Mummey, H. M. | bioRxiv Science

bioRxiv2025

Exploiting TGF-β-mediated Stromal Programming in Homologous Recombination-Deficient Pancreatic Cancer

The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. Here, we demonstrate that homologous recombination-defective (HRD) tumor epithelium reprograms the TME in a genotype-specific manner to enhance cancer aggressiveness. Using genetically engineered mouse models, pancreatic stellate cell (PSC) and cancer-associated fibroblast (CAF) co-culture systems, single-nucleus multiomics, and human PDAC models, we show that tumoral loss of ATM serine/threonine kinase drives CAFs toward SMA+ myofibroblastic differentiation, independently of P53 status. These myCAFs, in turn, promote cancer aggressiveness and chemoresistance. Mechanistically, ATM deficiency increases reactive oxygen species and contractility signaling, enhancing TGF-{beta}1 secretion. Pharmacological TGF-{beta} inhibition reverses myCAF differentiation, sensitizes tumors to chemotherapy, and impairs tumor progression in both murine and human ATM-null models. Our findings reveal that ATM-deficient tumors shape a cancer-promoting niche via TGF-{beta} signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy. SIGNIFICANCEHRD pancreatic cancers reprogram the tumor microenvironment in a genotype-specific manner through TGF-{beta}-driven myCAF-enrichment. Targeting this stromal axis alongside platinum-based chemotherapy improves therapeutic efficacy in ATM-deficient models. These findings highlight the need to integrate epithelial genotype and stromal context for truly personalized treatment strategies in PDAC.

cancer biology↗

bioRxiv2025

Linking molecular pathways and islet cell dysfunction in human type 1 diabetes

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of most insulin-producing {beta}-cells, along with dysregulated glucagon secretion from pancreatic -cells. We conducted an integrated analysis that combines electrophysiological and transcriptomic profiling, along with machine learning, of islet cells from T1D donors to investigate the mechanisms underlying their dysfunction. Surviving {beta}-cells exhibit altered electrophysiological properties and transcriptomic signatures indicative of increased antigen presentation, metabolic reprogramming, and impaired protein translation. In -cells, we observed hyper-responsiveness and increased exocytosis, which are associated with upregulated immune signaling, disrupted transcription factor localization and lysosome homeostasis, as well as dysregulation of mTORC1 complex signaling. Notably, key genetic risk signals for T1D were enriched in transcripts related to -cell dysfunction, including MHC class I which were closely linked with -cell dysfunction. Our data provide novel insights into the molecular underpinnings of islet cell dysfunction in T1D, highlighting pathways that may be leveraged to preserve residual {beta}-cell function and modulate -cell activity. These findings underscore the complex interplay between immune signaling, metabolic stress, and cellular identity in shaping islet cell phenotypes in T1D. HighlightsO_LISurviving {beta}-cells in T1D show disrupted electrical function linked to metabolic reprogramming and immune stress. C_LIO_LITranscripts associated with -cell dysfunction are enriched in genetic risk alleles for T1D. C_LIO_LIUpregulated MHC class I and impaired nuclear localization of key transcription factors associate with -cell dysfunction in T1D. C_LIO_LIT1D -cells exhibit increased hyper-activity, lysosomal imbalance and impaired mTORC1 signaling, which promotes dysregulated glucagon secretion. C_LI

cell biology↗