The tumor microenvironment (TME) has been identified as one of the driving factors of tumor progression and invasion. Within this microenvironment, cancer‐associated fibroblasts (CAF) have multiple ...tumor‐promoting functions and play key roles in drug resistance, through multiple mechanisms, including extracellular matrix (ECM) remodeling, production of growth factors, cytokines, and chemokines, and modulation of metabolism and angiogenesis. More recently, a growing body of evidence has shown that CAF also modulate immune cell activity and suppress anti‐tumor immune response. In this review, we describe the current knowledge on CAF heterogeneity in terms of identity and functions. Moreover, we analyze how distinct CAF subpopulations differentially interact with immune cells, with a particular focus on T lymphocytes. We address how specific CAF subsets contribute to cancer progression through induction of an immunosuppressive microenvironment. Finally, we highlight potential therapeutic strategies for targeting CAF subpopulations in cancer.
Although fibroblast heterogeneity is recognized in primary tumors, both its characterization in and its impact on metastases remain unknown. Here, combining flow cytometry, immunohistochemistry and ...RNA-sequencing on breast cancer samples, we identify four Cancer-Associated Fibroblast (CAF) subpopulations in metastatic lymph nodes (LN). Two myofibroblastic subsets, CAF-S1 and CAF-S4, accumulate in LN and correlate with cancer cell invasion. By developing functional assays on primary cultures, we demonstrate that these subsets promote metastasis through distinct functions. While CAF-S1 stimulate cancer cell migration and initiate an epithelial-to-mesenchymal transition through CXCL12 and TGFβ pathways, highly contractile CAF-S4 induce cancer cell invasion in 3-dimensions via NOTCH signaling. Patients with high levels of CAFs, particularly CAF-S4, in LN at diagnosis are prone to develop late distant metastases. Our findings suggest that CAF subset accumulation in LN is a prognostic marker, suggesting that CAF subsets could be examined in axillary LN at diagnosis.
Cell-to-cell communication can be inferred from ligand-receptor expression in cell transcriptomic datasets. However, important challenges remain: global integration of cell-to-cell communication; ...biological interpretation; and application to individual cell population transcriptomic profiles. We develop ICELLNET, a transcriptomic-based framework integrating: 1) an original expert-curated database of ligand-receptor interactions accounting for multiple subunits expression; 2) quantification of communication scores; 3) the possibility to connect a cell population of interest with 31 reference human cell types; and 4) three visualization modes to facilitate biological interpretation. We apply ICELLNET to three datasets generated through RNA-seq, single-cell RNA-seq, and microarray. ICELLNET reveals autocrine IL-10 control of human dendritic cell communication with up to 12 cell types. Four of them (T cells, keratinocytes, neutrophils, pDC) are further tested and experimentally validated. In summary, ICELLNET is a global, versatile, biologically validated, and easy-to-use framework to dissect cell communication from individual or multiple cell-based transcriptomic profiles.
In the last years, metabolic reprogramming, fluctuations in bioenergetic fuels, and modulation of oxidative stress became new key hallmarks of tumor development. In cancer, elevated glucose uptake ...and high glycolytic rate, as a source of adenosine triphosphate, constitute a growth advantage for tumors. This represents the universally known Warburg effect, which gave rise to one major clinical application for detecting cancer cells using glucose analogs: the positron emission tomography scan imaging. Recent Advances: Glucose utilization and carbon sources in tumors are much more heterogeneous than initially thought. Indeed, new studies emerged and revealed a dual capacity of tumor cells for glycolytic and oxidative phosphorylation (OXPHOS) metabolism. OXPHOS metabolism, which relies predominantly on mitochondrial respiration, exhibits fine-tuned regulation of respiratory chain complexes and enhanced antioxidant response or detoxification capacity.
OXPHOS-dependent cancer cells use alternative oxidizable substrates, such as glutamine and fatty acids. The diversity of carbon substrates fueling neoplastic cells is indicative of metabolic heterogeneity, even within tumors sharing the same clinical diagnosis. Metabolic switch supports cancer cell stemness and their bioenergy-consuming functions, such as proliferation, survival, migration, and invasion. Moreover, reactive oxygen species-induced mitochondrial metabolism and nutrient availability are important for interaction with tumor microenvironment components. Carcinoma-associated fibroblasts and immune cells participate in the metabolic interplay with neoplastic cells. They collectively adapt in a dynamic manner to the metabolic needs of cancer cells, thus participating in tumorigenesis and resistance to treatments.
Characterizing the reciprocal metabolic interplay between stromal, immune, and neoplastic cells will provide a better understanding of treatment resistance. Antioxid. Redox Signal. 26, 462-485.
Women diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, particularly when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases). ...These tumors show a desmoplastic reaction with accumulation of extracellular matrix proteins and high content of cancer-associated fibroblasts. Using patient-derived xenograft mouse models of Mesenchymal and Non-Mesenchymal HGSOC, we show here that HGSOC exhibit distinct stiffness depending on their molecular subtype. Indeed, tumor stiffness strongly correlates with tumor growth in Mesenchymal HGSOC, while Non-Mesenchymal tumors remain soft. Moreover, we observe that tumor stiffening is associated with high stromal content, collagen network remodeling, and MAPK/MEK pathway activation. Furthermore, tumor stiffness accompanies a glycolytic metabolic switch in the epithelial compartment, as expected based on Warburg's effect, but also in stromal cells. This effect is restricted to the central part of stiff Mesenchymal tumors. Indeed, stiff Mesenchymal tumors remain softer at the periphery than at the core, with stromal cells secreting high levels of collagens and showing an OXPHOS metabolism. Thus, our study suggests that tumor stiffness could be at the crossroad of three major processes, i.e. matrix remodeling, MEK activation and stromal metabolic switch that might explain at least in part Mesenchymal HGSOC aggressiveness.
Anti‐cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in ...DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD‐/Nrf2‐antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly‐ubiquitination and promotes its degradation by the proteasome. ROS‐mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple‐Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2‐antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS‐mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients.
Synopsis
This work gives new insights into the regulation of H2AX protein turnover under chronic oxidative stress that affects DNA damage response. H2AX degradation upon chronic stress sensitizes tumour cells to chemotherapy and is indicative of better survival in triple‐negative breast cancer patients.
Physiological conditions of chronic oxidative stress, mediated by the loss of JunD or Nrf2 transcription factors, are associated with a reduced protein level of the histone variant H2AX.
Under conditions of chronic stress due to junD or Nrf2 deficiency, H2AX protein is targeted for degradation by the proteasome.
ROS‐dependent H2AX degradation is mediated by enhanced interaction of H2AX protein with the E3 ubiquitin ligase RNF168.
H2AX decrease by chronic oxidative stress increases tumour cell genomic instability and death.
Chemosensitivity and survival of triple‐negative breast cancer patients are improved by stress‐mediated H2AX degradation following successive cycles of chemotherapy.
This work gives new insights into the regulation of H2AX protein turnover under chronic oxidative stress that affects DNA damage response. H2AX degradation upon chronic stress sensitizes tumour cells to chemotherapy and is indicative of better survival in triple‐negative breast cancer patients.
•CAFs exhibit a phenotypic heterogeneity that define their functions in tumors.•Different CAF subsets are associated with an immunosuppressive microenvironment.•CAFs immunosuppressive functions act ...on both innate and adaptive immune response.•CAFs emerge as an attractive target for the development of anti-cancer therapies.
In tumors, Cancer-Associated Fibroblasts (CAFs) constitute the most prominent component of the tumor microenvironment (TME). CAFs are heterogeneous and composed of different CAF subsets exerting distinct functions in tumors. Specific CAF subpopulations actively influence various aspects of tumor growth, including cancer cell survival and proliferation, angiogenesis, extracellular matrix (ECM) remodeling, metastatic spread and chemoresistance. During the past decade, some CAF subsets have also been shown to modulate anti-tumor immune response. Indeed, they can increase the content in regulatory T lymphocytes and inhibit the activity of effector and cytotoxic immune cells. These functions are mainly controlled by their constitutive secretion of cytokines, chemokines, growth factors and ECM proteins, either directly in the surrounding extracellular space or through micro-vesicles. Some CAFs also express key regulators of immune checkpoints. The different roles played by CAFs, both as immunosuppressor or as physical support for tumor cell progression, set them as promising targets for anti-tumor therapies. In this review, we describe the main current knowledge on CAFs heterogeneity and immunosuppressive microenvironment, as well as their potential therapeutic implications.
JunD regulates genes involved in antioxidant defence. We took advantage of the chronic oxidative stress resulting from junD deletion to examine the role of reactive oxygen species (ROS) in tumour ...development. In a model of mammary carcinogenesis, junD inactivation increased tumour incidence and revealed an associated reactive stroma. junD‐inactivation in the stroma was sufficient to shorten tumour‐free survival rate and enhance metastatic spread. ROS promoted conversion of fibroblasts into highly migrating myofibroblasts through accumulation of the hypoxia‐inducible factor (HIF)‐1α transcription factor and the CXCL12 chemokine. Accordingly, treatment with an antioxidant reduced the levels of HIF and CXCL12 and numerous myofibroblast features. CXCL12 accumulated in the stroma of HER2‐human breast adenocarcinomas. Moreover, HER2 tumours exhibited a high proportion of myofibroblasts, which was significantly correlated to nodal metastases. Interestingly, this subset of tumours exhibited a significant nuclear exclusion of JunD and revealed an associated oxido‐reduction signature, further demonstrating the relevance of our findings in human cancers. Collectively, our data uncover a new mechanism by which oxidative stress increases the migratory properties of stromal fibroblasts, which in turn potentiate tumour dissemination.
High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor ...patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four subsets of carcinoma-associated fibroblasts (CAF-S1-4). Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25
FOXP3
T lymphocytes. The beta isoform of the CXCL12 chemokine (CXCL12β) specifically accumulates in the immunosuppressive CAF-S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12β expression in CAF-S1 cells plays a crucial role in CAF-S1 immunosuppressive activity and is a reliable prognosis factor in HGSOC, in contrast to CXCL12α. Thus, our data highlight the differential regulation of the CXCL12α and CXCL12β isoforms in HGSOC, and reveal a CXCL12β-associated stromal heterogeneity and immunosuppressive environment in mesenchymal HGSOC.
During the past decades, metabolism and redox imbalance have gained considerable attention in the cancer field. In addition to the well-known Warburg effect occurring in tumor cells, numerous other ...metabolic deregulations have now been reported. Indeed, metabolic reprograming in cancer is much more heterogeneous than initially thought. In particular, a high diversity of carbon sources used by tumor cells has now been shown to contribute to this metabolic heterogeneity in cancer. Moreover, the molecular mechanisms newly highlighted are multiple and shed light on novel actors. Furthermore, the impact of this metabolic heterogeneity on tumor microenvironment has also been an intense subject of research recently. Here, we will describe the new metabolic pathways newly uncovered in tumor cells. We will also have a particular focus on Cancer-Associated Fibroblasts (CAF), whose identity, function and metabolism have been recently under profound investigation. In that sense, we will discuss about the metabolic crosstalk between tumor cells and CAF.
PDF
