Biology subjects

Tonelli, C.

Publications and source records attributed to Tonelli, C..

3 recordsLinked to original sources

bioRxiv2023

Engrailed-1 Promotes Pancreatic Cancer Metastasis

Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, we report that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating a role in the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. Our findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.

cancer biology↗

bioRxiv2022

SPDEF promotes the classical subtype of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) samples reveal extensive cellular heterogeneity. Using single-cell RNA sequencing, we uncover multiple tumor cell populations distinguished by their differentiation state and associated with different stages of tumor progression in a mouse model of PDA. We identify Spdef as a factor required for tumorigenesis in pancreatic cancer cells of epithelial and mucinous nature. By comparative analysis of cell differentiation states in mice and humans, we find that the Spdef program is highly expressed by human PDAs of the classical subtype. Mouse and human PDA cells expressing elevated levels of Spdef are dependent upon this transcription factor for tumor progression in vivo. The tumor-promoting function of Spdef is recapitulated by two Spdef target genes that regulate protein folding and endoplasmic reticulum activity, Agr2 and Ern2/Ire1{beta}. These findings offer insights into the factors controlling differentiation states in PDA and identify new vulnerabilities in the most common subtype of pancreatic cancer.

cancer biology↗

bioRxiv2022

Loss of p53 tumor suppression function drives invasion and genomic instability in models of murine pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is a deadly disease with few treatment options. There is an urgent need to better understand the molecular mechanisms that drive disease progression, with the ultimate aim of identifying early detection markers and clinically actionable targets. To investigate the transcriptional and morphological changes associated with pancreatic cancer progression, we analyzed the KrasLSLG12D/+; Trp53LSLR172H/+; Pdx1-Cre (KPC) mouse model. We have identified an intermediate cellular event during pancreatic carcinogenesis in the KPC mouse model of PDA that is represented by a subpopulation of tumor cells that express KrasG12D, p53R172H and one allele of wild-type Trp53. In vivo, these cells represent a histological spectrum of pancreatic intraepithelial neoplasia (PanIN) and acinar-to-ductal metaplasia (ADM) and rarely proliferate. Following loss of wild-type p53, these precursor lesions undergo malignant de-differentiation and acquire invasive features. We have established matched organoid cultures of pre-invasive and invasive cells from murine PDA. Expression profiling of the organoids led to the identification of markers of the pre-invasive cancer cells in vivo and mechanisms of disease aggressiveness.

cancer biology↗