Biology subjects

Flores-Figueroa, E.

Publications and source records attributed to Flores-Figueroa, E..

5 recordsLinked to original sources

bioRxiv2025

The subclonal footprint of pervasive early dissemination in pancreatic cancer

Early is too late describes a central problem in pancreatic cancer referring to its relentless drive to disseminate and highlights the need to understand how this disease spreads so rapidly. In this study, we profiled 1,013 samples from 277 donors, including tissue whole genome and RNA sequencing combined with plasma whole genome sequencing at [~]25x. Strikingly, local primary tumours, including some reaching 7cm, were found to shed little to no circulating tumour DNA (ctDNA). Instead, metastatic burden in the liver but not extrahepatic sites, was a main physiologic determinant of ctDNA levels. Whole-genome duplication (WGD), high cell cycle activity, and non-glandular differentiation emerged as tumour-intrinsic features related to increased ctDNA shedding. By contrast, decreased shedding was related to extrinsic features including a reactive microenvironment and unexpectedly, humoral immunity. Analysis of tumour clonal architecture showed that in patients with low ctDNA levels, the signal disproportionately originated from subclones and this signal persisted even when the primary tumour was removed. Disseminated subclones were a significant source of ctDNA in early-stage patients. Longitudinal analysis of patients revealed that subclones seeded metastases and shed ctDNA in the blood years before detection. This first report of paired tissue and plasma whole genomes in pancreatic cancer is a unique resource and has broad implications for disease surveillance, treatment monitoring, and early detection in this disease.

cancer biology↗

bioRxiv2024

NEST: Spatially-mapped cell-cell communication patterns using a deep learning-based attention mechanism

Dysregulation of communication between cells mediates complex diseases such as cancer and diabetes. However, detecting cell-cell communication (CCC) at scale remains one of the greatest challenges in transcriptomics. While gene expression measured with single-cell RNA sequencing and spatial transcriptomics reinvigorated computational approaches to detecting CCC, most existing methods exhibit high false positive rates, do not integrate spatial proximity of ligand-receptor interactions, and cannot detect CCC between individual cells. We overcome these challenges by presenting NEST (NEural network on Spatial Transcriptomics), which uses a graph attention network paired with an unsupervised contrastive learning approach to decipher patterns of communication while retaining the strength of each signal. We introduce new synthetic benchmarking experiments which demonstrate how NEST outperforms existing tools and detects biologically-relevant CCC along with directionality and confidence across spot- and cell-based technologies measuring several different tissues and diseases. In our applications, NEST identifies T-cell homing signals in human lymph nodes, aggressive cancer CCC in lung adenocarcinoma, and discovers new patterns of communication that act as relay networks in pancreatic cancer. Beyond two-dimensional data, we also highlight NESTs ability to detect CCC in three-dimensional spatial transcriptomic data.

bioinformatics↗

bioRxiv2023

Molecular and phenotypic blueprint of the hematopoietic compartment reveals proliferation stress as a driver of age-associated human stem cell dysfunctions

Hematopoietic stem/progenitor cell (HSPC) aging studies have been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across human aging is lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis across the lifespan. Although primitive HSPC numbers were stable during aging, overall cellularity was reduced, especially for erythroid and lymphoid lineages. Notably, HSPC from aged individuals had superior repopulating frequency than younger counterparts in xenografts; yet aged HSPC displayed epigenetic dysregulation of cell cycle, inflammatory signatures, and a reduced capacity to counteract activation-induced proliferative stress with concomitant accumulation of DNA damage and senescence-like features upon xenotransplantation. This phenotype was recapitulated by enforcing proliferative stress in vivo on cord blood (CB) HSPC. Overall, our work sheds light on dysregulated responses to activation-induced proliferation underlying HSPC aging and establishes CB xenotransplantation-based models as suitable for studying age-associated hematopoietic defects.

cell biology↗

bioRxiv2023

Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSC) acquire mutations in genes, including DNMT3A and TET2, conferring a competitive advantage through a mechanism that remains unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on CH bone marrow samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared to HSC from non-CH samples, revealing a non-cell autonomous mechanism. However, DNMT3A and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are more resistant to the deleterious impact of inflammation and aging.

cancer biology↗

bioRxiv2023

A hematopoietic stem cell subset that retains memory of prior inflammatory stress accumulates in aging and clonal hematopoiesis

Inflammation activates many blood cell types, driving aging and malignancy. Yet, hematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long blood production. To understand HSC adaptation to inflammation, we developed xenograft inflammation-recovery models and performed single cell multiomics on isolated human HSC. Two transcriptionally and epigenetically distinct HSC subsets expressing canonical HSC programs were identified. Only one showed sustained transcriptional and epigenetic changes after recovery from inflammatory treatments. This HSC inflammatory memory (HSC-iM) program is enriched in memory T cells and HSCs from recovered COVID-19 patients. Importantly, HSC-iM accumulates with age and with clonal hematopoiesis. Overall, heritable molecular alterations in a subset of human HSCs, an adaptation to long-term inflammatory stress, may predispose to heightened age-related risk of blood cancer and infection. One-Sentence SummaryInflammation across a lifetime rewires human HSCs to produce a distinct HSC subset with both beneficial and deleterious fitness consequences.

cell biology↗