Biology subjects

McLaughlan, S.

Publications and source records attributed to McLaughlan, S..

4 recordsLinked to original sources

bioRxiv2026

Lactate-fueled hydride transfer metabolon drives breast cancer metastasis

Metabolic plasticity of cancer cells plays a major role in metastasis. Use of alternative carbon fuels (e.g., lactate) boosts metabolic plasticity, but the underlying mechanisms remain obscure. We show that lactate dehydrogenase B (LDHB) cooperates with the hydride ion transfer complex (HTC) comprised of pyruvate carboxylase (PC), malic enzyme (ME1) and malate dehydrogenase (MDH1) to form a metabolon that confers metabolic flexibility through lactate assimilation under physiological conditions. HTC/LDHB metabolon assembles in the aggressive breast cancer subtypes and reprograms nicotinamide adenine dinucleotide (NAD) metabolism to promote migration, invasion and escape from anoikis - thereby driving metastasis. Altogether, this work identifies a lactate-fueled metabolon that propels metastatic dissemination of breast cancer.

Cancer Biology↗

bioRxiv2026

A Chemical-Genetic Interaction Matrix Reveals Drug Mechanism and Genetic Architecture

To probe drug mechanism of action (MOA) and interrogate the genetic architecture of human cells, we carried out isogenic genome-wide CRISPR/Cas9 knockout screens against 310 diverse drugs, bioactive compounds, and stress conditions. Stringent statistical correction for gene knockout fitness defects yielded a large-scale matrix of >12,000 high confidence chemical-genetic interactions (CGIs). This dataset revealed many previously unappreciated off-target effects for well-characterized compounds and novel MOAs for uncharacterized compounds. The CGI matrix uncovered dense genetic modules that yielded new biological insights into phospholipidosis, mitotic regulation, metabolism, the DNA damage response, and mTOR signaling. The dataset allowed identification of multi-drug sensitization and resistance mechanisms, inference of gene function, elaboration of cross-process connectivity, evaluation of the cell type specificity of CGIs, prediction of chemical synergism, and extensive annotation of understudied genes. This resource provides a map of the genetic landscape in human cells and a framework to help guide drug discovery.

systems biology↗

bioRxiv2024

Reduction in ETFDH expression optimizes cancer cell bioenergetics

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM-6 cells, and its expression is reduced across human cancers. ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilization but paradoxically increases cancer cell bioenergetics and accelerates neoplastic growth by activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerate neoplastic growth.

cancer biology↗

bioRxiv2017

Translational and HIF1α-dependent metabolic reprograming underpin oncometabolomeplasticity and synergy between oncogenic kinase inhibitors and biguanides.

There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI - biguanide combinations is impeded by HIF1 and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.

cancer biology↗