Biology subjects

Chen, C.-F.

Publications and source records attributed to Chen, C.-F..

5 recordsLinked to original sources

bioRxiv2023

Uncovering Minimal Pathways in Melanoma Initiation

Cutaneous melanomas are clinically and histologically heterogeneous. Most display activating mutations in Braf or Nras and complete loss of function of one or more tumor suppressor genes. Mouse models that replicate such mutations produce fast-growing, pigmented tumors. However, mice that combine Braf activation with only heterozygous loss of Pten also produce tumors and, as we show here, in an Albino background this occurs even with Braf activation alone. Such tumors arise rarely, grow slowly, and express low levels of pigmentation genes. The timing of their appearance was consistent with a single step stochastic event, but no evidence could be found that it required de novo mutation, suggesting instead the involvement of an epigenetic transition. Single-cell transcriptomic analysis revealed such tumors to be heterogeneous, including a minor cell type we term LNM (Low-pigment, Neural- and extracellular Matrix-signature) that displays gene expression resembling "neural crest"-like cell subsets detected in the fast-growing tumors of more heavily-mutated mice, as well as in human biopsy and xenograft samples. We provide evidence that LNM cells pre-exist in normal skin, are expanded by Braf activation, can transition into malignant cells, and persist with malignant cells through multiple rounds of transplantation. We discuss the possibility that LNM cells not only serve as a pre-malignant state in the production of some melanomas, but also as an important intermediate in the development of drug resistance.

cancer biology↗

bioRxiv2021

Structure-based Design of CDC42 Effector Interaction Inhibitors For the Treatment of Cancer

CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here we use computer-aided drug design to discover a new chemical entity (ARN22089) that targets CDC42 GTPases and blocks CDC42 effector interactions without affecting the binding between closely related GTPases (RAC1, RAS, RAL) and their downstream effectors. Our lead compound has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in three-dimensional vascularized microtumor models (VMT) in vitro. In addition, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. Taken together, this work identifies a promising new class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.

molecular biology↗

bioRxiv2021

Do forest over- and understory respond to the same environmental variables when viewed at the taxonomic and trait level?

While the relative importance of climate filtering is known to be higher for woody species assemblages than herbaceous assemblage, it remains largely unexplored whether this pattern is also reflected between the woody overstory and herbaceous understory of forests. While climatic variation will be more buffered by the tree layer, the understory might also respond more to small-scale soil variation, next to experiencing additional environmental filtering due to the overstorys effects on light and litter quality. For (sub)tropical forests, the understory often contains a high proportion of fern and lycophyte species, for which environmental filtering is even less well understood. We explored the proportional importance of climate proxies and soil variation on the species, functional trait and (functional) diversity patterns of both the forest overstory and fern and lycophyte understory along an elevational gradient from 850 to 2100 m a.s.l. in northern Taiwan. We selected nine functional traits expected to respond to soil nutrient or climatic stress for this study and furthermore verified whether they were positively related across vegetation layers, as expected when driven by similar environmental drivers. We found that climate was a proportionally more important predictor than soil for the species composition of both vegetation layers and trait composition of the understory. The stronger than expected proportional effect of climate for the understory was likely due to fern and lycophytes higher vulnerability to drought, while the high importance of soil for the overstory seemed driven by deciduous species. The environmental drivers affected different response traits in both vegetation layers, however, which together with additional overstory effects on understory traits, resulted in a strong disconnection of community-level trait values across layers. Interestingly, species and functional diversity patterns could be almost exclusively explained by climate effects for both vegetational layers, with the exception of understory species richness. This study illustrates that environmental filtering can differentially affect species, trait and diversity patterns and can be highly divergent for forest overstory and understory vegetation, and should consequently not be extrapolated across vegetation layers or between composition and diversity patterns.

ecology↗

bioRxiv2021

Decreased synthesis and variable gene transcripts of oxytocin in a domesticated avian species

The Bengalese finch was domesticated more than 250 years ago from the wild white-rumped munia. Similar to other domesticated species, Bengalese finches show a reduced fear response and have lower corticosterone levels, compared to white-rumped munias. Bengalese finches and munias also have different song types. Since oxytocin (OT) has been found to be involved in stress coping and auditory processing, we tested whether the OT sequence and brain expression pattern and content differ in wild munias and domesticated Bengalese finches. We identified intra-strain variability in the untranslated regions of the OT sequence in Bengalese finches in comparison to the munia OT. Several of these changes fall in specific transcription factor binding sites, which show either a conserved or a relaxed evolutionary trend in the avian lineage, and in vertebrates in general. Although in situ hybridization in several hypothalamic nuclei did not reveal significant differences in the number of cells expressing OT between the two strains, real-time quantitative PCR showed significantly lower OT mRNA expression in the diencephalon of the Bengalese finches relative to munias. Our study thus points to a decreased OT synthesis in the domestic strain compared with the wild strain in birds. This is an opposite pattern from that found in some domesticated mammals, suggesting that different processes of OT function might have occurred in mammals and birds under domestication.

neuroscience↗

bioRxiv2020

Dynamics of nevus development implicate cell cooperation in the growth arrest of transformed melanocytes

Mutational activation of the BRAF proto-oncogene in melanocytes reliably produces benign nevi (pigmented "moles"), yet the same change is the most common driver mutation in melanoma. The reason nevi stop growing, and do not progress to melanoma, is widely attributed to a cell-autonomous process of "oncogene-induced senescence". Using a mouse model of Braf-driven nevus formation, analyzing both proliferative dynamics and single-cell gene expression, we found no evidence that nevus cells are senescent, either compared with other skin cells, or other melanocytes. We also found that nevus size distributions could not be fit by any simple cell-autonomous model of growth arrest, yet were easily fit by models based on collective cell behavior, e.g. in which arresting cells release an arrest-promoting factor. We suggest that nevus growth arrest is more likely related to the cell interactions that mediate size control in normal tissues, than to any cell-autonomous, "oncogene-induced" program of senescence.

cancer biology↗