow us to study cancer growth in environments that closely mimic physiological conditions.

Goals and societal relevance
The overarching goal of our research is to advance our understanding of cancer biology to discover new therapeutic targets and strategies. By dissecting the molecular mechanisms of tumor progression and genetic instability, we strive to develop more effective treatments. Our efforts support the German Cancer Research Centre’s mission to address major challenges in cancer research, particularly in identifying and overcoming resistance mechanisms to improve patient outcomes.

Projects

The image displays a complex biological sample with various colors highlighting different cell types and structures. It features sections stained with DAPI for nuclei, GFP for specific proteins, and additional markers, showcasing intricate cellular arrangements and interactions within the tissue.

Deciphering the Genetic Landscape of Non-Small Cell Lung Cancer: Fusion Variants and Therapeutic Opportunities

Non-small cell lung cancer (NSCLC) is one of the most common and deadly cancers worldwide. A significant driver of NSCLC is the fusion between the genes anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4). To date, approximately 15 distinct EML4-ALK fusion variants have been identified, each with unique characteristics affecting their stability, genomic localization, responsiveness to targeted therapies, and implications for prognosis.

Our research is dedicated to unraveling the intricate mechanisms that drive development and progression of these fusion variants. We are particularly interested in how co-occurring genetic alterations, such as the loss of TP53, influence the behavior of these variants and identify new therapeutic targets. Beyond EML4-ALK fusions, our team is exploring other chromosomal rearrangements that contribute to NSCLC pathogenesis, including the effects of Y-chromosome loss, and the role of specific epigenetic regulators such as Kdm5d and Uty in the disease.

To probe these genetic intricacies, we leverage CRISPR/Cas9 gene editing to generate genetically engineered mouse models, enabling the inducible expression of specific gene fusions and the targeted inactivation of genes associated with NSCLC. Our approach integrates cutting-edge techniques, including tailored in vivo tumor models that mimic human disease, organoids derived from mice and patients, and sequential gene perturbation assays conducted in vivo. This comprehensive methodology not only replicates the histopathological and molecular characteristics observed in human lung cancer but also provides a powerful platform for dissecting NSCLC's molecular drivers and developing groundbreaking treatment options.

Lab pictures

Team

Prof. Dr. Rocio Sotillo Roman

Group Leader

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Maria Bandeira Ferreira Ramos
Ayushi Bhanushali
Natascha Bäuerle

Ph.D. Student
Maria Capone
Can Gürkaslar

Lab technician

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Janina Hattemer

Visiting student
Anoushka Imo

Administrative Assistant

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Amelie Mahr

PhD student

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Mulham Najajreh

PhD student

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Laura Saverino
Valeria Seifert
Steve Paul Smarduch
Dr. Kalman Somogyi

Senior scientist

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Selected Publications

2024 - BioRxiv

EML4-ALK variant-specific genetic interactions shape lung tumorigenesis.

Diaz-Jimenez, A., Shuldiner, E. G., Somogyi, K., Gonzalez, O., Akkas, F., Murray, C. W., Andrejka, L., Tsai, M. K., Brors, B., Sivakumar, S., Sisoudiya, S. D., Sokol, E. S., Petrov, D. A., Winslow, M. M., & Sotillo, R

2024 - Drug Resist Updat.

Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome.

Diaz-Jimenez A, Ramos M, Helm B, Chocarro S, Frey DL, Agrawal S, Somogyi K, Klingmüller U, Lu J, Sotillo R.

2023 - Genome Biol.

Acute expression of human APOBEC3B in mice results in RNA editing and lethality.

Alonso de la Vega A, Temiz NA, Tasakis R, Somogyi K, Salgueiro L, Zimmer E, Ramos M, Diaz-Jimenez A, Chocarro S, Fernández-Vaquero M, Stefanovska B, Reuveni E, Ben-David U, Stenzinger A, Poth T, Heikenwälder M, Papavasiliou N, Harris RS, Sotillo R

All Publications

Bioinformatics. 2026.

XenoMix: estimating mouse content from DNA methylation data of Patient-Derived Xenograft models.

Esmaeelpour N, Mücke O, Altun G, Cornick J, Capone M, Sotillo R, Llamazares-Prada M, Plass C, Scherer M.

Semin Cancer Biol. 2026.

Tumor microenvironment evolution in lung cancer: Spatio-temporal dynamics and clinical implications.

Dizdarević S, Timofeev O, Kazdal D, Pullamsetti SS, Sotillo R, Loges S, Kobold S, Stenzinger A, Stiewe T, Savai R.

Genome Med. 2025.

Discriminating activating, deactivating and resistance variants in protein kinases.

Singh G, Schmenger T, Gonzalez-Sanchez JC, Kutkina A, Bremec N, Diwan GD, Mozas P, López C, Siebert R, Sotillo R, Russell RB.

Cancer Discov. 2026.

EML4-ALK Variant-Specific Genetic Interactions Shape Lung Tumorigenesis.

Diaz-Jimenez A, Shuldiner EG, Somogyi K, Shih KY, González-Velasco Ó, Najajreh M, Kim S, Akkas F, Murray CW, Andrejka L, Tsai MK, Brors B, Hofmann I, Sivakumar S, Sisoudiya SD, Sokol ES, Cai H, Petrov DA, Winslow MM, Sotillo R.

Nat Biomed Eng. 2025.

Efficient and multiplexed somatic genome editing with Cas12a mice.

Hebert JD, Xu H, Tang YJ, Ruiz PA, Detrick CR, Wang J, Hughes NW, Donosa O, Siah VP, Andrejka L, Karmakar S, Aboiralor I, Tang R, Sotillo R, Sage J, Cong L, Petrov DA, Winslow MM.

Cancer Res. 2025.

The Lung Cancer Autochthonous Model Gene Expression Database Enables Cross-Study Comparisons of the Transcriptomic Landscapes Across Mouse Models.

Cai L, Wu F, Zhou Q, Gao Y, Yao B, DeBerardinis RJ, Acquaah-Mensah GK, Aidinis V, Beane JE, Biswal S, Chen T, Concepcion-Crisol CP, Grüner BM, Jia D, Jones RA, Kurie JM, Lee MG, Lindahl P, Lissanu Y, Lorz C, MacPherson D, Martinelli R, Mazur PK, Mazzilli SA, Mii S, Moll HP, Moorehead RA, Morrisey EE, Ng SR, Oser MG, Pandiri AR, Powell CA, Ramadori G, Santos M, Snyder EL, Sotillo R, Su KY, Taki T, Taparra K, Tran PT, Xia Y, van Veen JE, Winslow MM, Xiao G, Rudin CM, Oliver TG, Xie Y, Minna JD.

Drug Resist Updat. 2025.

Osmotic stress influences microtubule drug response via WNK1 kinase signaling.

Monfort-Vengut A, Sanz-Gómez N, Ballesteros-Sánchez S, Ortigosa B, Cambón A, Ramos M, Lorenzo ÁM, Escribano-Cebrián M, Rosa-Rosa JM, Martínez-López J, Sánchez-Prieto R, Sotillo R, de Cárcer G.

Nat Commun. 2024.

Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress.

de Jaime-Soguero A, Hattemer J, Bufe A, Haas A, van den Berg J, van Batenburg V, Das B, di Marco B, Androulaki S, Böhly N, Landry JJM, Schoell B, Rosa VS, Villacorta L, Baskan Y, Trapp M, Benes V, Chabes A, Shahbazi M, Jauch A, Engel U, Patrizi A, Sotillo R, van Oudenaarden A, Bageritz J, Alfonso J, Bastians H, Acebrón SP.

EMBO Rep. 2024.

Chronic spindle assembly checkpoint activation causes myelosuppression and gastrointestinal atrophy.

Karbon G, Schuler F, Braun VZ, Eichin F, Haschka M, Drach M, Sotillo R, Geley S, Spierings DC, Tijhuis AE, Foijer F, Villunger A.

ACS Nano. 2024.

Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment.

Horvat NK, Chocarro S, Marques O, Bauer TA, Qiu R, Diaz-Jimenez A, Helm B, Chen Y, Sawall S, Sparla R, Su L, Klingmüller U, Barz M, Hentze MW, Sotillo R, Muckenthaler MU.