Biology subjects

Chang, A. C.

Publications and source records attributed to Chang, A. C..

3 recordsLinked to original sources

bioRxiv2024

Hope for Others: Research Results from the University of Pittsburgh Rapid Autopsy Program for Breast Cancer

Breast cancer affects 1/8 of women throughout their lifetimes, with over 90% of cancer deaths being caused by metastasis. However, metastasis poses unique challenges to research, as complex changes in the microenvironment in different metastatic sites and difficulty obtaining tissue for study hinder the ability to examine in depth the changes that occur during metastasis. Rapid autopsy programs thus fill a unique need in advancing metastasis research. Here, we describe our protocol and processes for establishing and improving the US-based Hope for OTHERS (Our Tissue Helping Enhance Research and Science) program for organ donation in metastatic breast cancer. As of August 2024, we consented 114 patients and performed 37 autopsies, from which we collected 551 unique metastatic frozen tumor samples, 1244 FFPE blocks, 90 longitudinal liquid biopsy samples and developed 14 patient-derived organoid and 8 patient-derived xenograft models. We report in-depth clinical and histopathological information and discuss extensive new research and novel findings in patient outcomes, metastatic phylogeny, and factors in successful living model development. Our results reveal key logistical and protocol improvements that are uniquely beneficial to certain programs based on identifiable features, such as working closely with patient advocates, methods to rescue RNA quality in cases where tissue quality may degrade due to time delays, as well as guidelines and future expansions of our program. Statement of SignificanceRapid autopsy programs are unique research settings with huge potential for studying metastatic cancer, however, they have complex research challenges. Our work provides a valuable resource in advancing this field of research.

cancer biology↗

bioRxiv2023

O-GlcNAc Signaling Increases Neuron Regeneration Through One-Carbon Metabolism in Caenorhabditis elegans

Cellular metabolism plays an essential role in the regrowth and regeneration of a neuron following physical injury. Yet, our knowledge of the specific metabolic pathways that are beneficial to neuron regeneration remains sparse. Previously, we have shown that modulation of O-linked {beta}-N-acetylglucosamine (O-GlcNAc), a ubiquitous post-translational modification that acts as a cellular nutrient sensor, can significantly enhance in vivo neuron regeneration. Here we define the specific metabolic pathway by which mutation of the O-GlcNAc transferase (ogt-1) increases regenerative outgrowth. Performing in vivo laser axotomy and measuring subsequent regeneration of individual neurons in C. elegans, we find that the ogt-1 mutation increases regeneration by diverting the metabolic flux of enhanced glycolysis towards one carbon metabolism (OCM) and the downstream transsulfuration metabolic pathway (TSP). These effects are abrogated by genetic and/or pharmacological disruption of OCM or the serine synthesis pathway (SSP) that links OCM to glycolysis. Testing downstream branches of this pathway, we find that enhanced regeneration is dependent only on the vitamin B12 independent shunt pathway. These results are further supported by RNA-sequencing that reveals dramatic transcriptional changes, by the ogt-1 mutation, in the genes involved in glycolysis, OCM, TSP and ATP metabolism. Strikingly, the beneficial effects of the ogt-1 mutation can be recapitulated by simple metabolic supplementation of the OCM metabolite methionine in wild-type animals. Taken together, these data unearth the metabolic pathways involved in the increased regenerative capacity of a damaged neuron in ogt-1 animals and highlight the therapeutic possibilities of OCM and its related pathways in the treatment of neuronal injury. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/531166v1_ufig1.gif" ALT="Figure UFIG"> View larger version (19K): org.highwire.dtl.DTLVardef@7da18eorg.highwire.dtl.DTLVardef@1f997d6org.highwire.dtl.DTLVardef@15fa337org.highwire.dtl.DTLVardef@1d476bd_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOAbstarct Figure.C_FLOATNO Metabolic pathways involved in the enhanced neuronal regeneration in ogt-1 animalsThe green highlighted pathway illustrates the metabolic rewiring in ogt-1 mutant animals supporting enhanced axonal regeneration of injured neurons in vivo. C_FIG

neuroscience↗

bioRxiv2019

Regulation and dynamics of force transmission at individual cell-matrix adhesion bonds

Integrin-based adhesion complexes link the cytoskeleton to the extracellular matrix (ECM) and are central to the construction of multicellular animal tissues. How biological function emerges from the 10s-1000s of proteins present within a single adhesion complex has remained unclear. We used fluorescent molecular tension sensors to visualize force transmission by individual integrins in living cells. These measurements revealed an underlying functional modularity in which integrin class controlled adhesion size and ECM ligand specificity, while the number and type of connections between integrins and F-actin determined the force per individual integrin. In addition, we found that most integrins existed in a state of near-mechanical equilibrium, a result not predicted by existing models of cytoskeletal force transduction. A revised model that includes reversible crosslinks within the F-actin network accounts for this result, and suggests how cellular mechanical homeostasis can arise at the molecular level.

cell biology↗