Basal-like breast cancer (BLBC) is the most aggressive subtype of breast tumors with poor prognosis and limited molecular-targeted therapy options. We show that BLBC cells have a high Cys demand and reprogrammed Cys metabolism. Patient-derived BLBC tumors from four different cohorts exhibited elevated expression of the transsulfuration enzyme cystathione β-synthetase (CBS). CBS silencing (shCBS) made BLBC cells less invasive, proliferate slower, more vulnerable to oxidative stress and cystine (CySSCy) deprivation, prone to ferroptosis, and less responsive to HIF1-α activation under hypoxia. shCBS xenograft tumors grew slower than controls and exhibited impaired angiogenesis and larger necrotic areas. Sulfur metabolite profiling suggested that realigned sulfide/persulfide-inducing functions of CBS are important in BLBC tumor progression. Supporting this, the exclusion of serine, a substrate of CBS for producing Cys but not for producing sulfide/persulfide, did not exacerbate CySSCy deprivation–induced ferroptosis in shCBS BLBC cells. Impaired Tyr phosphorylation was detected in shCBS cells and xenografts, likely due to persulfidation-inhibited phosphatase functions. Overexpression of cystathione γ-lyase (CSE), which can also contribute to cellular sulfide/persulfide production, compensated for the loss of CBS activities, and treatment of shCBS xenografts with a CSE inhibitor further blocked tumor growth. Glutathione and protein-Cys levels were not diminished in shCBS cells or xenografts, but levels of Cys persulfidation and the persulfide-catabolizing enzyme ETHE1 were suppressed. Finally, expression of enzymes of the oxidizing Cys catabolism pathway was diminished, but expression of the persulfide-producing CARS2 was elevated in human BLBC tumors. Hence, the persulfide-producing pathways are major targetable determinants of BLBC pathology that could be therapeutically exploited.

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Table of contentsMELANOMA BRIDGE 2015KEYNOTE SPEAKER PRESENTATIONSMolecular and immuno-advancesK1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanomaVashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. DaviesK2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistanceGennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita ManciniK3 Tumor-intrinsic beta-catenin signaling mediates tumor-immune avoidanceStefani Spranger, Thomas F. GajewskiK4 Intracellular tumor antigens as a source of targets of antibody-based immunotherapy of melanomaYangyang Wang, Soldano FerroneCombination therapiesK5 Harnessing radiotherapy to improve responses to immunotherapy in cancerClaire Vanpouille-Box, Erik Wennerberg, Karsten A. Pilones, Silvia C. Formenti, Sandra DemariaK6 Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockadeHaidong Tang, Yang Wang, Yang-Xin FuK7 Biomarkers for treatment decisions?Reinhard DummerK8 Combining oncolytic therapies in the era of checkpoint inhibitorsIgor PuzanovK9 Immune checkpoint blockade for melanoma: should we combine or sequence ipilimumab and PD-1 antibody therapy?Michael A. PostowNews in immunotherapyK10 An update on adjuvant and neoadjuvant therapy for melanomAhmad TarhiniK11 Targeting multiple inhibitory receptors in melanomaJoe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sanders, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. ZarourK12 Improving adoptive immune therapy using genetically engineered T cellsDavid F. StroncekTumor microenvironment and biomarkersK13 Myeloid cells and tumor exosomes: a crosstalk for assessing immunosuppression?Veronica Huber, Licia RivoltiniK14 Update on the SITC biomarker taskforce: progress and challengesMagdalena ThurinWorld-wide immunoscore task force: an updateK15 The immunoscore in colorectal cancer highlights the importance of digital scoring systems in surgical pathologyTilman Rau, Alessandro LugliK16 The immunoscore: toward an integrated immunomonitoring from the diagnosis to the follow up of cancer’s patientsFranck PagèsEconomic sustainability of melanoma treatments: regulatory, health technology assessment and market access issuesK17 Nivolumab, the regulatory experience in immunotherapyJorge Camarero, Arantxa SanchoK18 Evidence to optimize access for immunotherapiesClaudio JommiORAL PRESENTATIONSMolecular and immuno-advancesO1 Ipilimumab treatment results in CD4 T cell activation that is concomitant with a reduction in Tregs and MDSCsYago Pico de Coaña, Maria Wolodarski, Yuya Yoshimoto, Giusy Gentilcore, Isabel Poschke, Giuseppe V. Masucci, Johan Hansson, Rolf KiesslingO2 Evaluation of prognostic and therapeutic potential of COX-2 and PD-L1 in primary and metastatic melanomaGiosuè Scognamiglio, Francesco Sabbatino, Federica Zito Marino, Anna Maria Anniciello, Monica Cantile, Margherita Cerrone,...

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