Mercier, O. | Search bioRxiv

bioRxiv2026

Glycometabolic, inflammatory and exocrine plasma proteins predict cancer in individuals with cardiovascular disease

Cancer development is preceded by systemic immune, metabolic and tissue perturbation. We asked whether a minimal circulating-protein signature anticipates incident cancer in patients with atheromatous cardiovascular disease (ACVD) exposed to tobacco. Discovery used a nested case-control set drawn from the longitudinal FLEMENGHO cohort (n=156; 38 incident lung cancers). Multi-omic profiling returned a two-step classifier: four proteins, smoking status, personal cancer history. Preprocessing constants, classifiers and both thresholds were fixed before transfer to PREVALUNG (n=397; 58 incident cancers, 26 of them lung). There, low O-GlcNAcase (OGA) with low interleukin-6 (IL-6) defined a very-low-risk stratum holding 1 of 58 cancers (sensitivity 98.3%, negative predictive value 98.8%); low chymotrypsin C (CTRC) with high beta microseminoprotein (MSMB) defined a high-risk stratum in which 15 of 28 participants developed cancer. No additional omic feature (metabolomic, immunophenotypic, clonal-haematopoietic or metagenomic) was retained as a reproducible improvement to the classifier under our selection framework. Discrimination was greater for cancers diagnosed more than 12 months after sampling than for near-term cancers (AUC 0.766, 95% CI 0.671-0.857, versus 0.589, 0.485-0.692), arguing against performance being driven principally by occult disease. These estimates are conditional on the cancer frequency of this population. They require prospective confirmation before any imaging schedule is changed.

cancer biology↗

bioRxiv2024

Integrating in silico predictions with an engineered tissue assay identifies Perlecan as an age-perturbed re-quiescence cue for muscle stem cells

Skeletal muscle regeneration is mediated by resident muscle stem cells that produce progeny to repair or recreate muscle. Critical to this function is the ability to transition between states of proliferation and quiescence. This balancing act is disrupted with age, leading to eroded regenerative capacity. Notwistanding, mechanisms by which the regenerating niche directs MuSCs return to the dormant state are largely unknown. Since single-cell RNAseq methods exclude the analysis of multinucleated cells, we generated single-nuclei RNAseq datasets of regenerating muscle to capture the full breadth of myogenic progression. With this, we uncovered new transition states between differentiating myocytes and syncytial multinucleated cells. Using cell communication inference tools, we highlighted receptor-ligand interactions between MuSCs and fusing nuclei. We leveraged a bespoke biomimetic 3D niche that induces MuSC quiescence, to filter the predicted interactions using a Cas9-based functional genomics approach. We found the proteoglycan Perlecan (Hspg2) promotes MuSC re-quiescence. Hspg2 silencing in vivo, during muscle regeneration, induced an aging-like phenotype and perturbed MuSC re-quiescence. Notably, the temporal profile and overall levels of Perlecan were altered with age. Exogenous supplementation with Endorepellin (truncated Perlecan) rescued MuSC decline following aged muscle regeneration, offering a new therapeutic target. Thus, coupling in silico predictions with a 3D in vitro assay followed by in vivo investigations revealed a previously inaccessible window of biology; that spatiotemporal coordination of MuSC re-quiescence is directed by fusing myonuclei.

cell biology↗