Biology subjects

Arya, N.

Publications and source records attributed to Arya, N..

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↗

bioRxiv2023

ABI1 regulates transcriptional activity of Androgen Receptor by novel DNA and AR binding mechanism

Transcription regulates key functions of living organisms in normal and disease states, including cell growth and development, embryonic and adult tissue organization, and tumor progression. Here we identify a novel mechanism of transcriptional regulation by an actin regulatory and signaling protein, Abelson Interactor 1 (ABI1). Using prostate cancer models, we uncover a reciprocal regulation between ABI1 and the Androgen Receptor (AR). ABI1 is a direct, androgen-regulated target; in turn, ABI1 interacts with AR and its splice variant ARv7, and co-regulates a subset of specific transcriptional targets. ABI1 directs transcription through transient yet well-defined interaction of its intrinsically disordered region with DNA. Clinical evaluation shows that the ABI1-DNA binding (through Exon 4 splicing) and ABI1-AR interaction are regulated during androgen deprivation therapy and prostate cancer progression, thus controlling tumor plasticity through connecting actin cytoskeleton and cellular signaling to transcriptional regulation. We propose ABI1 as epigenetic regulator of transcriptional homeostasis in AR-driven cancers. Statement of importanceThis study describes fundamental discovery in prostate cancer identifying novel mechanism of transcription by unique DNA binding mechanism involving actin cytoskeleton regulatory protein ABI1. ABI1-DNA binding activity predicts survival of prostate cancer patients. Moreover, we discover ABI1-AR reciprocal regulation that has far reaching implications for tumor plasticity and androgen-sensitive pathogenesis.

cancer biology↗