Biology subjects

Kwon, R.

Publications and source records attributed to Kwon, R..

3 recordsLinked to original sources

bioRxiv2025

Longitudinal Analysis of Matched Patient Biospecimens Reveals Neural Reprogramming of Cancer-Associated Fibroblasts Following Chemotherapy in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). How chemotherapy alters the TME, and whether these changes drive chemoresistance, is poorly understood. We examined matched pre- and post-treatment tissue specimens and found near-universal enrichment of axonal guidance genes in cancer-associated fibroblasts (CAFs) after treatment. These CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrence lesions had the highest prevalence of these CAFs versus primary tumors and untreated metastasis. These CAFs showed elevated non-canonical Wnt mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Our findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising target for this disease. Statement of SignificanceTherapeutic resistance remains a major challenge in pancreatic cancer. Our findings shed light on the changes in the complex tumor microenvironment in response to chemotherapy and identify fibroblasts high in axonal-guidance genes that may drive tumor progression and chemoresistance, thus uncovering a potential avenue for targeting pancreatic cancer.

cancer biology↗

bioRxiv2025

Spatial analysis of IPMNs defines a paradoxical KRT17-positive, low-grade epithelial population harboring malignant features

Background & AimsIntraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that represent one of the few radiologically identifiable precursors to pancreatic ductal adenocarcinoma (PDAC). Though the IPMN-bearing patient population represents a unique opportunity for early detection and interception, current guidelines provide insufficient accuracy in determining which patients should undergo resection versus surveillance, resulting in a sizable fraction of resected IPMNs only harboring low-grade dysplasia, suggesting that there may be overtreatment of this clinical entity. MethodsTo investigate the transcriptional changes that occur during IPMN progression, we performed spatial transcriptomics using the Nanostring GeoMx on patient samples containing the entire spectrum of IPMN disease including low-grade dysplasia, high-grade dysplasia, and IPMN-derived carcinoma. Single cell RNA sequencing was performed on side branch and main duct IPMN biospecimens. ResultsWe identified a subpopulation of histologically low-grade IPMN epithelial cells that express malignant transcriptional features including KRT17, S100A10 and CEACAM5, markers that are enriched in PDAC. We validated this high-risk gene signature in both single-cell RNA sequenced samples and an external ST dataset containing a larger number of IPMN samples including non-tumor bearing IPMN (i.e. low-grade IPMN in isolation). Immunofluorescence staining of a large cohort of patient tissues confirmed the presence of KRT17-positive cells, which were found to comprise a small subset of epithelial cells within histologically low-grade IPMN in a patchy distribution. ConclusionsOur study demonstrates that KRT17 marks a distinct transcriptional signature in a subpopulation of epithelial cells within histologically low-grade IPMN. This population of cells likely represents a transitional state of histologically low-grade epithelial cells undergoing progression to a higher grade of dysplasia and thus may represent a higher risk of progression to carcinoma. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/643943v2_ufig1.gif" ALT="Figure 1000"> View larger version (43K): org.highwire.dtl.DTLVardef@47d380org.highwire.dtl.DTLVardef@18e7ab2org.highwire.dtl.DTLVardef@1193ffeorg.highwire.dtl.DTLVardef@b84a98_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

cancer biology↗

bioRxiv2024

B lymphocytes acquire myeloid and autoimmune phenotypes via the downregulation of lymphocyte-specific protein-1

Actin-binding proteins (ABPs) have been established as important mediators of immune homeostasis, but their effects on lymphocytes are poorly understood. Here, we demonstrated that LSP1, an ABP, is a master regulator for innate immune responses in B lymphocytes. Lsp1 deficiency in B cells upregulated the expression of myeloid genes, including CD11b, CD11c, and myeloperoxidase, and bestowed myeloid morphology. Strikingly, Lsp1-deficient B cells exhibited dual functions, namely, strong phagocytic activity and high antibody (Ab) production, like chimera. The PKC{beta}-CEBP{beta} pathway was found to be required for such functional chimerism. Moreover, Lsp1 deficiency induced the myeloid B cell phenotype and autoantibody production in B cells and consequently accelerated the progression of experimental lupus in mice. These changes were abrogated by retinoic acid, which upregulated LSP1 expression. In lupus patients, LSP1 expression in B cells was downregulated and inversely correlated with myeloperoxidase (MPO) expression. Overall, this study reveals a new role of the ABP LSP1 in B lymphocytes and emphasizes its critical involvement in promoting autoimmune responses, particularly by generating functionally chimeric B cells.

immunology↗