Biology subjects

Baldwin, J. R.

Publications and source records attributed to Baldwin, J. R..

3 recordsLinked to original sources

bioRxiv2026

Ex Vivo Culture of Patient-Derived Primary, Metastatic, and Post-Mortem Lung Cancer Reveals Targetable States of EMT and Metabolic Plasticity

Lung cancer is a highly heterogeneous disease and remains the leading cause of cancer-related mortality worldwide. While mouse models and patient-derived organoids have advanced our understanding of lung cancer, key interactions within the tumor microenvironment (TME) remain poorly characterized. We developed microtumor models from lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) using mouse and patient samples, including surgical resections and rapid autopsy specimens. Microtumors preserve structural, cellular, and molecular features of the native TME, enabling mechanistic studies of tumor progression ex vivo. Multi-omics analyses of LUAD microtumors revealed progression-associated changes, including increased epithelial-to-mesenchymal transition (EMT) and metabolic reprogramming toward fatty acid synthesis. Pharmacologic inhibition of fatty acid synthesis through ACC1/2 reduced proliferation in patient-derived microtumors, identifying a targetable vulnerability. This platform provides a robust system for studying tumor progression, therapeutic response, and resistance mechanisms in lung cancer, including culturing postmortem specimens that are not accessible in current models.

cancer biology↗

bioRxiv2025

TAp73 mediates anti-tumor immunity through regulation of lipid metabolism in the lung tumor microenvironment

While immunotherapy has become the standard of care for lung adenocarcinoma (LUAD) patients without actionable genomic alterations, only a subset of patients benefits from a long-lasting response to immunotherapy. Activation of p53-related signals has emerged as a potential mediator of the lung tumor microenvironment (TME). Given that mutant-p53 interacts with p73 extensively and TAp73-deficient mice develop LUAD, we engineered a mouse model with conditional deletion of TAp73 to understand the interactions of the p53 family in the TME and in metabolic pathways that impact anti-tumor immunity. We demonstrated that TAp73 exerts a tumor-suppressive role in KrasG12D-driven LUAD by regulating lipid metabolism in the TME. We identified a TAp73-driven transcriptional signature involving genes in the arachidonic acid metabolism pathway operational in tumor-associated macrophages that favors T-cell activation and thus anti-tumor immunity. Similar transcriptional changes are seen in macrophages from LUAD patients with p53 mutations and in association with response to immunotherapy. SIGNIFICANCEThere is a need to understand how the LUAD TME impacts patient response to immunotherapy. We identified a transcriptional program enacted by TAp73 in tumor alveolar macrophages that supports T-cell activation. Transcriptional and metabolomic data from LUAD patients supports the relevance of this program in response to immune checkpoint inhibition.

cancer biology↗

bioRxiv2021

Genetic nurture effects on education: a systematic review and meta-analysis

Child educational development is associated with major psychological, social, economic and health milestones throughout the life course. Understanding the early origins of educational inequalities and their reproduction across generations is therefore crucial. Recent genomic studies provide novel insights in this regard, uncovering "genetic nurture" effects, whereby parental genotypes influence offsprings educational development via environmental pathways rather than genetic transmission. These findings have yet to be systematically appraised. We conducted the first systematic review and meta-analysis to quantify genetic nurture effects on educational outcomes and investigate key moderators. Twelve studies comprising 38,654 distinct parent(s)-offspring pairs or trios from eight cohorts were included, from which we derived 22 estimates of genetic nurture effects. Multilevel random effects models showed that the effect of genetic nurture on offsprings educational outcomes ({beta}genetic nurture = 0.08, 95% CI [0.07, 0.09]) was about half the size of direct genetic effects ({beta}direct genetic = 0.17, 95% CI [0.13, 0.20]). Maternal and paternal genetic nurture effects were similar in magnitude, suggesting comparable roles of mothers and fathers in determining their childrens educational outcomes. Genetic nurture effects were largely explained by parental educational level and family socioeconomic status, suggesting that genetically influenced environments play an important role in shaping child educational outcomes. Even after accounting for genetic transmission, we provide evidence that environmentally mediated parental genetic influences contribute to the intergenerational transmission of educational outcomes. Further exploring these downstream environmental pathways may inform educational policies aiming to break the intergenerational cycle of educational underachievement and foster social mobility. Public Significance StatementThis meta-analysis demonstrates that parents genetics influence their childrens educational outcomes through the rearing environments that parents provide. This "genetic nurture" effect is largely explained by family socioeconomic status and parental education level, is similar for mothers and fathers (suggesting that both parents equally shape their childrens educational outcomes) and is about half the size of direct genetic effects on childrens educational outcomes. Interventions targeting such environmental pathways could help to break the intergenerational cycle of educational underachievement and foster social mobility.

genetics↗