Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications.

OBJECTIVE: The diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed. We aimed to generate a novel molecular iCCA classifier that incorporates elements of the stroma, tumour and immune microenvironment ('STIM' classification). DESIGN: We applied virtual deconvolution to transcriptomic data from ~900 iCCAs, enabling us to devise a novel classification by selecting for the most relevant TME components. Murine models were generated through hydrodynamic tail vein injection and compared with the human disease. RESULTS: iCCA is composed of five robust STIM classes encompassing both inflamed (35%) and non-inflamed profiles (65%). The inflamed classes, named immune classical (~10%) and inflammatory stroma (~25%), differ in oncogenic pathways and extent of desmoplasia, with the inflammatory stroma showing T cell exhaustion, abundant stroma and KRAS mutations (p<0.001). Analysis of cell-cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, the desert-like class (~20%) harbours the lowest immune infiltration with abundant regulatory T cells (p<0.001), whereas the hepatic stem-like class (~35%) is enriched in 'M2-like' macrophages, mutations in IDH1/2 and BAP1, and FGFR2 fusions. The remaining class (tumour classical: ~10%) is defined by cell cycle pathways and poor prognosis. Comparative analysis unveils high similarity between a KRAS/p19 murine model and the inflammatory stroma class (p=0.02). The KRAS-SOS inhibitor, BI3406, sensitises a KRAS-mutant iCCA murine model to anti-PD1 therapy. CONCLUSIONS: We describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies.

Novel insights into molecular and immune subtypes of biliary tract cancers.

Biliary tract cancers (BTCs), which include cholangiocarcinoma (CCA) and gallbladder cancer (GBC), are heterogenous malignancies characterized by distinct molecular features often associated with specific clinical traits and/or outcomes. Such complex molecular heterogeneity, both within each BTC subtype and between distinct subtypes, poses a great challenge to personalized medicine. Recent technological advances have allowed the integration of multiple -omics derived from large cohorts of patients with distinct solid cancers to ultimately design stratification algorithms for prognostic prediction or more efficient treatment allocation. In this regard, although BTCs lag behind other tumors when it comes to our understanding of their molecular complexity, over the past decade, tremendous efforts have been made to generate supervised or unsupervised molecular classifications. As a result, CCAs and GBCs can be assigned to distinct molecular and/or prognostic classes. Notably, the discovery of biologically relevant subgroups of tumors harboring frequent targetable alterations (i.e., mutations in IDH1, FGFR2 fusion proteins) holds important therapeutic implications for BTCs, particularly iCCA. Furthermore, the recent application of single cell-based technologies or more conservative (and less precise) "virtual microdissection" algorithms to isolate signals derived from the immune and stromal cells has identified the first microenvironment-based classes. In this chapter, we will review the molecular and immune classes of BTCs, with a particular focus on their clinical implications.

The Molecular Pathogenesis and Targeted Therapies for Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a group of malignancies of the bile ducts with high mortality rates and limited treatment options. In the past decades, remarkable efforts have been dedicated toward elucidating the specific molecular signaling pathways and oncogenic loops driving cholangiocarcinogenesis to ultimately develop more effective therapies. Despite some recent advances, an extensive intra- and inter-tumor heterogeneity together with a poorly understood immunosuppressive microenvironment significantly compromises the efficacy of available treatments. Here, we provide a concise review of the latest advances and current knowledge of the molecular pathogenesis of CCA focusing on clinically relevant aberrations as well as future research avenues.

Evaluating the therapeutic potential of ADAR1 inhibition for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the deadliest form of breast cancer. Unlike other types of breast cancer that can be effectively treated by targeted therapies, no such targeted therapy exists for all TNBC patients. The ADAR1 enzyme carries out A-to-I editing of RNA to prevent sensing of endogenous double-stranded RNAs. ADAR1 is highly expressed in breast cancer including TNBC. Here, we demonstrate that expression of ADAR1, specifically its p150 isoform, is required for the survival of TNBC cell lines. In TNBC cells, knockdown of ADAR1 attenuates proliferation and tumorigenesis. Moreover, ADAR1 knockdown leads to robust translational repression. ADAR1-dependent TNBC cell lines also exhibit elevated IFN stimulated gene expression. IFNAR1 reduction significantly rescued the proliferative defects of ADAR1 loss. These findings establish ADAR1 as a novel therapeutic target for TNBC tumors.