Biology subjects

Geyer, N.

Publications and source records attributed to Geyer, N..

3 recordsLinked to original sources

bioRxiv2026

A distal CTCF-binding site drives MYC expression plasticity in a negative feed-forward loop

Oncogene expression heterogeneity systemically diversifies cancer cell phenotypes, enabling selection and cancer evolution. Here we document that the level of MYC expression variation is coordinated by a negative feed-forward loop involving the non-coding CCAT1 eRNA and the MYC gating process. While CCAT1 eRNA indirectly antagonizes MYC gating by promoting MYC transcriptional initiation and elongation, the MYC protein promotes gated MYC expression in a feedback loop by inhibiting both MYC transcription and CCAT1 expression. This entire process is coordinated by a CTCF binding site positioned within CCAT1 at a distal, oncogenic super-enhancer, which functions as a master switch by coordinating both CCAT1 and gated MYC expression to diversify cells toward both low and high MYC levels, as determined by heterogeneity metrics. As hallmarks of this principle are frequent in breast cancer and colorectal tumors, the dynamics of this new principle may underlie transitions between therapy-resistant low-MYC, and proliferative high-MYC tumor cells. Highlights- Transcriptional rate regulates MYC gating frequency - CCAT1 expression indirectly inhibits MYC gating by promoting MYC transcription - High MYC protein levels promote gated expression by inhibiting both MYC transcription and CCAT1 expression - These features are controlled by a single CTCF binding in the distant super-enhancer to drive expression plasticity in colorectal cancer cells

cancer biology↗

bioRxiv2024

A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type characterized by a particularly extensive stroma. While different types of cancer-associated fibroblasts (CAFs) in this desmoplastic stroma have been described, areas of early invasion and nascent stroma are understudied. Here, we identify a distinctive PDAC niche within the pancreatic lobules, a compartment dominated by pancreatic exocrine cells and slender stroma. Cellular interaction profiling using machine learning on whole slide images of human PDAC reveals that the tumor invasion front in the lobules is dominated by specific interactions of tumor cells and exocrine cells that have undergone acinar-to-ductal metaplasia (ADM). Multiplex protein and mRNA stains confirm that tumor growth in the lobules is closely linked to ADM in the lobules, and reveal stromal protein gradients from the gracile lobular stroma to the characteristic desmoplastic stroma. We identify nascent CAFs (nCAFs), co-expressing expressing nerve growth factor receptor (NGFR) and platelet-derived growth factor receptor alpha (PDGFRa) that are absent in the mature, desmoplastic stroma. Lobular invasion and nCAFs are intertwined with phenotypic changes of the cancer cells, such that tumor cells in lobules express classical subtype markers, while those embedded in the desmoplastic are on the basal end of the phenotypic continuum. In mice, the PDAC subtype - basal or classical - similarly depends on tissue location, suggesting microenvironmental factors rather than clonal selection as important drivers of tumor phenotype identity. Clinically, our results mandate factoring in tumor tissue location when calling PDAC subtypes. Biologically, they identify pancreatic lobules as a distinctive tissue niche associated with nascent stroma, and they suggest that lobular colonization by tumor cells is a significant route of PDAC progression.

cancer biology↗

bioRxiv2020

Unsupervised cell interaction profiling reveals major architectural differences between small intestinal and colonic epithelial crypts

Cellular identity in complex multicellular organisms is strictly maintained over the course of life. This control is achieved in part by the organ structure itself, such that neighboring cells influence each others identity. However, large-scale investigation of the cellular interactome has been technically challenging. Here, we develop CIM-seq, an unsupervised and high-throughput method to analyze direct physical cell-cell interactions between every cell type in a given tissue. CIM-seq is based on RNA sequencing of incompletely dissociated cells, followed by computational deconvolution of these into their constituent cell types using machine learning. We use CIM-seq to define the cell interaction landscape of the mouse small intestinal and colonic epithelium, uncovering both known and novel interactions. Specifically, we find that the general architecture of the stem cell niche is radically different between the two tissues. In small intestine, the stem-Paneth cell interaction forms an exceptionally strong and exclusive niche, in which Paneth cells provide Wnt ligands1. In colonic epithelium, no similar compartment exists to support stem cells, and Wnt signaling is provided by a mesenchymal cell layer2,3. However, colonic stem cells are supported by an adjacent, previously unrecognized goblet cell subtype expressing the wound-healing marker Plet1, which is also highly upregulated during regeneration of colon epithelium. These results identify novel cellular interactions specific for the colonic stem cell niche and suggest an additional level of structural control in the colon. CIM-seq is broadly applicable to studies that aim to simultaneously investigate the constituent cell types and the global interaction profile in a specific tissue.

developmental biology↗