Biology subjects

Piwnica-Worms, H.

Publications and source records attributed to Piwnica-Worms, H..

3 recordsLinked to original sources

bioRxiv2026

Fasting primes small intestinal regeneration after damage via a microbiome metabolite chromatin axis

Fasting enhances small intestinal regeneration after radiation but the contribution of the gut microbiome to this process remains uncharacterized. We identify Akkermansia muciniphila (AKK) as a key mediator of this response. AKK was enriched in fasted mice and its antibiotic depletion abrogated radioprotection whereas reintroduction restored both organismal survival and intestinal integrity. Fasting elevated propionic acid, consistent with AKKs metabolic output. AKK-conditioned medium and propionate induced histone H3 acetylation in intestinal stem cell cultures while in vivo fasting induced AKK-dependent H3K27ac and H3K9ac, remodeling promoter-enhancer landscapes in crypt epithelial cells. Epigenetic profiling revealed a rewired core regulatory program enriched for pioneer transcription factors (Foxa, Gata, Klf), architectural organizers (Ctcf, Boris), and lineage-defining and metabolic regulators (Cdx2, Hnf4). This program supports expansion of a population of persister stem cells characterized by open chromatin accessibility at key stem and regenerative-associated loci including Clu, Olfm4, Lgr5, Ascl2, Lrig1, Sox9, Rnf43, and Axin2. These findings define a fasting-induced microbiome-metabolite-chromatin axis that epigenetically primes highly plastic persister stem cells for rapid regeneration of the intestinal epithelium following radiation-induced injury. Significance StatementFasting changes the gut microbiome, but how these changes help the body recover from damage is not well understood. We found that fasting increases a helpful bacterium, Akkermansia muciniphila, which produces propionate, which drives epigenetic changes by modifying histones and regulating gene activity. These changes promote the expansion of persister stem cells that help the intestine recover after radiation. This study shows how fasting and gut bacteria work together to protect healthy tissue and suggests that diet or microbial treatments could help reduce side effects of cancer radiotherapy.

cell biology↗

bioRxiv2025

Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction

Mechanical cues from the extracellular matrix (ECM) regulate various cellular processes. In breast cancer, increased tumor stiffness is associated with elevated metastasis risk and poor survival. We identify a unique role of the JAK family kinase TYK2 in suppressing breast cancer metastasis under low ECM stiffness. Genetic or pharmacological inhibition of TYK2 in mammary acini and patient-derived organoids leads to invasion at low ECM stiffness by promoting Epithelial-Mesenchymal Transition, which is independent of cytokine-induced JAK/STAT signaling. TYK2 blockade promotes metastasis in breast tumor cell- and patient-derived xenografts. TYK2 localizes at the plasma membrane via IFNAR1 association under low stiffness, but it becomes cytoplasmic and inactivated at high stiffness. Normal human breast epithelium displays membrane-localized TYK2, whereas invasive breast tumors exhibit cytoplasmic TYK2. These findings uncover a TYK2-dependent mechanism by which ECM rigidity suppresses breast cancer metastasis and underscore the need for vigilant breast cancer screening in patients receiving TYK2 inhibitors.

cancer biology↗

bioRxiv2024

An annotated biobank of triple negative breast cancer patient-derived xenografts featuring treatment-naive and longitudinal samples throughout neoadjuvant chemotherapy

Triple negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443) at MD Anderson Cancer Center, including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of PDX models were capable of lung metastasis. Comprehensive molecular profiling demonstrated conservation of genomes and transcriptomes between patient and corresponding PDX tumors, with representation of all major transcriptional subtypes. Transcriptional changes observed in the longitudinal PDX models highlight dysregulation in pathways associated with DNA integrity, extracellular matrix interactions, the ubiquitin-proteasome system, epigenetics, and inflammatory signaling. These alterations reveal a complex network of adaptations associated with chemoresistance. This PDX biobank provides a valuable resource for tackling the most pressing issues facing the clinical management of TNBC, namely chemoresistance and metastasis.

cancer biology↗