Biology subjects

Orecchioni, S.

Publications and source records attributed to Orecchioni, S..

2 recordsLinked to original sources

bioRxiv2022

High-fat diet promotes Acute Promyelocytic Leukemia through PPARδ-enhanced self-renewal of preleukemic progenitors

Obesity is associated with a higher risk of developing many cancer types including acute promyelocytic leukaemia (APL), a subset of acute myeloid leukemias (AML) characterized by expression of the PML-RAR oncogene. The molecular mechanisms linking obesity and APL development are not known. To model clinical observations, we established a mouse model of diet-induced obesity using transgenic mice constitutively expressing PML-RARA in the hematopoietic system (PML-RAR KI mice) fed either standard (SD) or high-fat (HFD) diets. HFD-fed PML-RAR KI mice developed leukaemia with reduced latency and increased penetrance, as compared to SD-fed mice. HFD leads to accumulation of DNA damage in hematopoietic stem cells (HSCs), but, surprisingly, this was not associated with mutational load gain, as shown by whole genome/exome sequencing of pre-leukemic and leukemic cells. Importantly, very few of the observed mutations were predicted to act as cancer drivers, suggesting the relevance of nongenetic mechanisms. HFD led to an expansion of hematopoietic progenitor cells with a concomitant reduction in long-term hematopoietic stem cells, and in the presence of PML-RAR this was also accompanied by an enhancement of in vitro and in vivo self-renewal. Interestingly, Linoleic Acid (LA), abundant in HFD, recapitulates the effect of HFD on the self-renewal of PML-RAR HPCs by activating the peroxisome proliferator-activated receptor delta (PPAR{delta}), a central regulator of fatty acid metabolism involved in the promotion of cancer progression. Our findings have implications for dietary or pharmacological interventions aimed at counteracting the cancer-promoting effect of obesity. Key pointsO_LIhigh fat diet (HFD) promotes APL leukemogenesis in mouse models, reproducing the exquisite sensitivity to obesity observed in humans C_LIO_LIalthough HFD leads to DNA damage and mutations, the molecular mechanism is nongenetic and linked to the transcription factor PPAR{delta} C_LI

cancer biology↗

bioRxiv2021

A single-cell transcriptomic landscape of innate and adaptive intratumoral immunity in triple negative breast cancer during chemo- and immunotherapies

Breast cancer (BC) constitutes a major health problem worldwide, making it the most common malignancy in women. Current treatment options for BC depend primarily on histological type, molecular markers, clinical aggressiveness and stage of disease. Immunotherapy, such as anti-PD-1, have shown combinatorial clinical activity with chemotherapy in triple negative breast cancer (TNBC) delineating some therapeutic combinations as more effective than others. However, a clear overview of the main immune cell populations involved in these treatments has never been provided. Here, an assessment of the immune landscape in the tumour microenvironment (TME) of two TNBC mouse models (4T1 and EMT6 cell lines) has been performed using single-cell RNA sequencing (scRNA-seq) technology. Specifically, immune cells were evaluated in untreated conditions and after being treated with chemotherapy or immunotherapy used as single agents or in combination. A decrease of regulatory T cells, compared to the untreated TME, was found in treatments with in vivo efficacy as well as {gamma}{delta} T cells, which have a pro-tumoral activity in mice. Focusing on Cd8 T cells, across all the conditions, a general increase of exhausted-like Cd8 T cells was confirmed in pre-clinical treatments with low efficacy; on the other hand, an opposite trend was found for the proliferative Cd8 T cells. Regarding macrophages, M2-like cells were found enriched in treatments with low efficacy while opposite behaviour was associated with M1-like macrophages. For both cell lines, similar proportions of B cells were detected with an increase of proliferative B cells in treatments that involved cisplatin in combination with anti-PD-1. The fine-scale characterization of the immune TME in this work can lead to new insights on the diagnosis and treatment of TNBC for a possible application at the clinical level.

cancer biology↗