Biology subjects

Barretina, J.

Publications and source records attributed to Barretina, J..

5 recordsLinked to original sources

bioRxiv2026

Convergent stromal and immune remodeling defines spatial tumor dynamics in PARP inhibitor-resistant high-grade serous ovarian cancer

Acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) remains a major barrier to durable clinical benefit in patients with high-grade serous ovarian cancer (HGSOC), yet the profiles of tumors at resistance remain poorly understood. We profiled longitudinal HGSOC patient tumors spanning diagnosis, post-neoadjuvant therapy, and progression on PARPi with complementary spatial transcriptomics platforms, integrating single-cell-resolution Xenium analysis in paired longitudinal cases with cohort-level Visium profiling. PARPi failure was associated with spatial remodeling of the tumor microenvironment, marked by hypoxia-associated malignant transcriptional programs, increased stromal compartmentalization, and exclusion of effector immune cells. Together, these findings indicate that PARPi resistance in HGSOC is accompanied by reproducible spatial niche remodeling, underscoring the tumor microenvironment as a key contextual determinant of therapeutic failure.

cancer biology↗

bioRxiv2022

Charting the Spatial Landscape of Cancer Hallmarks

Tumors are complex ecosystems with dozens of interacting cell types. The concept of Cancer Hallmarks distills this complexity into a set of underlying principles that govern tumor growth. Here, we exploit this abstraction to explore the physical distribution of Cancer Hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that Hallmark activity is spatially organized-with 7 out of 13 Hallmarks consistently more active in cancer cells than within the non-cancerous tumor microenvironment (TME). The opposite is true for the remaining six Hallmarks. Additionally, we discovered that genomic distance between tumor subclones correlates with differences in Cancer Hallmark activity, even leading to clone-Hallmark specialization in some cases. Finally, we demonstrate interdependent relationships between Cancer Hallmarks at the junctions of TME and cancer compartments. In conclusion, including the spatial dimension, particularly through the lens of Cancer Hallmarks, can improve our understanding of tumor ecology. SignificanceWe explored Cancer Hallmarks in 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. This study unveiled spatial patterns in Hallmark activity, with some being more active in cancer cells and others in the non-cancerous tumor environment. Genomic distance impacted Hallmark activity, and we identified interdependencies at the TME-cancer junctions, improving our understanding of tumor ecology.

cancer biology↗

bioRxiv2021

The effect of external stimulation on functional networks in the aging healthy human brain

Understanding the brain changes occurring during aging can provide new insights for developing treatments that alleviate or reverse cognitive decline. Neurostimulation techniques have emerged as potential treatments for brain disorders and to improve cognitive functions. Nevertheless, given the ethical restrictions of neurostimulation approaches, in silico perturbation protocols based on causal whole-brain models are fundamental to gaining a mechanistic understanding of brain dynamics. Furthermore, this strategy could serve as a more specific biomarker relating local activity with global brain dynamics. Here, we used a large resting-state fMRI dataset divided into middle-aged (N=310, aged < 65 years) and older adults (N=310, aged[≥] 65) to characterize brain states in each group as a probabilistic metastable substate (PMS) space, each with a probabilistic occurrence and frequency. Then, we fitted the PMS to a whole-brain model and applied in silico stimulations with different intensities in each node to force transitions from the brain states of the older group to the middle-age group. We found that the precuneus, a brain area belonging to the default mode network and the rich club, was the best stimulation target. These findings might have important implications for designing neurostimulation interventions to revert the effects of aging on whole-brain dynamics.

neuroscience↗

bioRxiv2020

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

Black women of African ancestry experience more aggressive breast cancer with higher mortality rates than White women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast tumors, with RNA-seq in a subset, from indigenous African patients in Nigeria in comparison to The Cancer Genome Atlas (n=76) revealed a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations and a 10.5-year younger age at diagnosis. We also found evidence for non-coding mutations in two novel drivers (ZNF217 and SYPL1) and a novel INDEL signature strongly associated with African ancestry proportion. This comprehensive analysis of an understudied population underscores the need to incorporate diversity of genomes as a key parameter in fundamental research with potential to tailor clinical intervention and promote equity in precision oncology care.

genomics↗

bioRxiv2020

Whole-brain dynamics in aging: disruptions in functional connectivity and the role of the rich club

Normal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state fMRI studies have found significant age-related alterations in functional connectivity across various networks. Nevertheless, most of the studies have focused mainly on static functional connectivity. Studying the dynamics of resting-state brain activity across the whole-brain functional network can provide a better characterization of age-related changes. Here we employed two data-driven whole-brain approaches based on the phase synchronization of blood-oxygen-level-dependent (BOLD) signals to analyze resting-state fMRI data from 620 subjects divided into two groups ( middle-age group (n=310); age range, 50-65 years vs. older group (n=310); age range, 66-91 years). Applying the Intrinsic-Ignition Framework to assess the effect of spontaneous local activation events on local-global integration, we found that the older group showed higher intrinsic ignition across the whole-brain functional network, but lower metastability. Using Leading Eigenvector Dynamics Analysis, we found that the older group showed reduced ability to access a metastable substate that closely overlaps with the so-called rich club. These findings suggest that functional whole-brain dynamics are altered in aging, probably due to a deficiency in a metastable substate that is key for efficient global communication in the brain.

neuroscience↗