Biology subjects

Froid, M.

Publications and source records attributed to Froid, M..

3 recordsLinked to original sources

bioRxiv2026

Selection for targeted therapy resistance leads to an indirect selection for higher phenotypic plasticity and enhanced evolvability to orthogonal stressors

Acquired resistance to targeted therapies is a primary barrier to durable cancer control. Resistance frequently coincides with stem-like features and EMT-associated cell-state changes (partial EMT), yet whether these programs directly cause resistance or instead enable escape by increasing phenotypic plasticity remains debated. Integrating computational modeling, functional experimental assays, and lineage tracing, we investigated how cell-state plasticity shapes acquired resistance to ALK inhibition in ALK+ lung cancer models. Our results support a model in which drug exposure selects for cells with higher phenotypic plasticity, progressively increasing their representation as resistance emerges. Consequently, resistant populations show enhanced capacity to adapt to orthogonal therapeutic and environmental stressors and exhibit heightened metastatic potential. Bulk ATAC-seq showed that highly plastic cells have increased chromatin accessibility at regulators of EMT and stemness. Consistent with this, boosting plasticity via Yamanaka-factor induction or EMT-factor expression reduced ALKi sensitivity over time. In contrast, constraining plasticity (SOX2 knockdown or epigenetic inhibition) reduced long-term resistance outgrowth and prolonged ALKi response. Together, our results indicate that targeted therapy indirectly selects for cells with increased phenotypic plasticity, providing the substrate from which multifactorial resistance and metastatic competence evolve. Further, it suggests that constraining plasticity could delay resistance and extend response durability.

cancer biology↗

bioRxiv2025

Rethinking the seven-day treatment-free interval in T-cell engager therapy using agent-based modeling

BackgroundThe CD3/CD19 bispecific T cell engager (TCE) blinatumomab has shown efficacy in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), but response rates are often limited by T cell exhaustion. Recent preclinical studies suggest that incorporating treatment-free intervals (TFIs) into dosing schedules may enhance therapeutic outcomes. MethodsTo systematically evaluate alternative TFI strategies, we developed an agent-based model (ABM) of tumor-T cell interactions under various blinatumomab dosing regimens. The model was calibrated using published in vitro data and incorporated spatial, stochastic, and mechanistic rules governing T cell activation, cytotoxicity, proliferation, and exhaustion. ResultsOur ABM recapitulates experimental observations showing that a 7-day TFI improved T cell function over continuous dosing during the initial 28-day treatment period. However, when simulations were extended to a full 42-day cycle to mimic clinical regimen, this advantage was lost. In contrast, shorter TFIs consistently outperformed both 7-day and continuous schedules, leading to superior tumor control at all timepoints. A translationally oriented Monday-through-Friday (MO_FR) regimen also achieved comparable benefits. ConclusionsOur results indicate that the empirically tested 7-day TFI schedule may not be optimal. TFI with shorter intervals as well as translationally relevant schedules such as MO_FR, may offer greater therapeutic benefit. This work demonstrates the value of ABM in preclinical immunotherapy design and supports model-guided refinement of TCE dosing strategies prior to clinical translation. Future work will focus on validating these predictions in more complex in vivo models and leveraging patient-derived data to guide personalized TCE treatment design.

cancer biology↗

bioRxiv2025

Overcoming treatment resistance mediated by the bone marrow vascular niche in acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematologic malignancy originating in the bone marrow, frequently progressing to extramedullary sites. Despite advances in molecularly targeted therapies and hematopoietic stem cell transplantation, clinical outcomes remain suboptimal. Tyrosine kinase inhibitors (TKIs) confer benefit in a subset of AML patients harboring FLT3-ITD mutations, yet relapse and resistance are common. These failures are driven by both intrinsic properties of leukemic stem cells (LSCs)--a quiescent, self-renewing population--and extrinsic cues from the tumor microenvironment. We previously demonstrated that arteriolar endothelial cells (ECs) produce miR-126, which is transferred to LSCs, promoting quiescence, treatment resistance, and niche retention. During disease progression, TNF- secreted by expanding blasts suppresses EC miR-126 production, enabling LSCs and their progeny to proliferate. Following TKI administration, blast reduction lowers TNF- levels, restoring EC miR-126 production and enabling LSCs to re-enter quiescence--thereby escaping therapy and facilitating relapse. To investigate this dynamic, we developed an agent-based computational model of the AML bone marrow microenvironment, parameterized with in vitro and in vivo data. The model captures vascular niche remodeling and the feedback between leukemic populations and endothelial signaling. Simulations reveal that LSC protection mediated by miR-126 can be overcome by combining TKIs with miRisten, a miR-126 inhibitor. When administered on a defined schedule, this combination disrupts the protective niche and enhances LSC eradication. These findings underscore the therapeutic potential of targeting microenvironmental feedback to overcome resistance and prevent AML relapse.

cancer biology↗