Schlumberger, M. | Search bioRxiv

bioRxiv2025

Type 2 Deiodinase in Cancer-Associated Fibroblasts is required to sustain growth of poorly and undifferentiated thyroid cancer

Poorly differentiated (PDTC) and anaplastic thyroid carcinomas (ATC) are characterized by rapid progression and poor patient survival. While the tumor microenvironment (TME) - particularly cancer-associated bibroblasts (CAFs)- plays a crucial role in supporting tumor growth, its metabolic contribution remains poorly understood. Here, we identify a critical role for type 2 deiodinase (D2), the enzyme that activates the thyroid hormone (TH) thyroxine (T4) into the biologically active triiodothyronine (T3), in sustaining a pro-tumorigenic TME in PDTC and ATC. We show that D2 is expressed not only in thyroid epithelial cancer cells, but at even higher levels in CAFs, especially inblammatory CAFs (iCAFs). In in vivo mouse models, pharmacological inhibition of D2 reduces tumor growth and alters composition of CAFs. In 3D co-culture spheroids, D2 activity proves essential for supporting tumor cell proliferation by establishing a paracrine loop between stromal and epithelial cancer cells that amplibies local TH signaling. Notably, human PDTC organoids expressing D2 respond to modulation of TH levels, conbirming the functional relevance of this metabolic axis in human tumors. In conclusion, these bindings identify D2 as a key mediator of stromal-epithelial crosstalk in PDTC and ATC, and highlight local TH metabolism as a potential therapeutic target in these lethal cancers.

cancer biology↗

bioRxiv2018

Microbiota stability in healthy individuals after single-dose lactulose challenge - a randomized controlled study

Background and aimsLactulose is a common food ingredient and widely used as a treatment for constipation or hepatic encephalopathy and a substrate for hydrogen breath tests. Lactulose is fermented by the colon microbiota resulting in the production of hydrogen (H2). H2 is a substrate for enteropathogens including Salmonella Typhimurium (S. Typhimurium) and increased H2 production upon lactulose ingestion might favor the growth of H2-consuming enteropathogens. We aimed to analyze effects of single-dose lactulose ingestion on the growth of intrinsic Escherichia coli (E. coli), which can be efficiently quantified by plating and which share most metabolic requirements with S. Typhimurium.\n\nMethods32 healthy volunteers (18 females, 14 males) were recruited. Participants were randomized for single-dose ingestion of 50 g lactulose or 50 g sucrose (controls). After ingestion, H2 in expiratory air and symptoms were recorded. Stool samples were acquired at days -1, 1 and 14. We analyzed 16S microbiota composition and abundance and characteristics of E. coli isolates.\n\nResultsLactulose ingestion resulted in diarrhea in 14/17 individuals. In 14/17 individuals, H2-levels in expiratory air increased by [≥]20 ppm within 3 hours after lactulose challenge. H2-levels correlated with the number of defecations within 6 hours. E. coli was detectable in feces of all subjects (2 x 102 - 109 CFU/g). However, the number of E. coli colony forming units (CFU) on selective media did not differ between any time point before or after challenge with sucrose or lactulose. The microbiota composition also remained stable upon lactulose exposure.\n\nConclusionIngestion of a single dose of 50 g lactulose does not significantly alter E. coli density in stool samples of healthy volunteers. 50 g lactulose therefore seems unlikely to sufficiently alter growth conditions in the intestine for a significant predisposition to infection with H2-consuming enteropathogens such as S. Typhimurium (www.clinicaltrials.gov NCT02397512).

microbiology↗