Biology subjects

Acevedo-Acevedo, S.

Publications and source records attributed to Acevedo-Acevedo, S..

4 recordsLinked to original sources

bioRxiv2026

Cancer cells acquire cysteine directly from a reduced tumor microenvironment

The metabolic environment of a tumor is shaped by the nutrients available in its interstitial fluid, yet the redox composition of that fluid is poorly defined. Measuring sulfur metabolites in the interstitial fluid of tumors, matched healthy organs, and serum across three mouse models of cancer, we find that the tumor microenvironment (TME) is a chemically reduced compartment in which free cysteine predominates over its oxidized form, cystine. This is especially pronounced in the lung TME, where cystine is nearly absent. We further show that lung cancer cells take up cysteine and cystine with comparable efficiency and proliferate on cysteine alone, and that the abundant glutathione in the TME helps keep cysteine reduced through disulfide exchange. In a medium formulated to match the sulfur composition of the lung tumor interstitial fluid, cells become independent of cystine import through xCT. Cells cultured in this medium were resistant to glutaminase inhibitors, oxidants and ferroptosis inducers, and better maintained NADPH levels under oxidative challenge. These findings suggest that standard culture conditions overestimate the dependence of cancer cells on cystine uptake and their vulnerability to oxidative stress-targeting therapies.

cancer biology↗

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↗

bioRxiv2022

LKB1 acts as a critical brake for the glucagon-mediated fasting response

As important as the fasting response is for survival, an inability to shut it down once nutrients become available can lead to exacerbated disease and severe wasting. The liver is central to transitions between feeding and fasting states, with glucagon being a key initiator of the hepatic fasting response. However, the precise mechanisms controlling fasting are not well defined. One potential mediator of these transitions is Liver Kinase B1 (LKB1) given its role in nutrient sensing. Here, we show LKB1 knockout mice have a severe wasting and prolonged fasting phenotype despite increased food intake. By applying RNA sequencing and intravital microscopy we show that loss of LKB1 leads to a dramatic reprogramming of the hepatic lobule through robust upregulation of periportal genes and functions. This is likely mediated through the opposing effect LKB1 has on glucagon pathways and gene expression. Conclusion: our findings show that LKB1 acts as a brake to the glucagon-mediated fasting response resulting in "periportalization" of the hepatic lobule and whole-body metabolic inefficiency. These findings reveal a new mechanism by which hepatic metabolic compartmentalization is regulated by nutrient-sensing.

physiology↗