The dynamics of hematopoiesis over the human lifespan.

Over a lifetime, hematopoietic stem cells (HSCs) adjust their lineage output to support age-aligned physiology. In model organisms, stereotypic waves of hematopoiesis have been observed corresponding to defined age-biased HSC hallmarks. However, how the properties of hematopoietic stem and progenitor cells change over the human lifespan remains unclear.

Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood.

Tumor suppressor heterozygosity and homologous recombination deficiency mediate resistance to front-line therapy in breast cancer.

The co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, but their combined biologic and clinical significance has not been evaluated. To assess the role of germline-somatic interactions on outcomes in routine practice, we developed an integrated clinicogenomic pipeline to analyze the genomes of over 4,500 patients with breast cancer. We find that germline (g) -associated tumors are enriched for loss-of-function mutations and manifest poor outcomes on standard-of-care, front-line CDK4/6 inhibitor (CDK4/6i) combinations.

RICTOR/mTORC2 downregulation in BRAF melanoma cells promotes resistance to BRAF/MEK inhibition.

Background: The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM.

Methods: After analyzing The Cancer Genome Atlas MM patients' database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAF MM cell lines on their response to BRAF/MEKi.

p140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response.

The p140Cap adaptor protein is a tumor suppressor in breast cancer associated with a favorable prognosis. Here we highlight a function of p140Cap in orchestrating local and systemic tumor-extrinsic events that eventually result in inhibition of the polymorphonuclear myeloid-derived suppressor cell function in creating an immunosuppressive tumor-promoting environment in the primary tumor, and premetastatic niches at distant sites. Integrative transcriptomic and preclinical studies unravel that p140Cap controls an epistatic axis where, through the upstream inhibition of β-Catenin, it restricts tumorigenicity and self-renewal of tumor-initiating cells limiting the release of the inflammatory cytokine G-CSF, required for polymorphonuclear myeloid-derived suppressor cells to exert their local and systemic tumor conducive function.

Developmental Deconvolution for Classification of Cancer Origin.

Unlabelled: Cancer is partly a developmental disease, with malignancies named based on cell or tissue of origin. However, a systematic atlas of tumor origins is lacking. Here we map the single-cell organogenesis of 56 developmental trajectories to the transcriptomes of over 10,000 tumors across 33 cancer types.

Cancer Metabolic Subtypes and Their Association with Molecular and Clinical Features.

The alterations of metabolic pathways in cancer have been investigated for many years, beginning long before the discovery of the role of oncogenes and tumor suppressors, and the last few years have witnessed renewed interest in this topic. Large-scale molecular and clinical data on tens of thousands of samples allow us to tackle the problem from a general point of view. Here, we show that transcriptomic profiles of tumors can be exploited to define metabolic cancer subtypes, which can be systematically investigated for associations with other molecular and clinical data.

Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties.

Background: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops.

Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel.

Epigenetic regulators play key roles in cancer and are increasingly being targeted for treatment. However, for many, little is known about mechanisms of resistance to the inhibition of these regulators. We have generated a model of resistance to inhibitors of protein arginine methyltransferase 5 (PRMT5).

SP1 and STAT3 Functionally Synergize to Induce the Small GTPase and a Subclass of Non-canonical WNT Responsive Genes Correlating with Poor Prognosis in Breast Cancer.

Breast cancer is a heterogeneous disease whose clinical management is very challenging. Although specific molecular features characterize breast cancer subtypes with different prognosis, the identification of specific markers predicting disease outcome within the single subtypes still lags behind. Both the non-canonical Wingless-type MMTV Integration site (WNT) and the Signal Transducer and Activator of Transcription (STAT)3 pathways are often constitutively activated in breast tumors, and both can induce the small GTPase Ras Homolog Family Member U .

Author Correction: The scaffold protein p140Cap limits ERBB2-mediated breast cancer progression interfering with Rac GTPase-controlled circuitries.

This corrects the article DOI: 10.1038/ncomms14797.

The IKK/NF-κB signaling pathway requires Morgana to drive breast cancer metastasis.

NF-κB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell metastasis. NF-κB is frequently hyperactivated in several cancers, including triple-negative breast cancer. Here we show that NF-κB activation in breast cancer cells depends on the presence of the CHORDC1 gene product Morgana, a previously unknown component of the IKK complex and essential for IκBα substrate recognition.

PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy.

Background: Nutrient deprivation, hypoxia, radiotherapy and chemotherapy induce endoplasmic reticulum (ER) stress, which activates the so-called unfolded protein response (UPR). Extensive and acute ER stress directs the UPR towards activation of death-triggering pathways. Cancer cells are selected to resist mild and prolonged ER stress by activating pro-survival UPR.

The scaffold protein p140Cap limits ERBB2-mediated breast cancer progression interfering with Rac GTPase-controlled circuitries.

The docking protein p140Cap negatively regulates tumour cell features. Its relevance on breast cancer patient survival, as well as its ability to counteract relevant cancer signalling pathways, are not fully understood. Here we report that in patients with ERBB2-amplified breast cancer, a p140Cap-positive status associates with a significantly lower probability of developing a distant event, and a clear difference in survival.

Experimental Approaches for Studying Semaphorin Signals in Tumor Growth and Metastasis in Mouse Models.

Tumor growth and metastatic dissemination are complex multistep processes. They clearly depend on the intrinsic behavior of cancer cells, but are remarkably influenced by a variety of stromal cells present in the tumor microenvironment, which include those implicated in tumor angiogenesis, as well as bone marrow-derived cells recruited from the circulation. Moreover, multiple molecular signals exchanged between cancer cells and non-neoplastic stromal cells control tumor growth and metastasis; notably, members of the semaphorin family are emerging players in this scenario.

Prostate-specific membrane antigen (PSMA) assembles a macromolecular complex regulating growth and survival of prostate cancer cells "in vitro" and correlating with progression "in vivo".

The expression of Prostate Specific-Membrane Antigen (PSMA) increases in high-grade prostate carcinoma envisaging a role in growth and progression. We show here that clustering PSMA at LNCaP or PC3-PSMA cell membrane activates AKT and MAPK pathways thus promoting proliferation and survival. PSMA activity was dependent on the assembly of a macromolecular complex including filamin A, beta1 integrin, p130CAS, c-Src and EGFR.