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Cancers arise in tissues that can replicate and self-renew. Like normal tissues, cancers can replenish themselves, grow, and metastasize because of stem cells that are similar to normal stem cells but seem to respond less well to environmental stop signals in their niche. Therapy that targets cancer stem cells may be the next avenue of cancer treatment.

Extreme fire seasons characterised by very large ‘mega-fires’ have demonstrably increased area burnt across forested regions globally. However, the effect of extreme fire seasons on fire severity, a measure of fire impacts on ecosystems, remains unclear. Very large wildfires burnt an unprecedented area of temperate forest, woodland and shrubland across south-eastern Australia in 2019/2020, providing an opportunity to examine the impact of extreme fires on fire severity patterns. We developed an atlas of wildfire severity across south-eastern Australia between 1988 and 2020 to test (a) whether the 2019/2020 fire season was more severe than previous fire seasons, and (b) if the proportion of high-severity fire within the burn extent (HSp) increases with wildfire size and annual area burnt. We demonstrate that the 2019/2020 wildfires in south-eastern Australia were generally greater in extent but not proportionally more severe than previous fires, owing to constant scaling between HSp and annual fire extent across the dominant dry-forest communities. However, HSp did increase with increasing annual fire extent across wet-forests and the less-common rainforest and woodland communities. The absolute area of high-severity fire in 2019/2020 (∼1.8 M ha) was larger than previously seen, accounting for ∼44% of the area burnt by high-severity fire over the past 33 years. Our results demonstrate that extreme fire seasons are a rare but defining feature of fire regimes across forested regions, owing to the disproportionate influence of mega-fires on area burnt.

Single-cell RNA sequencing (scRNA-seq) is a powerful approach for reconstructing cellular differentiation trajectories. However, inferring both the state and direction of differentiation is challenging. Here, we demonstrate a simple, yet robust, determinant of developmental potential—the number of expressed genes per cell—and leverage this measure of transcriptional diversity to develop a computational framework (CytoTRACE) for predicting differentiation states from scRNA-seq data. When applied to diverse tissue types and organisms, CytoTRACE outperformed previous methods and nearly 19,000 annotated gene sets for resolving 52 experimentally determined developmental trajectories. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. This study thus establishes a key RNA-based feature of developmental potential and a platform for delineation of cellular hierarchies.

Cancer incidence escalates exponentially with advancing age; however, the underlying mechanism remains unclear. In this study, we build a chronological molecular clock at single-cell transcription level with a mammary stem cell-enriched population to depict physiological aging dynamics in female mice. We find that the mammary aging process is asynchronous and progressive, initiated by an early senescence program, succeeded by an entropic late senescence program with elevated cancer associated pathways, vulnerable to cancer predisposition. The transition towards senescence program is governed by a stem cell factor Bcl11b , loss of which accelerates mammary ageing with enhanced DMBA-induced tumor formation. We have identified a drug TPCA-1 that can rejuvenate mammary cells and significantly reduce aging-related cancer incidence. Our findings establish a molecular portrait of progressive mammary cell aging and elucidate the transcriptional regulatory network bridging mammary aging and cancer predisposition, which has potential implications for the management of cancer prevalence in the aged. Aging-related cancer incidence remains not fully understood. Here, the authors depict a progressive process of senescence in murine mammary stem cells at single-cell resolution, which is governed by the transcription factor Bcl11b and associated with enhanced chemical-induced tumorigenesis in aged mice.

CDX2 is expressed in most colon cancers, but approximately 4% do not express this transcription factor. Lack of CDX2 expression marks a subset of cancers with a more aggressive natural history. Adjuvant chemotherapy primarily benefits patients with stage II CDX2-negative tumors. During the past decade, disease-free survival among patients with stage III colon cancer has increased significantly owing to the introduction of new adjuvant chemotherapy regimens. 1 – 3 This therapeutic success, however, has not translated into longer disease-free survival among patients with earlier-stage (stage I or II) cancer. 4 The lack of simple, reliable criteria for the identification of patients with early-stage disease who are at high risk for relapse has made it difficult to identify patients in whom the hazards of multiagent chemotherapy may be offset by benefits with respect to disease-specific survival. 4 – 9 To address this problem, researchers have explored the . . .

Patients generally die of cancer after the failure of current therapies to eliminate residual disease. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. It has been proposed, therefore, that failure to effectively treat cancer may in part be due to preferential resistance of these CSC to chemotherapeutic agents. The subpopulation of human colorectal tumor cells with an ESA(+)CD44(+) phenotype are uniquely responsible for tumorigenesis and have the capacity to generate heterogeneous tumors in a xenograft setting (i.e. CoCSC). We hypothesized that if non-tumorigenic cells are more susceptible to chemotherapeutic agents, then residual tumors might be expected to contain a higher frequency of CoCSC. Xenogeneic tumors initiated with CoCSC were allowed to reach approximately 400 mm(3), at which point mice were randomized and chemotherapeutic regimens involving cyclophosphamide or Irinotecan were initiated. Data from individual tumor phenotypic analysis and serial transplants performed in limiting dilution show that residual tumors are enriched for cells with the CoCSC phenotype and have increased tumorigenic cell frequency. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Aldehyde dehydrogenase 1 gene expression and enzymatic activity are elevated in CoCSC and using an in vitro culture system that maintains CoCSC as demonstrated by serial transplants and lentiviral marking of single cell-derived clones, we further show that ALDH1 enzymatic activity is a major mediator of resistance to cyclophosphamide: a classical chemotherapeutic agent. CoCSC are enriched in colon tumors following chemotherapy and remain capable of rapidly regenerating tumors from which they originated. By focusing on the biology of CoCSC, major resistance mechanisms to specific chemotherapeutic agents can be attributed to specific genes, thereby suggesting avenues for improving cancer therapy.

Not all cells in a tumor are alike, but our ability to characterize cancer heterogeneity in detail has been limited. Dalerba et al . use high-throughput single-cell expression analysis to define clinically relevant subpopulations in normal and cancerous colon tissue. Cancer is often viewed as a caricature of normal developmental processes, but the extent to which its cellular heterogeneity truly recapitulates multilineage differentiation processes of normal tissues remains unknown. Here we implement single-cell PCR gene-expression analysis to dissect the cellular composition of primary human normal colon and colon cancer epithelia. We show that human colon cancer tissues contain distinct cell populations whose transcriptional identities mirror those of the different cellular lineages of normal colon. By creating monoclonal tumor xenografts from injection of a single ( n = 1) cell, we demonstrate that the transcriptional diversity of cancer tissues is largely explained by in vivo multilineage differentiation and not only by clonal genetic heterogeneity. Finally, we show that the different gene-expression programs linked to multilineage differentiation are strongly associated with patient survival. We develop two-gene classifier systems ( KRT20 versus CA1 , MS4A12 , CD177 , SLC26A3 ) that predict clinical outcomes with hazard ratios superior to those of pathological grade and comparable to those of microarray-derived multigene expression signatures.

CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRPα, on macrophages and other immune cells. CD47 is expressed at different levels by neoplastic and normal cells. Here, to reveal mechanisms by which different neoplastic cells generate this dominant ‘don’t eat me’ signal, we analyse the CD47 regulatory genomic landscape. We identify two distinct super-enhancers (SEs) associated with CD47 in certain cancer cell types. We show that a set of active constituent enhancers, located within the two CD47 SEs, regulate CD47 expression in different cancer cell types and that disruption of CD47 SEs reduces CD47 gene expression. Finally we report that the TNF-NFKB1 signalling pathway directly regulates CD47 by interacting with a constituent enhancer located within a CD47 -associated SE specific to breast cancer. These results suggest that cancers can evolve SE to drive CD47 overexpression to escape immune surveillance. Super-enhancers (SEs) are big DNA regions regulating the transcription of oncogenes. Here the authors identify two SE regions regulating the expression of CD47, a protein expressed by cancer cells to avoid phagocytosis by macrophages, thus suggesting a potential mechanism of immune surveillance escape.

Reactive oxygen: role in tumour radiation resistance Michael Clarke and colleagues find that cancer stem cell in breast tumours have lower levels of reactive oxygen species (ROS) than the rest of the tumour cells. This property renders cancer stem cells less sensitive to radiation therapy, which may cause radio resistance in breast cancer. This study shows that cancer stem cell in breast tumours have lower levels of reactive oxygen species (ROS) than the rest of the tumour cells. This property renders cancer stem cells less sensitive to radiation therapy, which may cause radioresistance in breast cancer. The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells 1 , 2 and haematopoietic stem cells and early progenitors 3 , 4 , 5 , 6 contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing 7 , 8 , CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.

A small population of distinctive breast-cancer cells can recapitulate an entire breast cancer when injected into immunodeficient mice. These cells express a unique group of genes, which when expressed in patients with breast cancer portend a poor outcome. Surprisingly, this group of genes is also expressed in prostate and lung cancer and medulloblastoma. This gene group is associated with invasiveness in a range of neoplasms. A small population of distinctive breast-cancer cells express a unique group of genes, which when expressed in patients with breast cancer portend a poor outcome. This gene group is associated with invasiveness in a range of neoplasms. A growing body of evidence obtained from studies of different types of cancer strongly suggests that only a small subclass of cancer cells within a tumor are actually tumorigenic. 1 – 4 We have previously shown that in breast cancer, a small population of cancer cells characterized by CD44 expression but low or undetectable levels of CD24 (CD44+CD24−/low) have a high tumorigenic capacity when injected into immunodeficient mice. 1 The rest of the cancer cells, called nontumorigenic breast-cancer cells, have little or no such ability. Tumors in mice that originate from purified tumorigenic breast-cancer cells contain a mixture of both tumorigenic and nontumorigenic . . .