Biology subjects

Newman, L.

Publications and source records attributed to Newman, L..

7 recordsLinked to original sources

bioRxiv2026

Large oncosomes reprogram bone marrow mesenchymal stem cells to establish a pre-metastatic niche

Metastatic progression depends on the systemic remodeling of distant tissues before tumor cell arrival, yet the cancer-derived signals that orchestrate this process remain poorly understood. Large oncosomes (LOs) are atypically large (>1 um), tumor-derived extracellular vesicles shed by invasive cancer cells. Here, we demonstrate that LOs function as systemic mediators of pre-metastatic niche formation by activating innate immune sensing in bone marrow mesenchymal stem cells (BM-MSCs). Systemic administration of prostate- and breast cancer-derived LOs to immunocompetent tumor-bearing mice did not affect primary tumor growth but increased metastatic burden. LOs induced a robust, dose-dependent interferon-driven inflammatory program, characterized by interferon-stimulated genes and neutrophil chemokines. Mechanistically, this response was driven by LO-associated nucleic acids activating convergent cytosolic DNA- and RNA-sensing pathways in recipient stromal cells. LO-conditioned BM-MSCs promoted the accumulation and polarization of neutrophils toward an immunosuppressive, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) phenotype. In vivo, genetic suppression of LO shedding in tumor cells reduced PMN-MDSC accumulation in the bone marrow, which was reverted by systemic LO administration. Together, these findings establish LOs as specialized carriers of immunomodulatory signals that reprogram the bone marrow microenvironment to support metastatic colonization, identifying a previously unrecognized mechanism linking tumor vesiculation to immune remodeling at distant sites.

cancer biology↗

bioRxiv2026

Microstate Dynamics of Focused Attention Meditation

Focused-attention meditation provides a tractable model for examining how large-scale brain dynamics support attention and self-regulation. Using high-density EEG microstate analysis, we investigated how focused-attention meditation on the breath ([A]n[a]p[a]nasati) modulates intrinsic brain activity in 22 experienced practitioners, compared with baseline rest and deliberate mental imagery. Five canonical microstate classes (A-E) were identified. Meditation produced a robust reduction of Microstate C across coverage, duration, and occurrence, accompanied by increased presence of Microstates D and E (all Microstate x Condition interactions p < 0.0001). Source localization revealed that Microstate C was generated primarily in medial and lateral temporal regions including the hippocampus and parahippocampal cortex, whereas Microstate D involved posterior midline regions including the posterior cingulate cortex and precuneus, and Microstate E engaged frontoparietal and orbitolimbic networks. Together, these results indicate that focused-attention meditation reorganizes the temporal architecture of large-scale brain dynamics by downregulating microstate patterns associated with self-referential and memory-based processing while enhancing neural states supporting attentional stability and internal monitoring.

neuroscience↗

bioRxiv2025

Pan-Cancer PDOs Preserve Tumor Heterogeneity and Uncover Therapeutic Vulnerabilities

We developed a tumor-matched, pan-cancer patient-derived organoid (PDO) platform comprising 220 PDOs from 190 patients across 15 cancer types to advance functional precision oncology. Our comprehensively characterized PDOs showed 93% histopathology concordance, 80% median genomic concordance for driver mutations, and a 0.85 median gene expression correlation with parent tumors. Gene expression in PDOs remained stable across [≥] 10 passages, supporting reproducibility for long-term drug screening. Even PDOs with low genomic concordance retained oncogenic drivers, supporting their use as disease models. Clonality analysis revealed that 85% of PDOs preserved dominant tumor clones. Higher genomic concordance was associated with greater clonal similarity, while lower genomic concordance was associated with clonal divergence. Functional assays showed that 58% of PDOs from a subset of patients ineligible for FDA-approved PARP inhibitors responded to Talazoparib, with sensitivity linked to alterations in DNA damage repair. Combination screens revealed drugs that effectively overcame resistance, especially in TP53-mutant PDOs. In summary, our platform supports investigation of targeted therapies, identification of molecular features linked to drug sensitivity, and translational discovery, offering insights into personalized cancer treatment beyond current biomarker guidelines.

cancer biology↗

bioRxiv2023

Kinome focused CRISPR-Cas9 screens in African ancestry patient-derived breast cancer organoids identifies essential kinases and synergy of EGFR and FGFR1 inhibition.

Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapy strategies. These alterations are usually revealed via next generation sequencing of the tumor tissue. Yet, it is clear that some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. This is especially important in under-represented populations, whose mutational landscape and determinants of response to existing therapies are poorly characterized due to limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture in non-physiological conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in 3D-grown patient-derived tumor organoid (PDTO) models. We focused on identifying essential kinases that may translate to options for targeted therapies, including combination therapies. We first established a breast cancer PDTO biobank focused on underrepresented populations, including West African patients. We then performed a negative selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. We identified several previously unidentified kinase targets and showed that combination of FGFR1 and EGFR inhibitors synergizes to block organoids proliferation. Together these data demonstrate feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from under-represented cancer patients, and identify new targets for cancer therapy.

cancer biology↗

bioRxiv2023

Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment

Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased {psi}-H2AX protein expression. Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment.

cancer biology↗

bioRxiv2023

The biology of aging in a social world: insights from free-ranging rhesus macaques

Social adversity can increase the age-associated risk of disease and death, yet the biological mechanisms that link social adversities to aging remain poorly understood. Long-term naturalistic studies of nonhuman animals are crucial for integrating observations of social behavior throughout an individuals life with detailed anatomical, physiological, and molecular measurements. Here, we synthesize the body of research from one such naturalistic study system, Cayo Santiago Island, which is home to the worlds longest continuously monitored free-ranging population of rhesus macaques. We review recent studies of age-related variation in morphology, gene regulation, microbiome composition, and immune function. We also discuss ecological and social modifiers of age-markers in this population. In particular, we summarize how a major natural disaster, Hurricane Maria, affected rhesus macaque physiology and social structure and highlight the context-dependent and domain-specific nature of aging modifiers. Finally, we conclude by providing directions for future study, on Cayo Santiago and elsewhere, that will further our understanding of aging across different domains and how social adversity modifies aging processes.

immunology↗

bioRxiv2019

Germline murine immunoglobulin IGHV genes in wild-derived and classical inbred strains: a comparison

The genomes of classical inbred mouse strains include genes derived from all three major subspecies of the house mouse, Mus musculus. We recently posited that genetic diversity in the immunoglobulin heavy chain (IGH) gene loci of C57BL/6 and BALB/c mice reflect differences in subspecies origin. To investigate this hypothesis, we conducted high-throughput sequencing of IGH gene rearrangements to document IGH variable (IGHV), joining (IGHJ), and diversity (IGHD) genes in four inbred wild-derived mouse strains (CAST/EiJ, LEWES/EiJ, MSM/MsJ, and PWD/PhJ), and a single disease model strain (NOD/ShiLtJ), collectively representing genetic backgrounds of several major mouse subspecies. A total of 341 germline IGHV sequences were inferred in the wild-derived strains, including 247 not curated in the International Immunogenetics Information System. In contrast, 83/84 inferred NOD IGHV genes had previously been observed in C57BL/6 mice. Variability among the strains examined was observed for only a single IGHJ gene, involving a description of a novel allele. In contrast, unexpected variation was found in the IGHD gene loci, with four previously unreported IGHD gene sequences being documented. Very few IGHV sequences of C57BL/6 and BALB/c mice were shared with strains representing major subspecies, suggesting that their IGH loci may be complex mosaics of genes of disparate origins. This suggests a similar level of diversity is likely present in the IGH loci of other classical inbred strains. This must now be documented if we are to properly understand inter-strain variation in models of antibody-mediated disease.

immunology↗