Tumor Mutational Burden (TMB) has emerged as a crucial biomarker to guide patient eligibility for immunotherapy. However, whole exome sequencing, the gold-standard method for TMB measurement, remains limited in accessibility due to its high costs, operational complexity, and lengthy processing times. To address these limitations, we investigated whether Ultra-High-Frequency (UHF) technology could serve as a novel approach to assess TMB by analyzing the crossover frequencies or electromagnetic signature (EMS) of cancer cells on a lab-on-a-chip biosensor, integrating microfluidics and dielectrophoresis. In a panel of 12 cancer cell lines with varying TMB levels, we observed that EMS showed an upward shift correlating with higher TMB, particularly in solid tumor cell lines. This finding suggests a potential relationship between TMB and EMS. To further explore this hypothesis, we artificially increased mutation levels by treating cells with the highly mutagenic compound N-ethyl-N-nitrosourea (ENU). Results showed that EMS captured significant TMB variations in ENU-treated cells with enhanced proliferative capacity compared to their parental counterparts. These results underscore the importance of matched control samples for reliable EMS measurements. Altogether, our findings highlight the potential of EMS to detect TMB variations associated with proliferative activity, a key hallmark of cancer cells, thereby enabling a more precise stratification of cancer cells. Highlights: We propose a new biosensor to improve patient stratification for ICI eligibility High frequency fields and dielectric spectroscopy can estimate TMB in cancer cells Significant changes in UHF-DEP signatures correlate with varying TMB levels UHF-DEP provides a cheap, rapid and label-free method to predict ICI response Offers an innovative and complementary marker to conventional diagnostic approaches Graphical

Sortilin, a glycoprotein belonging to the Vps10 family, is mainly recognized for its contribution to protein sorting. Its dichotomous role in oncology, between tumor promotion and suppression, remains highly controversial. Our present study reveals a novel mechanism relying on the nuclear localization of sortilin, acting on transcription, chromatin reorganization and DNA repair. Its role in limiting tumor progression of lung adenocarcinoma cell lines was confirmed with sustained EGFR proliferative signaling. Furthermore, we report that sortilin overexpression limits the growth of NCI-H1975 and NCI-H3255 cell lines, regulating gene expression but also indirectly altering oncogenic pathways such as MTOR and AKT. Through its transcriptional action, sortilin interacts directly with proteins central to DNA repair mechanisms and chromatin reorganization. Finally, our findings reshape the traditional view of sortilin, suggesting implications not restricted to its simple protein transport, which contributes to explain its heterogeneous roles in different tumors. These insights also position sortilin as a promising candidate to engineer innovative therapeutics in lung adenocarcinoma.

En dépit des avancées dans le diagnostic et la prise en charge thérapeutique du cancer du poumon, ce dernier demeure la principale cause de mortalité par cancer dans le monde. Dans la perspective d’améliorer la prise en charge des patients, les biomarqueurs, qu’ils soient pronostiques ou prédictifs de la réponse aux traitements, constituent le socle de la médecine personnalisée. Pour répondre au besoin de nouveaux outils d’évaluation rapide et financièrement accessible, nous avons exploré les applications d’un laboratoire sur puce basé sur la diélectrophorèse à ultra-haute fréquence (DEP-UHF) pour évaluer deux biomarqueurs stratégiques : la sortiline et la charge mutationnelle tumorale (TMB). L’expression de la sortiline, identifiée comme biomarqueur pronostique potentiel dans le CBNPC, est associée à une survie prolongée et à une agressivité tumorale réduite. Nos travaux montrent qu’elle limite la prolifération et la formation de tumorosphères in vitro, et qu’elle induirait un engagement dans la sénescence des cellules EGFR mutées, renforçant ainsi son intérêt clinique pour le pronostic et le traitement. Cependant, les résultats obtenus avec la DEP-UHF n’ont pas permis d’identifier de signature électromagnétique (SEM) directement liée à la sortiline. Par ailleurs, la TMB, biomarqueur émergent pour prédire la réponse aux inhibiteurs de points de contrôle immunitaire (ICI), a été estimée indirectement via la DEP-UHF. Le biocapteur DEP-UHF a démontré sa capacité à discriminer des cellules présentant une TMB élevée par une augmentation corrélée de leur SEM. Ces résultats préliminaires nécessitent toutefois une validation par des études comparatives sur des cellules tumorales issues de tumeurs et leurs tissus sains appariés, ainsi qu’une exploration de la corrélation entre les SEM et le potentiel immunogène des cellules, permettant de prédire plus précisément une réponse favorable aux ICI. En offrant une évaluation rapide, sans marquage et accessible, le biocapteur pourrait compléter les méthodes de stratification actuelles et affiner la sélection des patients, ouvrant la voie à des stratégies thérapeutiques plus personnalisées, pour une oncologie de précision.

Tumor Mutational Burden (TMB) is a critical biomarker used to determine patient eligibility for immunotherapy with immune checkpoint inhibitors. However, its gold-standard assessment via whole exome sequencing is limited by high costs, technical complexity, and lengthy processing times. To address these challenges, we investigated whether Ultra-High-Frequency (UHF) electromagnetic wave sensing could serve as an alternative method for evaluating TMB. We analyzed the dielectrophoresis crossover frequency spectrum and corresponding electromagnetic signature (EMS) of cancer cells using a lab-on-a-chip biosensor that integrates microfluidics with dielectrophoresis-based electro-manipulation. Across seven solid tumor cell lines exhibiting diverse TMB levels, EMS exhibited an upward shift correlated with higher TMB, suggesting a relationship between mutational load and electromagnetic behavior. To further explore this connection, we artificially increased the somatic variant burden by exposing cells to the mutagen N-ethyl-N-nitrosourea (ENU). EMS measurements reliably detected the induced increase in variant load in ENU-treated cells. Overall, these findings demonstrate that EMS can detect both intrinsic TMB differences and experimentally induced increases in mutational burden, enabling refined categorization of cancer cells. Although further validation is required, this work lays the foundation for developing complementary, rapid, and accessible tools to support cancer cell stratification and guide immunotherapy decision-making.