Biology subjects

Possemato, A.

Publications and source records attributed to Possemato, A..

3 recordsLinked to original sources

bioRxiv2025

Cell signaling pathways discovery from multi-modal data

Deciphering cell signaling pathways is key to understanding biology, disease mechanisms, and developing new therapies. Although advances in multi-omics technologies provide richer insight into signaling, the data remain high-dimensional, heterogeneous, and difficult to interpret, and current computational tools for inferring signaling pathways are limited. To address this, we developed Incytr, a method for efficient discovery of cell signaling pathways through integration of diverse data modalities, including transcriptomics, ATAC-seq, proteomics, phosphoproteomics, and kinomics. We demonstrate its application in COVID-19, Alzheimers disease, and cancer, where it successfully recovers known pathways and generates novel, cell-type-specific hypotheses supported by multiple data types. We further show how integrating Incytr-derived pathways with biomarker and drug databases can support target and drug discovery. Finally, we show that using Incytr-derived signaling pathways as training data for simple natural language processing models can deepen our understanding of cell-cell communication and immune cell dynamics, while helping identify new therapeutic targets.

bioinformatics↗

bioRxiv2024

The ataxia-telangiectasia disease protein ATM controls vesicular protein secretion via CHGA and microtubule dynamics via CRMP5

The autosomal recessive disease ataxia-telangiectasia (A-T) presents with cerebellar degeneration, immunodeficiency, radiosensitivity, capillary dilatations, and pulmonary infections. Most symptoms outside the nervous system can be explained by failures of the disease protein ATM as Ser/Thr-kinase to coordinate DNA damage repair. However, ATM in adult neurons has cytoplasmic localization and vesicle association, where its roles remain unclear. Here, we defined novel ATM protein targets in human neuroblastoma cells and filtered initial pathogenesis events in ATM-null mouse cerebellum. Profiles of global proteome and phosphorylome - both direct ATM/ATR-phosphopeptides and overall phosphorylation changes - confirmed previous findings on NBN, MRE11, MDC1, CHEK1, EIF4EBP1, AP3B2, PPP2R5C, SYN1 and SLC2A1. Even stronger downregulation of ATM/ATR-phosphopeptides after ATM-depletion was documented for CHGA, EXPH5, NBEAL2 and CHMP6 as key factors of protein secretion and endosome dynamics, as well as for CRMP5, DISP2, PHACTR1, PLXNC1, INA and TPX2 as neurite extension factors. Prominent affection of semaphorin-CRMP5-microtubule signals and ATM association with CRMP5 were validated. As a functional consequence, microtubules were stabilized, and neurite retraction ensued. The ATM impact on secretory granules confirms previous ATM-null cerebellar transcriptome findings. Our study provides the first link of A-T neural atrophy to growth cone collapse and aberrant microtubule dynamics.

cell biology↗

bioRxiv2021

Craniofacial cartilage organoids from human embryonic stem cells via a neural crest cell intermediate

Severe birth defects or major injuries to the face require surgical reconstruction and rehabilitation. The ability to make bona fide craniofacial cartilage - cartilage of the head and face - from patient-derived induced pluripotent stem cells (iPSCs) to repair these birth defects and injuries has tremendous translational applications, but is not yet possible. The neural crest is the normal developmental pathway for craniofacial cartilage, however, the knowledge of cell signaling pathways that drive neural crest differentiation into craniofacial chondrocytes is limited. Here we describe a differentiation protocol that generated self-organizing craniofacial cartilage organoids from human embryonic stem cells (hESCs) and IPSCs through a neural crest stem cell (NCSC) intermediate. Histological staining of cartilage organoids revealed tissue architecture typical of hyaline cartilage. Organoids were composed of rounded aggregates of glassy, gray matrix that contained scattered small nuclei in lacunae. Mass spectrometry shows that the organoids express robust levels of cartilage markers including aggrecan, perlecan, proteoglycans, and many collagens. Organoids expressed markers indicative of neural crest lineage, as well as growth factors that are candidates for chondrocyte differentiation factors. The data suggest that chondrocyte differentiation is initiated by autocrine loops driven by a combination of secreted growth factors that bind to chondrocyte receptors. Craniofacial cartilage organoids were continuously cultured for one year, reaching up to one centimeter in diameter. The ability to grow craniofacial cartilage from NCSCs provides insights into the cell signaling mechanisms of differentiation into craniofacial cartilage, which lays the groundwork for understanding mechanistic origins of congenital craniofacial anomalies and repairing cartilaginous structures of the head and face.

developmental biology↗