The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from ...cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations. We illustrate how these immunological or metabolic changes alter immunosurveillance and thus hinder or promote the development of primary liver cancer. In addition, we describe how inflammatory and metabolic niches affect the spreading of cancer metastases into or within the liver. Finally, we review the current therapeutic options in this context and the resulting challenges that must be surmounted.
Immune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, however, robust markers ...to predict therapy response are missing. Here we show that blood platelets interact with lung cancer cells and that PD-L1 protein is transferred from tumor cells to platelets in a fibronectin 1, integrin α5β1 and GPIbα-dependent manner. Platelets from NSCLC patients are found to express PD-L1 and platelet PD-L1 possess the ability to inhibit CD4 and CD8 T-cells. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1
), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Our data suggest that platelet PD-L1 reflects the collective tumor PD-L1 expression, plays important roles in tumor immune evasion and overcomes limitations of histological quantification of often heterogeneous intratumoral PD-L1 expression.
Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, ...metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. ...Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer.
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•An RNAi screen identifies 50 specific SASP regulators•The splicing factor PTBP1 regulates a pro-inflammatory SASP subset•PTBP1 regulates alternative splicing of EXOC7 to control the SASP•PTBP1 depletion safely inhibits inflammation-driven cancer
By performing a genetic screen for regulators of the senescence-associated secretory phenotype (SASP), Georgilis et al. identify PTBP1, which controls SASP by regulating alternative splicing of genes involved in intracellular trafficking such as EXOC7. PTBP1 knockdown blocks the tumor-promoting functions of SASP.
Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess ...stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC.
Chemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.
Cholangiocarcinoma (CCA) and other liver cancer subtypes often develop in damaged organs. Physiological agents or extrinsic factors, like toxins, can induce cell death in such tissues, triggering ...compensatory proliferation and inflammation. Depending on extracellular and intracellular factors, different mechanisms, like apoptosis, necroptosis, ferroptosis, or autophagy, can be triggered. Each of them can lead to protumorigenic or anti-tumorigenic events within a cell or through regulation of the microenvironment. However, the exact role of each cell death mechanism in CCA onset, progression, and treatment is not well known. Here, we summarize current knowledge of different cell death mechanisms in patients with CCA and preclinical CCA research. We discuss cell death–related drugs with relevance to CCA treatment and how they could be used in the future to improve targeted CCA therapy.
Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with ...breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFβ in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.
Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and ...subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.
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•Major transcriptional and super-enhancer subtypes of triple-negative breast cancer (TNBC)•Multiomics factor analysis of TNBC epigenetic, functional, and clinical heterogeneity•PRRX1 is a main transcriptional regulator of mesenchymal TNBC subtype
Jovanović et al. define the cellular, molecular, and functional heterogeneity of TNBC and integrated these using multiomics factor analysis into clinically relevant subtypes. Luminal, basal, and mesenchymal gene expression and super-enhancer subtypes do not match DNA methylation, histone modification, and metabolic patterns. PRRX1 is a central transcription factor in mesenchymal TNBC.
The Worst from Both Worlds: cHCC-ICC Seehawer, Marco; D'Artista, Luana; Zender, Lars
Cancer cell,
06/2019, Letnik:
35, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Prognosis of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma, a type of primary liver cancer comprising areas with HCC and ICC histopathology, is dismal, and it is unclear if such ...tumors develop clonally and how they should be treated. In this issue of Cancer Cell, Xue et al. (2019) provide answers to these questions.
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring ...cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.
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•Hepatic mitochondrial dysfunction induces premalignant cholangiocellular lesions•Hepatocytes under oxidative stress activate Tnf-producing Kupffer cells•Kupffer cell-derived Tnf triggers cholangiocyte overgrowth through JNK•JNK inhibition impairs intrahepatic cholangiocarcinoma development in several models
Yuan et al. show that mitochondrial dysfunction and oxidative stress in the liver increase tumor necrosis factor (TNF) expression by Kupffer cells to cause JNK-mediated cholangiocellular proliferation and transformation. The ROS/TNF/JNK axis may be an effective target for intrahepatic cholangiocarcinoma therapy.
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