Biology subjects

Lorenzoni, M.

Publications and source records attributed to Lorenzoni, M..

3 recordsLinked to original sources

bioRxiv2024

Microbiome Modulation Uncouples Efficacy and Toxicity Induced by Programmed Death-1/Programmed Death-Ligand1 Blockade

While asymptomatic smoldering multiple myeloma (SMM) holds an overall risk of progression to multiple myeloma (MM) at 10% per year, only active surveillance is offered to most patients affected by SMM, which leaves them in anxiety and frustration. Intestinal microbiota and gut-born T helper 17 (Th17) lymphocytes may act as drivers of MM evolution. In transgenic Vk*MYC mice developing de novo MM, which invariably evolves from Early-MM that mimics SMM to full-blown Late-MM, we investigated the impact of gut microbiota modulation on disease progression and susceptibility to immune checkpoint blockade (ICB). We report that administering the human commensal Prevotella melaninogenica to mice affected by Early-MM significantly delayed evolution to Late-MM. Mechanistically, treatment with P. melaninogenica induced increased production of short chain fatty acids. Butyrate prevented skew of dendritic cells towards a pro-Th17 phenotype and treated mice accumulated less disease induced Th17 cells in their bone marrow. P. melaninogenica also synergized with anti-PD-L1 antibodies by restraining Th17 cell expansion while unleashing ICB-induced full effector CD8+ T cells, eventually blocking progression to full-blown disease. Similar results were obtained in mice challenged with bortezomib-resistant Vk*MYC tumor cells, a model of more aggressive MM. When mice were exposed to imiquimod to mimic ICB-associated psoriasis-like lesions, P. melaninogenica ameliorated skin lesions caused by ICB. Thus, modulation of the gut microbiota with P. melaninogenica might represent a treatment for patients affected by SMM and would allow fully exploiting the antitumor potential of ICB in plasma cell dyscrasias. Key pointsAdministration of the human commensal Prevotella melaninogenica to Vk*MYC mice delayed evolution to symptomatic multiple myeloma; P. melaninogenica therapeutically synergized with PD-1/PD-L1 blockade also limiting immune-related adverse events.

immunology↗

bioRxiv2024

Rarγ-Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer

Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in directing body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling promotes cell lineage identity in different tissues is often missing. Here, leveraging prostate organoid technology, we demonstrated that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and ultimately, proper specification of the prostatic lumen. Mechanistically, RA-dependent RAR{gamma} activation promotes the expression of the pioneer factor Foxa1, which synergizes with the androgen pathway for proper luminal expansion, cytoarchitecture and function. FOXA1 nucleotide variants are common in human prostate and breast cancers and considered driver mutations, though their pathogenic mechanism is incompletely understood. Combining functional genetics experiments with structural modeling of FOXA1 folding and chromatin binding analyses, we discovered that FOXA1F254E255 is a loss-of-function mutation leading to compromised transcriptional function and lack of luminal fate commitment of prostate progenitors. Overall, we define RA as a crucial instructive signal for glandular identity in adult prostate progenitors. We propose deregulation of vitamin A metabolism as a risk factor for benign and malignant prostate disease, and identified cancer associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors. Summary: Retinoic acid signaling orchestrates luminal differentiation of adult prostate progenitors

cancer biology↗

bioRxiv2021

Intra-epithelial non-canonical Activin A signalling safeguards prostate progenitor quiescence

The healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during ageing, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF-{beta} ligands have been known to induce cytostasis in a large variety of epithelia, but the intracellular pathway mediating this signal in the prostate, as well as its relevance for quiescence, have remained elusive. Here, using mouse prostate organoids to model epithelial progenitors, we found that intra-epithelial non-canonical Activin A signalling inhibited cell proliferation in a Smad-independent manner. Mechanistically, Activin A triggered Tak1 and p38 MAPK activity, leading to p16 and p21 nuclear import. Spontaneous evasion from this quiescent state occurred upon prolonged culture, due to reduced Activin A secretion, a condition associated with DNA replication stress and aneuploidy. Organoids capable to escape quiescence in vitro were also able to implant with increased frequency into immunocompetent mice. Our study demonstrates that non-canonical Activin A signalling safeguards epithelial quiescence in the healthy prostate, with potential implications for the understanding of cancer initiation, and the development of therapies targeting quiescent tumour progenitors.

cancer biology↗