Fouassier, L. | bioRxiv Science

bioRxiv2025

ZEB1 regulates BCL2 in cancer-associated fibroblasts to promote cholangiocarcinoma chemoresistance to gemcitabine and cisplatin

Intrahepatic cholangiocarcinoma (iCCA) is an agressive tumour from the biliary tree that is characterized by a prominent desmoplastic stroma mainly composed of cancer-associated fibroblasts (CAF) and a poor prognosis due to its late clinical presentation and the lack of effective non-surgical treatments. Current therapies still include chemotherapeutic combinations of gemcitabine and cisplatin for the majority of the patients showing poor results due the apparition of resistance. This situation led us to interrogate the potential role in the development of chemoresistance of ZEB1, an EMT-inducing transcription factor (EMT-TF) that we previously identified as a pro tumorigenic factor in tumour cells and CAF of iCCA. By analysing human CCA samples and sc-RNAseq public databases, we show here that ZEB1 is present in the tumour microenvironment of all iCCA patients tested and is prominently expressed by CAF. Using cellular models of CAF, we show that cells depleted for ZEB1 are more sensitive to gemcitabine and cisplatin, via a mechanism involving the regulation of the anti-apoptotic gene BCL2. Moreover, ZEB1 expressing CAF protect iCCA tumour cells against the toxicity of the chemotherapeutic drugs, an event that could be reversed by a BCL2 inhibitor venetoclax. Therefore, our results point to the use of BCL2 inhibitors to improve the efficacy of current chemotherapeutic regimens of gemcitabine and cisplatin in iCCA patients.

cancer biology↗

bioRxiv2020

Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing 5 preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase (LOX) was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

cancer biology↗