Phosphoinositide Conversion Inactivates R-RAS and Drives Metastases in Breast Cancer

Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R-RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof-of-concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α-overexpressing breast cancer, thereby suggesting a novel strategy for anti-breast cancer therapy

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer

Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer death in women worldwide. Although early diagnosis and cancer growth inhibition has significantly improved breast cancer survival rate over the years, there is a current need to develop more effective systemic treatments to prevent metastasis. One of the most commonly altered pathways driving breast cancer cell growth, survival, and motility is the PI3K/AKT/mTOR signaling cascade. In the past 30 years, a great surge of inhibitors targeting these key players has been developed at a rapid pace, leading to effective preclinical studies for cancer therapeutics. However, the central role of PI3K/AKT/mTOR signaling varies among diverse biological processes, suggesting the need for more specific and sophisticated strategies for their use in cancer therapy. In this review, we provide a perspective on the role of the PI3K signaling pathway and the most recently developed PI3K-targeting breast cancer therapies

Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma

Abstract Background Multiple myeloma (MM) is an incurable plasma cell malignancy, accounting for approximately 1% of all cancers. Despite recent advances in the treatment of MM, due to the introduction of proteasome inhibitors (PIs) such as bortezomib (BTZ) and carfilzomib (CFZ), relapses and disease progression remain common. Therefore, a major challenge is the development of novel therapeutic approaches to overcome drug resistance, improve patient outcomes, and broaden PIs applicability to other pathologies. Methods We performed genetic and drug screens to identify new synthetic lethal partners to PIs, and validated candidates in PI-sensitive and -resistant MM cells. We also tested best synthetic lethal interactions in other B-cell malignancies, such as mantle cell, Burkitt’s and diffuse large B-cell lymphomas. We evaluated the toxicity of combination treatments in normal peripheral blood mononuclear cells (PBMCs) and bone marrow stromal cells (BMSCs). We confirmed the combo treatment’ synergistic effects ex vivo in primary CD138+ cells from MM patients, and in different MM xenograft models. We exploited RNA-sequencing and Reverse-Phase Protein Arrays (RPPA) to investigate the molecular mechanisms of the synergy. Results We identified lysine (K)-specific demethylase 1 (LSD1) as a top candidate whose inhibition can synergize with CFZ treatment. LSD1 silencing enhanced CFZ sensitivity in both PI-resistant and -sensitive MM cells, resulting in increased tumor cell death. Several LSD1 inhibitors (SP2509, SP2577, and CC-90011) triggered synergistic cytotoxicity in combination with different PIs in MM and other B-cell neoplasms. CFZ/SP2509 treatment exhibited a favorable cytotoxicity profile toward PBMCs and BMSCs. We confirmed the clinical potential of LSD1-proteasome inhibition in primary CD138+ cells of MM patients, and in MM xenograft models, leading to the inhibition of tumor progression. DNA damage response (DDR) and proliferation machinery were the most affected pathways by CFZ/SP2509 combo treatment, responsible for the anti-tumoral effects. Conclusions The present study preclinically demonstrated that LSD1 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients and that this combination might be exploited for the treatment of other B-cell malignancies, thus extending the therapeutic impact of the project

LA DIAGNOSI ED IL TRATTAMENTO DEL CONDROSARCOMA

La linea guida affronta l’approccio alla diagnosi e al trattamento del condrosarcoma dello scheletro degli arti e del cingolo pelvico e scapolare. Non è incluso nel presente documento il trattamento del condrosarcoma della colonna vertebrale. È stata eseguita una ricerca bibliografica su PubMed, utilizzando le parole chiave chondrosarcoma, cartilaginous tumor, chondroid tumor, selezionando studi inerenti la diagnosi ed il trattamento del condrosarcoma dello scheletro pubblicati negli ultimi 15 anni. Sono stati considerati anche alcuni studi pubblicati in precedenza per la particolare rilevanza delle casistiche. Per l’introduzione descrittiva è stato utilizzato come riferimento il manuale del professor Mario Campanacci Bone and soft tissue tumors edito da Springer Verlag nel 1999. Sono state valutate infine le pubblicazioni relative all’esperienza nel trattamento del condrosarcoma degli Istituti internazionali più accreditati nella diagnosi e cura dei tumori dell’apparato muscolo-scheletrico. Il metodo di grading delle prove utilizzato per il Progetto Linee Guida SIOT è quello descritto nel manuale metodologico del Sistema Nazionale Linee Guida (www.snlg.it) dell’Istituto Superiore di Sanità. Le raccomandazioni vengono qualificate con un livello di evidenza (da I a IV) e di forza della raccomandazione (da A a E). Nel caso del presente documento tuttavia, a causa della difficoltà o dell’impossibilità nell’eseguire studi controllati randomizzati, la letteratura di supporto è costituita integralmente da studi retrospettivi tipo caso-controllo e studi osservazionali, in particolare provenienti da Istituzioni specializzate che effettuano sistematicamente la documentazione e l’archiviazione dei casi trattati (Box 1: Studi clinici). Questo documento è stato inviato ad un panel di esperti in ambito nazionale al fine di valutare la chiarezza, la rilevanza clinica e l’applicabilità delle raccomandazioni. I revisori esterni sono i rappresentanti dei principali Centri di Riferimento Nazionali per la diagnosi e la cura dei tumori dell’apparato muscolo-scheletrico ed esperti di metodologia di ricerca clinica del GLOBE

PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation

Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)-–dependent control of membrane remodeling at the midbody, a subcellular organelle that defines the cleavage site. Alteration of ESCRT function can lead to cataract, but the underlying mechanism and its relation to cytokinesis are unclear. We found a lens-specific cytokinetic process that required phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2α (PI3K-C2α), its lipid product PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate), and the PI(3,4)P2-–binding ESCRT-II subunit VPS36 (vacuolar protein-sorting-–associated protein 36). Loss of each of these components led to impaired cytokinesis, triggering premature senescence in the lens of fish, mice, and humans. Thus, an evolutionarily conserved pathway underlies the cell type-–specific control of cytokinesis that helps to prevent early onset cataract by protecting from senescence

Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

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