Biology subjects

Kotagiri, V.

Publications and source records attributed to Kotagiri, V..

2 recordsLinked to original sources

bioRxiv2026

Subtype-Specific SASP Dynamics Predict Mesenchymal Transition in Recurrent Glioblastoma

BackgroundTherapy-induced senescence is hypothesized to promote glioblastoma recurrence through senescence-associated secretory phenotype (SASP) factors, yet no longitudinal study has tracked SASP dynamics across matched primary-recurrent pairs. We used the GLASS consortium to characterize {Delta}SASP trajectories and their clinical implications. MethodsWe analyzed 167 matched primary-recurrent GBM pairs from the GLASS consortium. SASP scores were calculated from a 10-gene signature. Patients were classified by {Delta}SASP trajectory (Accumulators vs Clearers). We tested associations with proneural-to-mesenchymal transition (PMT) and validated findings in TCGA (n=52). ResultsSASP dynamics were subtype-specific: Mesenchymal tumors showed significant SASP clearance ({Delta}SASP = -0.83, p = 0.0001), while Classical tumors remained stable (p = 0.86). Among individual genes, HGF was the only factor that increased at recurrence ({Delta} = +0.23, p = 0.016), while IL1A, IL1B, and MMP9 decreased significantly. {Delta}SASP strongly predicted mesenchymal transition (OR = 5.06, 95% CI: 2.30-11.18, p < 0.0001), which itself conferred worse survival (HR = 2.48, p = 0.0001). Strikingly, Clearers were nearly completely protected from PMT (2.4% vs 27.3% in Accumulators, p = 0.0008). {Delta}SASP correlated with immunosuppressive infiltration ({rho} = 0.65 with M2 macrophages, p < 0.0001). Baseline SASP predicted worse survival (HR = 1.65, p < 0.0001), an effect that persisted in IDH-wildtype tumors (HR = 1.32, p = 0.015) and was validated in the CGGA cohort (HR = 1.35, p = 0.003). External validation confirmed the SASP-Mesenchymal association in both TCGA (d = 1.75) and CGGA (d = 1.14). ConclusionsSASP trajectories are heterogeneous and subtype-specific. Patients who fail to clear SASP represent a high-risk subgroup undergoing mesenchymal transition and immunosuppression. These Accumulators may be optimal candidates for senolytic therapy, while Clearers demonstrate effective senescence surveillance that could be therapeutically reinforced.

cancer biology↗

bioRxiv2026

CD276 (B7-H3) as a Companion Diagnostic Biomarker for Glioblastoma: Multi-Platform Validation and Therapeutic Implications

Glioblastoma (GBM) remains the most lethal primary brain tumor, with median survival of 14-16 months despite aggressive multimodal therapy[1,2]. The failure of PD-1/PD-L1 checkpoint inhibitors in GBM (CheckMate-143)[3] has highlighted the need for alternative immunotherapeutic targets and companion diagnostics. CD276 (B7-H3) has emerged as a promising target, with multiple anti-B7-H3 therapies in clinical development including monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR-T cells[4-6]. However, no validated companion diagnostic exists to stratify patients for these therapies. Here we present comprehensive validation of CD276 as a prognostic biomarker in GBM across multiple independent platforms. Using discovery analysis in TCGA (n=154) and independent validation in CPTAC proteomics (n=99)[7], we demonstrate that CD276-high expression is associated with significantly shorter survival ({Delta}=3.5-4.0 months, p=0.003-0.013). RNA expression correlates strongly with protein (r=0.75, p<0.0001), enabling flexible companion diagnostic development. Single-cell analysis of 338,564 cells from 110 patients[8] reveals CD276 is highest on tumor vasculature, supporting ADC targeting strategies that bypass the blood-brain barrier. Critically, we identify a novel therapeutic vulnerability: CD276-high tumors exhibit significantly reduced expression of ATP-binding cassette (ABC) drug efflux transporters ABCG2 (0.61-fold, p=0.0002) and ABCB1 (0.64-fold, p=0.005)[9]. Since these transporters actively efflux common ADC payloads including MMAE and DXd, their reduced expression suggests CD276-high tumors may be paradoxically more vulnerable to cytotoxic payloads despite their aggressive phenotype. This inverse relationship between target expression and drug efflux capacity provides mechanistic rationale for prioritizing CD276-high patients for ADC therapy. CD276 significantly outperforms PD-L1 across all metrics, consistent with PD-L1s clinical failure in GBM.

cancer biology↗