Deciphering and targeting cellular senescence in lymphomagenesis and lymphoma therapy

• Applicant: Dr. Maja Milanovic
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562940225

Oncogene-induced senescence (OIS) is a major tumor-suppressive mechanisms that prevents the proliferation of pre-neoplastic cells. Overcoming this barrier is a prerequisite for full malignant transformation and requires additional genomic lesions to deactivate OIS signaling. In contrast, tumorigenesis in cells with preexisiting OIS defects evolves with no pressure to deactivate the proliferative OIS barrier. We therefore postulate that tumorigenesis in senescence-deficient cells relies on different oncogenic networks in comparison to OIS-intact cells. This in turn defines the biology of the resulting tumors, their oncogenic dependencies and treatment vulnerabilities. To address this, we generated mouse models where lymphoma development is driven by PiggyBac transposon mutagenesis in combination with a genomic deletion of the crucial senescence mediator Suv39h1. We observed an accelerated lymphoma onset in senescence/Suv39h1-deficient mice as compared to senescence competent Suv39h1-wt mice, which confirms the collaborative effect of OIS deactivation in lymphomagenesis and suitability of our model for studying lymphomagenesis in senescence-deficient background. By sequencing of the transposon insertion sites in Suv39h1-proficient and -deficient cohorts, we aim to identify the oncogenic networks associated with and causally involved in lymphomagenesis in OIS-impaired background. Even though OIS needs to be suppressed to allow malignant transformation, manifest cancer cells can still be forced to undergo treatment-induced senescence (TIS) if exposed to genomic stress. Similar to OIS preventing proliferation of premalignant cells, TIS acts as a proliferative break for overt cancer cells and intact TIS capacity correlates with better disease control and survival. To assess the role of TIS in the development of treatment resistance, we will use PB-driven lymphomas with Suv39h1 deletion (central mediator of TIS as well as OIS). Resistance will be induced by repeated chemotherapy treatment in vivo. Continuous PB transposition in combination with chemotherapy as a new selective pressure would lead to new genomic events relevant for treatment survival. We hypothesize that this survival network evolves differently in the absence of tumor-suppressive TIS capacity and that therefore senescence-impaired lymphomas are predisposed to different mechanisms of therapy resistance. We will apply our novel cutting-edge technology which integrates genomic data (transposon insertions) and transcriptomes in single cell resolution, to address the evolution of resistance-relevant mutations. By comparing transposon insertions in longitudinal tumor samples before and after developing resistance, we aim to define genes specifically engaged in surviving treatment, to provide novel treatments which overcome drug resistance in senescence-impaired lymphomas.

• DFG Programme: Research Grants