Biology subjects

Lyons, S. K.

Publications and source records attributed to Lyons, S. K..

6 recordsLinked to original sources

bioRxiv2026

The Spliceosome Scaffold Component BCAS2 Promotes Pancreatic Cancer Progression through Weak 5 Splice Site Dependent Splicing Regulation

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. Dysregulated RNA splicing has emerged as a critical mechanism contributing to PDAC progression. However, whether structural components of the spliceosome regulate oncogenic alternative splicing was not known. Here, we identify the nineteen complex (NTC) component BCAS2/SPF27 as a critical regulator of PDAC progression. Elevated expression of BCAS2 in PDAC is associated with poor patient outcomes. Transcriptomic analyses revealed that BCAS2 specifically regulates alternative exons with weak splice sites. In particular, BCAS2 promotes SOS1 exon 21 inclusion and consequently RAC-signaling activation. Furthermore, splice-switching antisense oligonucleotide (ASO) mediated skipping of SOS1 exon 21 suppressed PDAC proliferation and migration. Our findings uncover a role of BCAS2 in the regulation of weak splice site usage and identify the BCAS2/SOS1/RAC signaling axis as a potential therapeutic vulnerability in pancreatic cancer.

cancer biology↗

bioRxiv2026

Microbial induction of MHC-II expression in colon cancer cells overcomes immunotherapy resistance and limits metastasis

Colorectal cancer remains a major cause of cancer mortality, and most microsatellite stable tumors derive little benefit from immune checkpoint blockade. Here, we identify a microbiome-dependent mechanism that converts immune-refractory colorectal cancer into a more immunologically responsive state. Using orthotopic mouse models spanning distinct genetic and immunologic contexts, we show that a Helicobacter-containing microbiome suppresses primary tumor growth and limits metastasis. This protective state is associated with increased intratumoral lymphocyte infiltration and stronger effector programs. Mechanistically, microbial exposure induces MHC class II expression in colon cancer cells to promote anti-tumor immunity. Tumor-intrinsic loss of CIITA abrogates microbial protection, whereas enforced CIITA expression is sufficient to increase intratumoral T cell accumulation, restrict progression and metastasis, and sensitize microsatellite-stable tumors to PD-1 and CTLA-4 blockade. In human microsatellite-stable patient-derived organoids, increased cancer-cell MHC-II enhanced interactions with autologous immune cells and increased tumor cell apoptosis. Together, these findings define a microbiome-cancer cell antigen presentation axis that restrains metastasis and overcomes immunotherapy resistance in colorectal cancer.

immunology↗

bioRxiv2025

The relationship between body size and skull and dental characters in cricetid rodents from Nebraska

Body size in mammals spans 20 orders of magnitude and is strongly correlated with ecology, making it one of the most important characteristics for a mammal. Body mass must be estimated for fossil mammals because the whole organism is rarely fully preserved. Although the relationships between anatomical characters and body mass have been calculated for many groups of mammals, rodents are less well studied. Previous work had limited sampling of species or used a species average for body size and may not be accurate. Because rodents are the most species rich order of mammals having accurate relationships for the different families of rodents is crucial for understanding the evolution of body size in rodents. I analysed the relationship between body size and three skull characters (skull, molar (M1), and toothrow length) in 11 species of cricetid rodents from Nebraska using reduced major axis regressions. I found a significant positive relationship between all characters and body size. Skull and toothrow length are the best predictors of body size. M1 length is not as good of a predictor because one genus (Microtus) has an unusually large M1 length for its body size. Separate regression equations for the Arvicolines and the Sigmodontids provide better predictors for body size using lower M1 length. This work will allow for more accurate predictions of body mass in extinct cricetids.

ecology↗

bioRxiv2023

Evaluating possible maternal effect lethality of Naa10 knockout mice, and modulation of phenotypes for embryonic and neonatal lethality by genetic background and environment

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/ymale mice on the inbred genetic background in this different animal facility.

genetics↗

bioRxiv2022

Internally-controlled and dynamic optical measures of functional tumor biology

Imaging defined aspects of functional tumor biology with bioluminescent reporter transgenes is a popular approach amongst the research community in drug development, as it is sensitive, relatively high-throughput and low cost. However, the lack of internal controls subject functional bioluminescence to a number of unpredictable variables that reduce this powerful tool to semi-quantitative interpretation of large-scale effects. Here we report the generation of sensitive and quantitative live reporters for two key measures of functional cancer biology and pharmacologic stress: the cell cycle and oxidative stress. We developed a two-colored readout, where two independent enzymes convert a common imaging substrate into spectrally distinguishable light. The signal intensity of one color is dependent upon biological state, whereas the other color is constitutively expressed. The ratio of emitted colored light corrects the functional signal for independent procedural variables, substantially improving the robustness and interpretation of relatively low-fold changes in functional signal intensity after drug treatment. The application of these readouts in vitro is highly advantageous, as peak cell response to therapy can now be readily visualized for single or combination treatments and not simply assessed at an arbitrary and destructive timepoint. Spectral imaging in vivo can be challenging, but we also present evidence to show that the reporters can work in this context as well. Collectively, the development and validation of these internally controlled reporters allow researchers to robustly and dynamically visualize tumor cell biology in response to treatment. Given the prevalence of bioluminescence imaging, this presents significant and much needed opportunities for preclinical therapeutic development.

cancer biology↗

bioRxiv2017

Endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases

Patients who have had their primary pancreatic ductal adenocarcinoma (PDA) surgically resected often develop metastatic disease, exemplifying the problem of latent metastases. Livers from patients and mice with PDA contained single, disseminated cancer cells (DCCs) with an unusual phenotype of being cytokeratin-19 (CK19)- and MHC class I (MHCI)-. We created a mouse model to determine how DCCs develop, their relationship to metastatic latency, and the role of immunity. Intra-portal injection of immunogenic PDA cells into pre-immunized mice seeded livers only with single, non-replicating DCCs lacking MHCI and CK19; naive recipients had macro-metastases. Transcriptomic analysis of PDA cells with the DCC phenotype demonstrated an endoplasmic reticulum (ER) stress response. Relieving ER stress with a chemical chaperone, in combination with T cell-depletion, stimulated outgrowth of macro-metastatic lesions containing PDA cells expressing MHCI and CK19. The ER stress response is the cell-autonomous reaction that enables DCCs to escape immunity and establish latent metastases.\n\nOne sentence summaryLatent pancreatic cancer metastases are created when T cells select disseminated cancer cells in which immune resistance and quiescence have been imposed by endoplasmic stress.

immunology↗