Biology subjects

Sears, R.

Publications and source records attributed to Sears, R..

9 recordsLinked to original sources

bioRxiv2025

Tumor-intrinsic MHC-II activation in pancreatic ductal adenocarcinoma enhances immune response and treatment efficacy

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME) and poor prognosis. While major histocompatibility complex class II (MHC-II) expression is traditionally associated with professional antigen-presenting cells, its role in PDAC malignant cells remains underexplored. Herein, we utilized single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA sequencing, multiplex immunohistochemistry (mIHC) and ex vivo studies in culture with both human and murine models to investigate the prognostic relevance of MHC-II expression in malignant PDAC cells. Elevated MHC-II expression in malignant cells was strongly associated with increased infiltration of CD4+ T and CD8+ T cells in human PDAC, and pronounced co-localization with plasma cells, indicative of an antigen-activated immune microenvironment. In the KPC mouse model of PDAC, pharmacologic induction of MHC-II expression by cobimetinib treatment in malignant epithelial cells significantly enhanced the therapeutic response to immune checkpoint blockade (ICB). These findings highlight the role of malignant cell- intrinsic MHC-II expression in promoting antigen presentation and fostering an anti-tumor immune microenvironment. Our results position MHC-II as a promising prognostic biomarker and therapeutic target in PDAC, paving the way for novel immunomodulatory strategies. Summary of highlightsSingle-cell and spatial transcriptomic analyses reveal that elevated MHC-II expression in malignant PDAC cells correlates with increased infiltration of CD4 and CD8 T cells. Stimulating MHC-II expression in tumors effectively enhances immunotherapeutic responses to ICB in the PDAC KPC mouse model, including PDAC tumors previously resistant to therapeutic interventions. MHC-II serves as a prognostic biomarker and a promising target for immunotherapy in PDAC.

cancer biology↗

bioRxiv2025

Hypoxia-induced histone methylation and NF-κB activation in pancreas cancer fibroblasts promote EMT-supportive growth factor secretion

The pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment contains hypoxic tissue subdomains and cancer-associated fibroblasts (CAFs) of multiple subtypes that play tumor-promoting and -restraining roles. Here, we demonstrate that hypoxia promotes an inflammatory-like CAF phenotype and that hypoxic CAFs selectively promote epithelial-mesenchymal transition (EMT) in PDAC cancer cells through growth factor-mediated cell crosstalk. By analyzing patient tumor single-cell transcriptomics and conducting an inhibitor screen, we identified IGF-2 and HGF as specific EMT-inducing growth factors produced by hypoxic CAFs. We further found that reactive oxygen species-activated NF-{kappa}B cooperates with hypoxia-dependent histone methylation to promote IGF-2 and HGF expression in hypoxic CAFs. In lineage-traced autochthonous PDAC mouse tumors, hypoxic CAFs resided preferentially near hypoxic, mesenchymal cancer cells. However, in subcutaneous tumors engineered with hypoxia fate-mapped CAFs, once-hypoxic re-oxygenated CAFs lacked a spatial correlation with mesenchymal cancer cells. Thus, hypoxia promotes reversible CAF-malignant cell interactions that drive EMT through druggable signaling pathways. One-sentence summaryWe show that hypoxic fibroblasts in pancreas cancer leverage histone methylation and ROS-mediated NF-{kappa}B activation to produce growth factors that drive epithelial-mesenchymal transition in malignant cells, demonstrating how tumor stromal features cooperate to initiate a signaling process for disease progression.

cancer biology↗

bioRxiv2023

Universal baleen whale microsatellite panel for individual identification and power to detect parentage

Highly polymorphic single tandem repeat loci (STR, also known as microsatellite loci) remain a familiar, cost efficient class of markers for genetic analyses in ecology, behavior and conservation. We characterize a new universal set of ten STR loci (from 28 potential candidate loci) in seven baleen whale species, which are optimized for PCR amplification in two multiplex reactions along with a Y chromosome marker for sex determination. The optimized, universal set of STR loci provides an ideal starting point for new studies in baleen whales aimed at individual-based and population genetic studies, and facilitates data sharing among research groups. Data from the new STR loci were combined with genotypes from other published STR loci to assess the power to assign parentage (paternity) using exclusion in four species: fin whales, humpback whales, blue whales and bowhead whales. We argue that parentage studies should present a power analysis to demonstrate that the specific data are sufficiently informative to assign parentage with statistical rigor.

genetics↗

bioRxiv2022

Direct estimation of genome mutation rates from pedigrees in free-ranging baleen whales

Current low germline mutation rate () estimates in baleen whales have greatly influenced research ranging from assessments of whaling impacts to evolutionary cancer biology. However, the reported rates were subject to methodological errors and uncertainty. We estimated directly from pedigrees in natural populations of four baleen whale species and the results were similar to primates. The implications of revised values include pre-exploitation population sizes at 14% of previous genetic diversity-based estimates and the conclusion that in itself is insufficient to explain low cancer rates in gigantic mammals (i.e., Petos Paradox). We demonstrate the feasibility of estimating from whole genome pedigree data in natural populations, which has wide-ranging implications for the many ecological and evolutionary inferences that rely on .

genetics↗

bioRxiv2020

Reducing shock imminence eliminates poor avoidance in rats

In signaled active avoidance (SigAA), rats learn to suppress Pavlovian freezing and emit actions to escape threats and prevent footshocks. SigAA is critical for understanding aversively-motivated instrumental behavior and anxiety-related active coping. However, with standard protocols [~]25% of rats exhibit high freezing and poor avoidance. This has dampened enthusiasm for the paradigm and stalled progress. We demonstrate that reducing shock imminence with long-duration warning signals leads to greater freezing suppression and perfect avoidance in all subjects. This suggests that instrumental SigAA mechanisms evolved to cope with distant harm and protocols that promote inflexible Pavlovian reactions are poorly-designed to study avoidance.

animal behavior and cognition↗

bioRxiv2020

Regulation of HDAC2-PDX1 by RNF125 defines pancreatic cancer development

There is an urgent need to define mechanisms underlying pancreatic adenocarcinoma (PDA) development. Our studies of ubiquitin ligases that may underlie PDA development led us to identify and characterize RNF125. We show that RNF125 exhibits nuclear expression in acinar cells, with reduced and largely cytosolic expression in ductal cells, PanIN and PDA specimens. We find that RNF125 interacts with histone deacetylase 2 (HDAC2) and promotes its non-canonical K63-linked ubiquitination. Inhibition of HDAC2 activity by RNF125 resulted in elevated expression of the pancreatic and duodenal homeobox 1 (PDX1). Correspondingly, inhibition of RNF125 expression enhanced organoid growth in culture and orthotopic tumor development. Conversely, restoration of PDX1 levels in human or mouse PDA cells and organoids depleted of RNF125, inhibited cell proliferation and growth, while expression of HDAC2 enhanced it. Notably, higher expression of RNF125 and PDX1 coincided with differentiated tumor phenotypes, and better outcome in PDA patients. In demonstrating the importance of RNF125 control of PDX1 expression via HDAC2 ubiquitination in PDA development, our findings highlight markers (RNF125, PDX1) and targets (HDAC2) for monitoring and possible treatment of PDA.

cancer biology↗

bioRxiv2018

The translatome of adult cortical axons is regulated by learning in vivo

Local translation can support memory consolidation by supplying new proteins to synapses undergoing plasticity. Translation in adult forebrain dendrites is an established mechanism of synaptic plasticity and is regulated by learning, yet there is no evidence for learning-regulated protein synthesis in adult forebrain axons, which have traditionally been believed to be incapable of translation. Here we show that axons in the adult rat amygdala contain translation machinery, and use translating ribosome affinity purification (TRAP) with RNASeq to identify mRNAs in cortical axons projecting to the amygdala, over 1200 of which were regulated during consolidation of associative memory. Mitochondrial and translation-related genes were upregulated, whereas synaptic, cytoskeletal, and myelin-related genes were downregulated; the opposite effects were observed in the cortex. Our results demonstrate that learning-regulated axonal translation occurs in the adult forebrain, and support the likelihood that local translation is more a rule than an exception in neuronal processes.

neuroscience↗

bioRxiv2018

Strong and lasting impacts of past global warming on baleen whale and prey abundance

AbstractThe demography of baleen whales and their prey during the past 30 thousand years was assessed to understand the effects of past rapid global warming on marine ecosystems. Mitochondrial and genome-wide DNA sequence variation in eight baleen whale and seven prey species revealed strong, ocean-wide demographic changes that were correlated with changes in global temperatures and regional oceanographic conditions. In the Southern Ocean baleen whale and prey abundance increased exponentially and in apparent synchrony, whereas changes in abundance varied among species in the more heterogeneous North Atlantic Ocean. The estimated changes in whale abundance correlated with increases in the abundance of prey likely driven by reductions in sea-ice cover and an overall increase in primary production. However, the specific regional oceanographic environment, trophic interactions and species ecology also appeared to play an important role. Somewhat surprisingly the abundance of baleen whales and prey continued to increase for several thousand years after global temperatures stabilized. These findings warn of the potential for dramatic, long-term effects of current climate changes on the marine ecosystem.\n\nOne Sentence SummaryThe effects of past global warming on marine ecosystems were drastic, system-wide and long-lasting.

evolutionary biology↗

bioRxiv2018

Fin whale (Balaenoptera physalus) mitogenomics: A cautionary tale of defining sub-species from mitochondrial sequence monophyly

HighlightsO_LIMitochondrial monophyly is commonly employed to define evolutionary significant units.\nC_LIO_LIMonophyly may be caused by insufficient sampling or a recent common ancestor.\nC_LIO_LIMitogenomic studies are generally based on few samples and prone to sampling issues.\nC_LIO_LIExpanded mitogenome sampling negates previous monophyly in fin whales.\nC_LI\n\nAbstractThe advent of massive parallel sequencing technologies has resulted in an increase of studies based upon complete mitochondrial genome DNA sequences that revisit the taxonomic status within and among species. Spatially distinct monophyly in mitogenomic genealogies, i.e., the sharing of a recent common ancestor among con-specific samples collected in the same region has been viewed as evidence for subspecies. Several recent studies in cetaceans have employed this criterion to suggest subsequent intraspecific taxonomic revisions. We reason that employing intra-specific, spatially distinct monophyly at non-recombining, clonally inherited genomes is an unsatisfactory criterion for defining subspecies based upon theoretical (genetic drift) and practical (sampling effort) arguments. This point is illustrated by a re-analysis of a global mitogenomic assessment of fin whales, Balaenoptera physalus spp., published by Archer et al. (2013) which proposed to further subdivide the Northern Hemisphere fin whale subspecies, B. p. physalus. The proposed revision was based upon the detection of spatially distinct monophyly among North Atlantic and North Pacific fin whales in a genealogy based upon complete mitochondrial genome DNA sequences. The extended analysis conducted in this study (1,676 mitochondrial control region, 162 complete mitochondrial genome DNA sequences and 20 microsatellite loci genotyped in 358 samples) revealed that the apparent monophyly among North Atlantic fin whales reported by Archer et al. (2013) to be due to low sample sizes. In conclusion, defining sub-species from monophyly (i.e., the absence of para-or polyphyly) can lead to erroneous conclusions due to relatively \"trivial\" aspects, such as sampling. Basic population genetic processes (i.e., genetic drift and migration) also affect the time to most recent common ancestor and hence the probability that individuals in a sample are monophyletic.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC=\"FIGDIR/small/488130v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@1e38e54org.highwire.dtl.DTLVardef@9533eborg.highwire.dtl.DTLVardef@183b5b5org.highwire.dtl.DTLVardef@eae09_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗