Latka, S. | Search bioRxiv

bioRxiv2026

FANCM restrains structural genome evolution and defines a synthetic lethal dependency in BRCA1-deficient breast cancer

BRCA1 deficient cancers experience persistent replication stress and structural genome instability yet retain the capacity for sustained proliferation, implying reliance on compensatory genome-maintenance mechanisms. Here, we establish BRCA1/FANCM synthetic lethality in human BRCA1 deficient breast cancer and exploit temporally controlled FANCM depletion to capture genome evolution over successive cell divisions before declining cellular fitness becomes limiting. We show that FANCM restrains genome wide structural variation in BRCA1 deficient breast cancer cells under endogenous replication stress. FANCM loss amplifies the characteristic BRCA1 associated short tandem duplication (TD) phenotype while permitting larger, including megabase-scale, TDs and diverse rearrangements to emerge. Newly emerged TDs preferentially associate with Pol II occupied regions, and FANCM depletion increases proximity between the replication machinery and elongating RNAPII in BRCA1 mutant breast cancer cells, linking FANCM-mediated genome protection to transcription replication encounters. BRCA1 altered human tumors with low FANCM expression recapitulate key features of this phenotype, while genome/transcriptome integration links newly emerged SVs to configuration dependent local transcriptional changes. Together, these findings establish FANCM as a replication stress safeguard coupling survival to restraint of structural genome evolution.

cancer biology↗

bioRxiv2026

Mitochondrial rewiring supports survival of triple negative breast cancer cells after ionizing radiation

Triple negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Conventional treatments include neoadjuvant chemo-immunotherapy followed by surgical resection and may include further adjuvant immunotherapy and/or radiotherapy of the tumor bed and lymph nodes. Nonetheless, TNBC patients with residual disease have rapid metastatic recurrence. While the roles of metabolic and mitochondrial adaptations in chemotherapeutic resistance have been the subject of many studies, their importance in the context of ionizing radiation (IR) therapy remains poorly understood. We established longitudinal in vitro models of post-IR human TNBC, characterized by cellular regression to a residual phenotypic state, then eventual cell repopulation. This was accompanied by plastic adoption of unique metabolic, proteomic, and morphologic features that largely reverted when cells regrew. Following IR, residual cells exhibited extensive mitochondrial rewiring, including elevated mitochondrial content, oxidative phosphorylation (oxphos) rates, cristae structures, and metabolite levels. Concomitantly, levels of the short protein isoform of the mitochondrial inner membrane protein optic atrophy 1 (OPA1) were significantly elevated in residual cells, and OPA1 knockout ablated mitochondrial adaptations induced by IR. OPA1 genetic or pharmacologic perturbations led to improved cellular responses to IR. Metabolomic and proteomic analyses of radio-residual cells uncovered a coordinated program of antioxidant and redox capacity elevation with mitochondrial metabolism, which was corroborated by analyses of external datasets. Together, these findings provide evidence that TNBC cells surviving radiotherapy adopt an OPA1-dependent program of mitochondrial reorganization that supports their survival and regrowth, thereby positioning OPA1 as a therapeutic dependency that could improve radiotherapy efficacy in TNBC.

cancer biology↗