Biology subjects

Iyengar, P.

Publications and source records attributed to Iyengar, P..

5 recordsLinked to original sources

bioRxiv2026

The aging mouse lipidome

Aging is associated with widespread metabolic changes that contribute to functional decline and disease. While prior studies have characterized age-associated changes in lipids, it still remains incompletely understood how the lipidome changes across tissues and between sexes during aging. Here, we performed targeted lipidomics across 10 organs collected from male and female mice at five ages spanning adolescence to old age. We analyzed 775 lipids across multiple lipid classes and found that aging affects the lipidome in an organ-specific manner. The thymus and quadriceps muscle had the most age-associated lipid changes, whereas lipid levels in organs such as the kidney and lung remained more stable. In quadriceps muscle, aging was associated with a decrease in specific phosphatidylcholine and phosphatidylethanolamine lipids, particularly those containing adrenic acid. We also identified sex-dependent differences in lipid composition, with the spleen showing differences throughout life. Spleens from female mice had lower levels of lysophosphatidylcholine and lysophosphatidylethanolamine compared to males. Together, these data provide a comprehensive atlas of age- and sex-associated lipid changes across mouse organs and complement existing metabolic and transcriptomic resources to support studies of mouse aging.

molecular biology↗

bioRxiv2024

Cancer Cachexia in STK11/LKB1-mutated NSCLC is Dependent on Tumor-secreted GDF15

Cachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations in STK11/LKB1, a regulator of the energy sensor AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are associated with cancer-related weight loss in NSCLC patients. Here we characterized the relevance of the NSCLC-associated cachexia factor growth differentiation factor 15 (GDF15) in several patient-derived and genetically engineered STK11/LKB1-mutant NSCLC cachexia lines. Both tumor mRNA expression and serum concentrations of tumor-derived GDF15 were significantly elevated in multiple mice transplanted with patient-derived STK11/LKB1-mutated NSCLC lines. GDF15 neutralizing antibody administered to mice transplanted with patient- or mouse-derived STK11/LKB1-mutated NSCLC lines suppressed cachexia-associated adipose loss, muscle atrophy, and changes in body weight. The silencing of GDF15 in multiple human NSCLC lines was also sufficient to eliminate in vivo circulating GDF15 levels and abrogate cachexia induction, suggesting that tumor and not host tissues represent a key source of GDF15 production in these cancer models. Finally, reconstitution of wild-type STK11/LKB1 in a human STK11/LKB1 loss-of-function NSCLC line that normally induces cachexia in vivo correlated with the absence of tumor-secreted GDF15 and rescue from the cachexia phenotype. The current data provide evidence for tumor-secreted GDF15 as a conduit and a therapeutic target through which NSCLCs with STK11/LKB1 loss-of-function mutations promote cachexia-associated wasting.

cancer biology↗

bioRxiv2024

Multiplexed dynamic control of temperature to probe and observe mammalian cells.

Temperature is aa critical parameter for biological function, yet there is a lack of approaches to modulate the temperature of biological specimens in a dynamic and high-throughput manner. We present the thermoPlate, a device for programmable control of temperature in each well of a 96-well plate, in a manner compatible with mammalian cell culture and live cell imaging. The thermoPlate maintains precise feedback control of temperature patterns independently in each well, with minutes-scale heating and cooling through {Delta}T [~]15-20{degrees}C. A computational model that predicts thermal diffusion guides optimal design of heating protocols. The thermoPlate allowed systematic characterization of both synthetic and natural thermo-responsive systems. We first used the thermoPlate in conjunction with live-cell microscopy to characterize the rapid temperature-dependent phase separation of a synthetic elastin-like polypeptide (ELP53). We then measured stress granule (SG) formation in response to heat stress, observing differences in SG dynamics with each increasing degree of stress. We observed adaptive formation of SGs, whereby SGs formed but then dissolved in response to persistent heat stress (> 42{degrees}C). SG adaptation revealed a biochemical memory of stress that depended on both the time and temperature of heat shock. Stress memories continued to form even after the removal of heat and persisted for 6-9 hours before dissipating. The capabilities and open-source nature of the thermoPlate will empower the study and engineering of a wide range of thermoresponsive phenomena.

bioengineering↗

bioRxiv2024

A temperature-inducible protein module for control of mammalian cell fate

Inducible protein switches allow on-demand control of proteins in response to inputs including chemicals or light. However, these inputs either cannot be controlled with precision in space and time or cannot be applied in optically dense settings, limiting their application in tissues and organisms. Here we introduce a protein module whose active state can be reversibly toggled with a small change in temperature, a stimulus that is both penetrant and dynamic. This protein, called Melt (Membrane localization through temperature), exists as a monomer in the cytoplasm at elevated temperatures but both oligomerizes and translocates to the plasma membrane when temperature is lowered. The original Melt variant switched states between 28-32{degrees}C, and state changes could be observed within minutes of temperature change. Melt was highly modular, permitting thermal control over diverse processes including signaling, proteolysis, nuclear shuttling, cytoskeletal rearrangements, and cell death, all through straightforward end-to-end fusions. Melt was also highly tunable, giving rise to a library of variants with switch point temperatures ranging from 30-40{degrees}C. The variants with higher switch points allowed control of molecular circuits between 37{degrees}C-41{degrees}C, a well-tolerated range for mammalian cells. Finally, Melt permitted thermal control of cell death in a mouse model of human cancer, demonstrating its potential for use in animals. Thus Melt represents a versatile thermogenetic module for straightforward, non-invasive, spatiotemporally-defined control of mammalian cells with broad potential for biotechnology and biomedicine.

synthetic biology↗

bioRxiv2020

JAK Inhibitors Suppress Colon Cancer Cachexia-Associated Anorexia and Adipose Wasting in Mice

BackgroundCachexia (CX), a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukemia inhibitor factor (LIF) which induces CX. We characterized how LIF promotes CX-associated weight loss and anorexia in mice through JAK-dependent changes in adipose and hypothalamic tissues. MethodsCX was induced in vivo with C26c20 colon adenocarcinoma cells or recombinant LIF administration in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cyto/adipokine ELISAs, immunoblot analysis, and quantitative RT-PCR. CX was induced in vitro by stimulating differentiated adipocytes with recombinant LIF or IL-6 in the absence or presence of lipase or JAK inhibitors. These activated adipocytes were processed for lipolysis, immunoblot analysis, and RT-PCR. ResultsTumor-secreted LIF induced changes in adipose tissue expression and serum levels of IL-6 and leptin in a JAK-dependent manner influencing CX-associated adipose wasting and anorexia. We identified two JAK inhibitors that block cytokine-mediated adipocyte lipolysis and IL-6 induction using an in vitro CX lipolysis assay. JAK inhibitors administered to in vivo colon cancer CX mouse models led to 1) a decrease in STAT3 phosphorylation in hypothalamic and adipose tissues, 2) a reverse in the CX serum cyto/adipokine signature, 3) a delay in colon cancer CX-associated anorexia and adipose loss, and 4) an improvement in overall survival. ConclusionsJAK inhibitors suppress cytokine-associated adipose loss and anorexia in multiple in vitro and in vivo models of cancer CX.

cancer biology↗