Biology subjects

Donato, E.

Publications and source records attributed to Donato, E..

6 recordsLinked to original sources

bioRxiv2026

Spatial multi-omics and single-cell transcriptomics uncover senescence-associated cellular programs during colon adenoma to cancer progression

Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.

cancer biology↗

bioRxiv2025

Inhibition of PTCH1 drug efflux activity enhances chemotherapy efficacy against triple negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subgroup characterized by a high risk of resistance to chemotherapies and high relapse potential. High levels of mRNA from the Hedgehog receptor PTCH1 are associated with poor prognosis in TNBC. PTCH1 is overexpressed in many aggressive cancers. We previously reported that PTCH1 is a multidrug transporter that triggers resistance to chemotherapy of adrenocortical carcinoma and melanoma cells, and that inhibiting PTCH1 drug efflux strongly enhanced chemotherapy efficacy on these cell lines both in vitro and in vivo. In the present study, we found that PTCH1 inhibition also significantly inhibited doxorubicin efflux in three TNBC cell lines leading to a strong increase of the cytotoxic effect of doxorubicin and docetaxel, and an inhibition of cell migration. Altogether, our data highlight the therapeutic potential of targeting PTCH1 drug efflux activity using drug association strategies for the treatment of TNBC patients.

cancer biology↗

bioRxiv2024

Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In our mouse model, hematopoietic Tet2 mutation enhanced immune checkpoint blockade (ICB) response. Enhanced ICB response with Tet2 mutation required phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially induced anti-tumor states and restricted cell states linked to tumor progression. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, lesser exhaustion and decreased regulatory phenotype. Our murine data was clinically relevant, since we found that melanomas from patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, T cell activation, and T cell memory programs. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

cancer biology↗

bioRxiv2022

Single-cell profiling uncovers a Muc4-expressing metaplastic gastric cell type sustained by Helicobacter pylori-specific inflammation

AbstractMechanisms for Helicobacter pylori (Hp)-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitant Hp infection and induction of constitutively active KRAS (Hp+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA-seq showed that Hp+KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucin Muc4 and the growth factor amphiregulin. Metaplastic pit cells were associated with macrophage and T cell inflammation and prevented by gastric immunosuppression. Lineage tracing showed that Muc4 was not dependent on cell-intrinsic KRAS activity, and lineage-derived cells had a limited propensity for growth as organoids, demonstrating that metaplastic pit cells are largely not self- renewing. Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify an Hp-associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven by Hp-dependent inflammation. Statement of SignificanceUsing a mouse model, we have delineated metaplastic pit cells as a pre-cancerous cell type whose expansion requires H. pylori-driven inflammation. In humans, metaplastic pit cells show enhanced proliferation as well as enrichment in precancer and early cancer tissues, highlighting an early step in the gastric metaplasia to cancer cascade.

microbiology↗

bioRxiv2022

HAPLN1 is a driver for peritoneal carcinomatosis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favored a more permissive microenvironment, which accelerated the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via hyaluronic acid synthesis and signaling, promoted adoption of a highly plastic cancer cell state, facilitating EMT, stemness, invasion and immunomodulation in a paracrine manner. Extracellular HAPLN1 modifies cancer cells as well as fibroblasts, rendering them immunomodulatory. We identify HAPLN1 as a prognostic marker and a driver for peritoneal metastasis in PDAC.

cancer biology↗

bioRxiv2020

Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer

Despite important advances in the treatment of breast cancer, the 5-year survival rate for patients with distant metastasis remains less than 30%. Metastasis is a complex, multi-step process beginning with local invasion and ending with the outgrowth of systemically disseminated cells into actively proliferating metastases that ultimately cause the destruction of vital organs. It is this last step that limits patient survival and, at the same time, remains the least understood mechanistically. Here, we focus on understanding determinants of metastatic outgrowth using metastatic effusion biopsies from stage IV breast cancer patients. By modelling metastatic outgrowth through xenograft transplantation, we show that tumour initiation potential of patient-derived metastatic breast cancer cells across breast cancer subtypes is strongly linked to high levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels are caused by the irreversible reprogramming to a mesenchymal state with concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to retain epithelial traits is tied to a global epigenetic program that limits the actions of EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide direct evidence that maintenance of epithelial identity is required for metastatic outgrowth while concomitant expression of mesenchymal markers enables plasticity. In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our data provide a framework for the intricate intercalation of mesenchymal and epithelial traits in metastatic growth.

cancer biology↗