Biology subjects

Thang, L.

Publications and source records attributed to Thang, L..

3 recordsLinked to original sources

bioRxiv2025

Granzyme-targeting quenched activity-based probes for assessing tumor response to immunotherapy

Molecular imaging of immune activation holds tremendous potential for the development of novel immunotherapy. In particular, chemical probes capable of detecting immune responses before changes in tumor size occur can guide early therapeutic strategies. Here, we present quenched activity-based probes targeting granzymes as a biomarker of antitumor immunity. Through optimization of peptide recognition element and functional chemical warhead, we have developed an optical imaging probe Cy5-IEPCyaPhP-QSY21, which rapidly reacts with GzmB at substoichiometric concentrations and enables efficient, selective labeling of the active enzyme in a complex proteome. With high specificity and minimal background signal, this probe produces GzmB-induced near-infrared fluorescence signals in the tumors of living mice shortly after injection. Both in vivo and ex vivo fluorescence signals correlate with GzmB expression and activity, and the population of CD8+ cells in tumor tissues. Moreover, it demonstrates the potential to track tumor response to immunotherapy. Thus, this study offers a chemical tool for assessing immune-mediated anticancer activity using noninvasive optical imaging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/643086v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1bff748org.highwire.dtl.DTLVardef@3c80dorg.highwire.dtl.DTLVardef@4301ceorg.highwire.dtl.DTLVardef@12b7c8a_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Metastatic organotropism in small cell lung cancer

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive bulk and single cell multiomic profiling of transcriptomes and chromatin accessibility, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.

cancer biology↗

bioRxiv2023

An electrochemical approach for rapid, sensitive, and selective detection of dynorphin

The endogenous opioid peptide systems are critical for analgesia, reward processing, and affect, but research on their release dynamics and function has been challenging. Here, we have developed microimmunoelectrodes (MIEs) for the electrochemical detection of opioid peptides using square-wave voltammetry. Briefly, a voltage is applied to the electrode to cause oxidation of the tyrosine residue on the opioid peptide of interest, which is detected as current. To provide selectivity to these voltammetric measurements, the carbon fiber surface of the MIE is coated with an antiserum selective to the opioid peptide of interest. To test the sensitivity of the MIEs, electrodes are immersed in solutions containing different concentrations of opioid peptides, and peak oxidative current is measured. We show that dynorphin antiserum-coated electrodes are sensitive to increasing concentrations of dynorphin in the attomolar range. To confirm selectivity, we also measured the oxidative current from exposure to tyrosine and other opioid peptides in solution. Our data show that dynorphin antiserum-coated MIEs are sensitive and selective for dynorphin with little to no oxidative current observed in met-enkephalin and tyrosine solutions. Additionally, we demonstrate the utility of these MIEs in an in vitro brain slice preparation using bath application of dynorphin as well as optogenetic activation of dynorphin release. Future work aims to use MIEs in vivo for real-time, rapid detection of endogenous opioid peptide release in awake, behaving animals.

neuroscience↗