Citations 2
Lysosomal lipid metabolism promotes tumor cell invasion through local energetics and membrane lipid remodeling
Nooren, Roseanne E. , Johnson, Katherine M. , Marley, Maxwell G., Rozeveld, Cody N., Gibbard, D., Correa, Zinnarky K Ortiz, Espe, Tianna, Hitosugi, Taro , Liu, Jun, McNiven, Mark A, Gibbard, Daniel F., Gedik, Mustafa Emre, Brownfield, Douglas G , Razidlo, Gina L , Johnson, Katherine M., Ortiz‐Correa, Zinnarky K., Gedik, Mustafa Emre , Lanza, Ian R. , Brownfield, Douglas , McNiven, Mark A. , Razidlo, Gina L.
No container title available | June 6, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Metabolic vulnerabilities in cancer have been targeted primarily to suppress tumor growth, but less is known about the metabolic requirements for tumor cell invasion. Here we report that lipid catabolism by cytosolic and lysosomal lipases supports pancreatic cancer cell invasion through both overlapping and distinct functional and metabolic mechanisms. Lysosomal acid lipase (LAL)-dependent lipid droplet catabolism promotes invadopodia formation and stabilization, enabling extracellular matrix degradation. In addition to modulating cellular energetics, lipidomics revealed that lipid droplet catabolism regulates cholesterol and membrane phospholipid levels. Using spatially resolved biosensors and cholesterol imaging, we found that lysosomal lipid catabolism occurs at invadopodia and sustains local ATP and membrane cholesterol. These findings identify spatially organized lipid catabolism as a mechanism that couples local energetics and membrane remodeling during the earliest steps of pancreatic cancer cell invasion.
Mitochondrial metabolism and epigenetic crosstalk drive the SASP
Martini, Hélène , Birch, Jodie , Victorelli, Stella , Lagnado, Anthony B. , Pirius, Nicholas, Han, Yeaeun , Havas, Aaron , Jurk, Diana , Adams, Peter D. , Passos, João F. , Victorelli, Stella , Lagnado, Anthony , Franco, Ana, Lee, Gung, Han, Yeaeun , Rowsey, Jennifer, Gaspar-Maia, Alexandre , Havas, Aaron , Porritt, Rebecca , Maddocks, Oliver , Jurk, Diana , Khosla, Sundeep , Adams, Peter , Passos, João F , Marques, Francisco Madeira , Franco, Ana Catarina , Lee, Gung , Rowsey, Jennifer L. , Ismail, Wazim Mohammed , Mazzone, Amelia , Espe, Tianna, Hitosugi, Taro , Li, Ya , Washington, Alexander M. , Murad, Rabi , Lei, Xue , Espíndola‐Netto, Jair Machado , Saul, Dominik , Khosla, Sundeep , Kostallari, Enis , Gaspar‐Maia, Alexandre
No container title available | December 5, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.