Biology subjects

Catalano, I.

Publications and source records attributed to Catalano, I..

5 recordsLinked to original sources

bioRxiv2026

TGF-β1-induced differentiation enhances chemotherapy response in metastatic colorectal cancer organoids

BackgroundIn metastatic colorectal cancer, systemic therapies frequently fail, partly due to underlying phenotypic plasticity rooted in pre-existing multi-type cell populations. Intratumoral lineage hierarchies within colorectal tumors require renovated efforts to decode growth principles, design rational therapeutic approaches, and accurately interpret drug response. Understanding the cell-state dynamics of untreated tumors and the degree of cell responsiveness to exogenous stimuli is therefore crucial to improving currently underwhelming therapeutic outcomes. MethodsHere, we leveraged patient-derived organoids established from hepatic metastases of colorectal cancer patients to deconstruct population hierarchies by combining single-cell transcriptomics with single-molecule RNA fluorescent in situ hybridization. Computational frameworks were used to identify independent gene modules. We then employed flow cytometry analysis to track cytokine-induced population shifts using a cell surface marker, validating our findings through bulk RNA analysis, functional assays, and viability assays in response to oxaliplatin. ResultsOur data substantiate the existence of a dual population configuration within untreated metastatic colorectal cancer organoids with diverse genetic backgrounds. Gene modules detected via single-cell transcriptomics delineate a stem-like (LGR5+) and a differentiated-like (KRT20+) population that fluctuate dynamically over time. Spatially and temporally resolved, single-cell level analysis through single molecule FISH captures the inherent stochasticity in cell fate decisions revealing surprising phenotypic variability even across different organoids derived from the same patient. By using GABRA2 as a surface marker we track the emergence of differentiated cells over the course of time and investigate the respective roles of TGF-{beta}1 and IL-6 in the differentiation of organoids. Our findings indicate that IL-6 exerts no major effect within our cell autonomous setting. In stark contrast, TGF-{beta}1 triggered cell cycle arrest and differentiation, while simultaneously reducing clonogenic capacity and significantly amplifying the cytotoxic potency of oxaliplatin. ConclusionsOur findings provide evidence of the dual Stem and Differentiated population hierarchy in metastatic colorectal cancer organoids, and demonstrate how this axis can be effectively hijacked by TGF-{beta}1 to suppress tumor growth. Our results suggest that further mechanistic exploitation of this cell-autonomous, tumor-suppressive arm of TGF-{beta}1 signalling could open unappreciated therapeutic windows in advanced colorectal cancer.

cancer biology↗

bioRxiv2025

Rearing condition affects behavioral response to cross-modal expectancy violation paradigm in zebra finches

Interacting in a multimodal world, including recognizing other individuals across multiple sensory modalities, is important for animals who rely on social relationships for survival. Social and sensory experiences shape how multisensory information is processed and integrated; however, we have less understanding of how multimodal recognition may be modulated by early sensory experience in a single modality. Zebra finches are gregarious songbirds that form lifelong pair-bonds with a single partner whom they recognize acoustically and visually. However, it is unknown to what extent multisensory signals might interact to enable recognition or whether this is affected by auditory exposure during development. In this paper, we tested females for responses to audio and visual stimuli from their mate or a stranger in a digital cross-modal expectancy violation paradigm. Using automated pose tracking, we determined that, like many species, zebra finches react differently when the stimuli are congruent versus incongruent. However, while birds reared in a colony setting and birds reared without exposure to adult song both detected audiovisual congruency, the degree of behaviors exhibited differed between the rearing conditions. Thus, multisensory integration appears to be important for females to identify their mates, but differences in developmental environment influence how recognition is behaviorally expressed.

animal behavior and cognition↗

bioRxiv2024

Early auditory and adult mating experiences interact with singer identity to shape neural responses to song in female zebra finches

Social and sensory experiences across the lifespan can shape social interactions, however, experience-dependent plasticity is widely studied within discrete life stages. In the socially monogamous zebra finch, in which females use learned vocal signals to identify individuals and form long-lasting pair bonds, developmental exposure to song is key for females to show species-typical song perception and preferences. While adult mating experience can still lead to pair-bonding and song preference learning even in birds with limited previous song exposure ("song-naive"), whether similarities in adult behavioral plasticity between normally-reared and song-naive females reflect convergent patterns of neural activity is unknown. We investigated this using expression of a marker of neural activity and plasticity (phosphorylated S6) in mated normally-reared and song-naive females in response to song from either their mate, a neighbor, or an unfamiliar male. We found that, in portions of a secondary auditory region (the caudomedial nidopallium NCM) and in dopaminergic neurons of the caudal ventral tegmental area, hearing the mates song significantly increased pS6 expression in females from both rearing conditions. In contrast, within other NCM subregions, song-identity drove different patterns of pS6 expression depending on the rearing condition. These data suggest that developmental experiences can have long-lasting impacts on the neural signatures of behaviors acquired in adulthood and that socially-driven behavioral plasticity in adults may arise through both shared and divergent neural circuits depending on an individuals developmental experiences.

neuroscience↗

bioRxiv2024

Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer

DNA sequence mutability in tumors with chromosomal instability is conventionally believed to remain uniform, constant, and low, based on the assumption that further mutational accrual in a context of marked aneuploidy is evolutionarily disadvantageous. However, this concept lacks robust experimental verification. We adapted the principles of mutation accumulation experiments, traditionally performed in lower organisms, to clonal populations of patient-derived tumoroids and empirically measured the spontaneous rates of accumulation of new DNA sequence variations in seven chromosomally unstable, microsatellite stable colorectal cancers (CRCs) and one microsatellite unstable CRC. Our findings revealed heterogeneous mutation rates (MRs) across different tumors, with variations in magnitude within microsatellite stable tumors as prominent as those distinguishing them from microsatellite unstable tumors. Moreover, comparative assessment of microsatellite stable primary tumors and matched synchronous metastases consistently documented a pattern of MR intensification during tumor progression. Therefore, wide-range diversity and progression-associated evolvability of DNA sequence mutational instability emerge as unforeseen hallmarks of microsatellite stable CRC, complementing karyotype alterations as selectable traits to increase genetic variation. One sentence summaryTumors with chromosomal instability accrue DNA sequence mutations at highly variable rates, which increase during metastatic progression.

cancer biology↗

bioRxiv2023

XENTURION, a multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients for population-level translational oncology

The breadth and depth at which cancer models are interrogated contribute to successful translation of drug discovery efforts to the clinic. In colorectal cancer (CRC), model availability is limited by a dearth of large-scale collections of patient-derived xenografts (PDXs) and paired tumoroids from metastatic disease, the setting where experimental therapies are typically tested. XENTURION is a unique open-science resource that combines a platform of 129 PDX models and a sister platform of 129 matched PDX-derived tumoroids (PDXTs) from patients with metastatic CRC, with accompanying multidimensional molecular and therapeutic characterization. A PDXT-based population trial with the anti-EGFR antibody cetuximab revealed variable sensitivities that were consistent with clinical response biomarkers, mirrored tumor growth changes in matched PDXs, and recapitulated the outcome of EGFR genetic deletion. Adaptive signals upregulated by EGFR blockade were computationally and functionally prioritized, and inhibition of top candidates increased the magnitude of response to cetuximab. These findings illustrate the probative value and accuracy of large ex vivo and in vivo living biobanks, highlight the importance of cross-platform and cross-methodology systematic validation, and offer avenues for molecularly informed preclinical research.

cancer biology↗