Jachimowicz, Ron D. - A 04
Targeting UBQLN1-Driven Oncogenesis in Lung Adenocarcinoma
PD Dr. Ron Daniel Jachimowicz
Dept. I of Internal Medicine
CMMC - PI - A 04
show more…
Dept. I of Internal Medicine
Cologne Center for Genomics University of Cologne Weyertal 115 b
50931 Cologne
Introduction
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related death, underscoring the urgent need for novel therapeutic strategies. Our preliminary data identify the ubiquitin-like protein UBQLN1 as a bona fide oncogene in LUAD. We found that UBQLN1 is frequently overexpressed in human cancers and that its overexpression in a murine model leads to spontaneous lung adenocarcinoma. Mechanistically, we begin to understand that UBQLN1 overexpression drives genome instability by impairing homologous recombination (HR) repair through the regulation of the DNA end-resection.
We will first dissect the precise mechanism of how UBQLN1 regulates DNA end-resection and a shift of DNA repair pathway choice towards error-prone repair, thereby fueling tumorigenesis. Second, we will perform a genome-wide CRISPR/Cas9 screen to identify synthetic lethal interaction partners of UBQLN1 overexpression, unveiling novel therapeutic vulnerabilities. Third, based on the observed HR-deficient phenotype, we will validate the efficacy of targeting alternative DNA repair mechanisms and synergistic pathways in our preclinical autochthonous in vivo models of UBQLN1-overexpressing LUAD. Moreover, to translate these findings to the clinic, we will validate a robust immunohistochemistry-based biomarker assay for UBQLN1 overexpression in a cohort of clinically annotated non-small cell lung cancer patients, paving the way for patient stratification.
Figure
Clinical Relevance
UBQLN1 overexpression promotes aggressive, genetically unstable lung tumors. By defining its mechanism, we can exploit this dependency for targeted therapies. This project will validate novel synthetic lethal interactions for these tumors and deliver a ready-to-use biomarker to identify patients who will benefit. This bench-to-bedside approach will enable a new precision medicine strategy for an aggressive cancer subtype.
Approach
- Use cell‑based DNA repair readouts and DNA resection assays to define how UBQLN1 overexpression alters repair pathway choice and promotes genome instability.
- Apply a genome‑wide genetic loss‑of‑function screen and follow‑up validation to identify genes that UBQLN1‑overexpressing tumor cells critically depend on.
- Test DNA repair‑targeted treatments in lung cancer mouse models and develop an UBQLN1‑based tissue staining assay as a clinical biomarker.
Lab Website
For more information, please check Research Group Jachimowicz.
Affiliations
Publications generated during 1/2026-12/2028 with CMMC affiliations
2026
Content will be made available as soon as possible.