Biology subjects

Henry, M. D.

Publications and source records attributed to Henry, M. D..

5 recordsLinked to original sources

bioRxiv2025

Brief Pulses of High-Level Fluid Shear Stress Enhance Metastatic Potential and Rapidly Alter the Metabolism of Cancer Cells.

Circulating tumor cells (CTCs) face challenges to their survival including mechanical and oxidative stresses that are different from cancer cells in solid primary and metastatic tumors. The impact of adaptations to the fluid microenvironment of the circulation on the outcome of the metastatic cascade are not well understood. Here we find that cancer cells (PC-3, MDA-MB-231, Myc-CaP) exposed to brief pulses of high-level FSS exhibit enhanced invasiveness and anchorage-independent proliferation in vitro and enhanced metastatic colonization/tumor formation in vivo. Cancer cells exposed to FSS rapidly alter their metabolism in a manner that promotes survival by providing energy for cytoskeletal remodeling and contractility as well as reducing equivalents to counter oxidative stress associated with cell detachment. Thus, exposure to FSS may provide CTCs an unexpected survival benefit that promotes metastatic colonization.

cancer biology↗

bioRxiv2025

PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted

Abstract/SummaryO_ST_ABSPurposeC_ST_ABSSarcomas are a heterogeneous group of cancers with few shared therapeutic targets. PI3K signaling is activated in various subsets of sarcomas, representing a shared oncogenic signaling pathway. Oncogenic PI3K signaling has been challenging to target therapeutically. An integrated view of PI3K and Hippo pathway signaling is examined to determine if this could be leveraged therapeutically. Experimental designA tissue microarray containing sarcomas of various histological types was evaluated for PTEN loss and correlated with levels of activated TAZ and YAP. PI3K and Hippo pathways were dissected in sarcoma cell lines. The role of TAZ and YAP were evaluated in a PI3K-driven mouse model. The efficacy of mTORC1 inhibition and TEAD inhibition were evaluated in sarcoma cell lines and in vivo. ResultsPI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30-60%), representing a common therapeutic target. TAZ and YAP are transcriptional co-activators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage independent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. Furthermore, this combination therapy showed a synergistic effect in vivo, reducing tumor proliferation and size. ConclusionsTAZ and YAP are transcriptional co-activators downstream of PI3K signaling, a pathway that has lacked a well-defined oncogenic transcription factor. This PI3K-TAZ/YAP axis exists in parallel to the known PI3K-Akt-mTORC1 axis allowing for synergistic combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1 in sarcomas.

cancer biology↗

bioRxiv2022

Metagenomic analysis reveals novel dietary-related viruses in the gut virome of marmosets hybrids (Callithrix jacchus x Callithrix penicillata), Brazil

Viral metagenomics has contributed enormously to the characterization of a wide range of viruses infecting animals of all phyla in the last decades. Among Neotropical primates, especially those free-living introduced, knowledge about viral diversity remains poorly studied. Therefore, through the use of metagenomics based on virus enrichment, we explored the viral microbiota present in the feces of introduced common marmosets (Callithrix sp.) in three locations from the Silva Jardim region in the State of Rio de Janeiro, Brazil. Fecal samples were collected from nine marmosets, pooled into three sample pools and sequenced on Illumina MiSeq platform. Sequence reads were analyzed using a viral metagenomic analysis pipeline and two novel insect viruses belonging to the Parvoviridae and Baculoviridae families were identified. The complete genome of a densovirus (Parvoviridae family) of 5,309 nucleotides (nt) was obtained. The NS1 and VP1 proteins share lower than 32% sequence identity with the corresponding proteins of known members of the subfamily Densovirinae. Phylogenetic analysis suggests that this virus represents a new genus, named Tritonambidensovirus due to telomeric structures at the 3 and 5 ends of the genome. The novel species received the name Fecalis tritonambidensovirus 1. The complete circular genome of a baculovirus of 107,191 nt was also obtained, showing 60.8% sequence identity with the most closely related member of the Baculoviridae family. Phylogenetic analysis suggests that this virus represents a new species of Betabaculovirus, named Callithrix fecalis granulovirus. In addition, sequences from several families of arthropods in the three pools evaluated were characterized (contigs ranging from 244 to 6,750 nt), corroborating the presence of possible insect hosts with which these new viruses may be associated. Our study expands the knowledge about two viral families known to infect insects, an important component of the marmosets diet. This identification in hosts feces samples demonstrates one of the many uses of this type of data and could serve as a basis for future research characterizing viruses in wildlife using noninvasive samples.

genomics↗

bioRxiv2020

Abl kinase deficiency promotes AKT pathway activation and prostate cancer progression and metastasis

Abl family kinases function as proto-oncogenes in various leukemias, and pro-tumor functions have been discovered for Abl kinases in solid tumors as well. However, a growing body of evidence indicates that Abl kinases can function to suppress tumor cell proliferation, motility, and in vivo tumor growth in some settings. To investigate the role of Abl kinases in prostate cancer, we generated Abl-deficient cells in a pre-clinical model of spontaneously metastatic, androgen-indifferent prostate cancer. Loss of Abl family kinase expression resulted in a highly aggressive, metastatic phenotype in vivo that was associated with AKT pathway activation, increased growth on 3D collagen matrix, and enhanced cell motility in vitro. Treatment of Abl kinase-expressing cells with the Abl kinase inhibitor imatinib phenocopied the malignant phenotypes observed in Abl-deficient tumor cells. In addition, inhibiting AKT pathway signaling abolished the increased 3D growth of Abl-deficient cells. Our data reveal that Abl family kinases can function as suppressors of prostate cancer progression and metastasis by restraining AKT signaling, a signaling pathway known to be associated with emergence of metastatic castration-resistant prostate cancer.

cancer biology↗

bioRxiv2019

Cancer cells resist mechanical destruction in the circulation via RhoA-myosin II axis

During metastasis cancer cells are exposed to potentially destructive hemodynamic forces including fluid shear stress (FSS) while en route to distant sites. However, prior work indicates that cancer cells are more resistant to brief pulses of high-level fluid shear stress (FSS) in vitro relative to non-transformed epithelial cells. Herein we identify a mechanism of FSS resistance in cancer cells, and extend these findings to mouse models of circulating tumor cells (CTCs). We show that cancer cells acutely isolated from primary tumors are resistant to FSS. Our findings demonstrate that cancer cells activate the RhoA-myosin II axis in response to FSS, which protects them from FSS-induced plasma membrane damage. Moreover, we show that the myosin II activity is protective to CTCs in mouse models. Collectively our data indicate that viable CTCs actively resist destruction by hemodynamic forces and are likely to be more mechanically robust than is commonly thought.

cancer biology↗