The team PLATON (Cell Plasticity, TGFβ and Oncology) aims at characterizing the determinants of cell plasticity involved in tumor progression, heterogeneity, and resistance to treatments to develop innovative therapeutic strategies (Fig. 1A). The team covers this issue from molecular mechanisms to therapeutic candidates and clinically relevant biomarkers by focusing on transcription factors and non-coding RNA (lncRNA, miRNA, circRNA) regulated by Transforming Growth Factor beta (TGFβ) signaling, Unfolded Protein Response (UPR) and Targeted Therapies. The team investigates these mechanisms in digestive cancers (liver, pancreas, colon) and melanoma (Fig. 1B).
Keywords: hepatocellular carcinoma, cholangiocarcinoma, colorectal carcinoma, melanoma, TGFβ, cell plasticity, EMT, UPR, lncRNA, miRNA, circRNA, CRISPR.
Cell plasticity requires gene expression adaptation. It depends on RNA neosynthesis and RNA decay, notably governed by transcription factors (TF) and microRNAs (miRNAs), respectively (Fig. 2).
Our first objective is to characterize transcriptional regulators of cell plasticity by focusing on TGFβ-regulated TF and AHR-SMAD3 axis. By gain and loss of function strategies and gene expression profiling, we aim at defining functional gene networks regulating cell plasticity in cancer cells, mainly in melanoma, hepatocellular carcinoma and cholangiocarcinoma (Fig. 3).
Our second objective is to investigate innovative molecular mechanisms explaining the loss of activity of miRNAs involved in cell plasticity. We are notably studying the sequestration of epithelial-to-mesenchymal transition (EMT)-associated miRNA by linear and circular RNAs (Fig. 4). The expected results will provide a rationale to design novel drugs (antisense oligonucleotides) preventing miRNA inactivity by sequestration in cancer.
Unsupervised and integrated analysis of novel EMT regulators (coding and non-coding) is also performed by CRISPR screens in hepatocellular carcinoma and melanoma (Fig. 5).
Our third objective is to investigate how tumor cells exploit the cellular stress response to control cell fate. In this transversal project with PROSAC & ASTER teams, we focus on novel factors bridging TGFβ and UPR signaling. Particularly, we investigate the role of AGR2, a key regulator of UPR, as a modulator of cell plasticity and a predictive biomarker and therapeutic target in patients with anal cancer, colorectal carcinoma and cholangiocarcinoma.
Our three objectives are achievable through robust and dynamic interactions between basic researchers and clinicians, leading to the discovery of innovative biomarker candidates and therapeutic targets in cancer.