Biology subjects

Ho, R.

Publications and source records attributed to Ho, R..

24 records · Page 2Linked to original sources

bioRxiv2021

Lineage Recording Reveals the Phylodynamics, Plasticity and Paths of Tumor Evolution

Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth, expansion to neighboring and distal tissues, and therapeutic resistance. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma which enabled us to track tumor evolution from single transformed cells to metastatic tumors at unprecedented resolution. We found that loss of the initial, stable alveolar-type2-like state was accompanied by transient increase in plasticity. This was followed by adoption of distinct fitness-associated transcriptional programs which enable rapid expansion and ultimately clonal sweep of rare, stable subclones capable of metastasizing to distant sites. Finally, we showed that tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates tumor progression by creating novel evolutionary paths. Overall, our study elucidates the hierarchical nature of tumor evolution, and more broadly enables the in-depth study of tumor progression.

cancer biology↗

bioRxiv2020

TMIGD1, a putative tumor suppressor, induces G2-M cell cycle checkpoint arrest in colon cancer cells

Colorectal cancer (CRC) is a leading non-familial cause of cancer mortality among men and women. Although various genetic and epigenetic mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remains incompletely understood. In this study, we demonstrate that cell adhesion molecule transmembrane and immunoglobulin domain containing1 (TMIGD1) is highly expressed in mouse and human normal intestinal epithelial cells. We have developed TMIGD1 knockout mice and show that the loss of TMIGD1 in mice results in the development of adenomas in small intestine and colon. Additionally, the loss of TMIGD1 in mouse impaired intestinal epithelium brush border formation, junctional polarity and maturation. Mechanistically, TMIGD1 inhibits tumor cell proliferation, cell migration, arrests cell cycle at G2/M phase and induces expression of p21CIP1 (cyclin-dependent kinase inhibitor 1), and p27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in the regulation of the cell cycle. Moreover, we demonstrate that TMIGD1 is progressively downregulated in sporadic human CRC and correlates with poor overall survival. Our findings identify TMIGD1 as a novel tumor suppressor gene and provide insights into the pathogenesis of colorectal cancer and possibilities as a potential therapeutic target.

cancer biology↗

bioRxiv2020

Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to energy sensing and autophagy

Immunoglobulin (Ig) and proline-rich receptor-1 (IGPR-1) is a cell adhesion molecule that regulates angiogenesis and endothelial barrier function. IGPR-1 is activated by shear stress and mediates endothelial cells response to shear stress. Autophagy plays critical roles in the maintenance of endothelial cells in response to cellular stress caused by blood flow. However, whether IGPR-1 is activated in response to, and mediates autophagy remains unknown. In this study, we demonstrate that IGPR-1 is activated by autophagy inducing stimuli, such as amino acid starvation, nutrient deprivation, rapamycin and lipopolysaccharide (LPS). We have identified I{kappa}B kinase{beta} (IKK{beta}) as a key serine/threonine kinase activated by autophagy stimuli and mediates phosphorylation of IGPR-1 at Ser220. Activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase (AMPK), which leads to phosphorylation of key pro-autophagy proteins, ULK1 and Beclin-1 (BECN1), increased LC3-II levels and accumulation of LC3 punctum. This study demonstrates that IGPR-1 is activated by and regulates autophagy, connecting cell adhesion to autophagy, a finding that has important significance for autophagy-driven pathologies such cardiovascular diseases and cancer.

cell biology↗

bioRxiv2020

Single-cell RNA-seq analysis of human iPSC-derived motor neurons resolves early and predictive ALS signatures

Induced pluripotent stem cell (iPSC) derived neural cultures from amyotrophic lateral sclerosis (ALS) patients can reflect disease phenotypes targetable by treatments. However, widely used differentiation protocols produce mixtures of progenitors, neurons, glia, and other cells at various developmental stages and rostrocaudal neural tube segments. Here we present a methodology using single-cell RNA sequencing analysis to distinguish cell type expression in C9orf72 ALS, sporadic ALS, control, and genome-edited cultures across multiple subjects, experiments, and commercial platforms. Combinations of HOX and developmental gene expression with global clustering classified rostrocaudal, progenitor, and mantle zone fates. This demonstrated that iPSC-differentiated cells recapitulate fetal hindbrain and spinal cord development and resolved early, reproducible, and motor neuron-specific signatures of familial and sporadic ALS. This includes downregulated ELAVL3 expression, which persists into disease endstages. Single-cell analysis thus yielded predictive ALS markers in other human and mouse models which were otherwise undiscovered through bulk omics assays.

neuroscience↗

bioRxiv2019

Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells

Parthenolide, a natural product from the feverfew plant and member of the large family of sesquiterpene lactones, exerts multiple biological and therapeutic activities including anti-inflammatory and anti-cancer effects. Herein, we further study parthenolide mechanism of action using activity-based protein profiling (ABPP)-based chemoproteomic platforms to map additional covalent targets engaged by parthenolide in human breast cancer cells. We find that parthenolide, as well as other related exocyclic methylene lactone-containing sesquiterpenes, covalently modify cysteine 427 (C427) of focal adhesion kinase 1 (FAK1) leading to impairment of FAK1-dependent signaling pathways and breast cancer cell proliferation, survival, and motility. These studies reveal a novel functional target exploited by members of a large family of anticancer natural products.

cancer biology↗

bioRxiv2018

Adipose fin development and its relation to the evolutionary origins of median fins

The dorsal, anal and caudal fins of vertebrates are proposed to have originated by the partitioning and transformation of the continuous median fin fold that is plesiomorphic to chordates. Evaluating this hypothesis has been challenging, because it is unclear how the median fin fold relates to the adult median fins of vertebrates. To understand how new median fins originate, here we study the development and diversity of adipose fins. Phylogenetic mapping shows that in all lineages except Characoidei (Characiformes) adipose fins develop from a domain of the larval median fin fold. To inform how the larvas median fin fold contributes to the adipose fin, we study Corydoras aeneus (Siluriformes). As the fin fold reduces around the prospective site of the adipose fin, a fin spine develops in the fold, growing both proximally and distally, and sensory innervation, which appears to originate from the recurrent ramus of the facial nerve and from dorsal rami of the spinal cord, develops in the adipose fin membrane. Collectively, these data show how a plesiomorphic median fin fold can serve as scaffolding for the evolution and development of novel, individuated median fins, consistent with the median fin fold hypothesis.

evolutionary biology↗