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Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of >13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies., Competing Interests: Declaration of interests An invention disclosure report related to findings reported herein has been submitted to the University of Texas. B.M.W. receives research funding from Celgene and Eli Lilly and does consulting for BioLineRx, Celgene, and GRAIL., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers that resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine, and lysophospholipids, which was validated in an independent set from another institution as predictive of non-durable response to CAR-T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL., Competing Interests: Declaration of interests An Invention Disclosure Report related to findings reported herein has been submitted to the University of Texas. M.S. has received industry research support from Amgen, Gilead, Miltenyi Biotec, Morphosys, Roche, and Seattle Genetics and has served as a consultant/advisor to Amgen, BMS, Celgene, Gilead, Pfizer, Novartis, and Roche. She sits on the advisory boards of Amgen, Celgene, Gilead, Janssen, Novartis, Pfizer, and Seattle Genetics and serves on the speakers' bureau at Amgen, Celgene, Gilead, Janssen, and Pfizer. N.Y.S. has intellectual property rights in the field of cellular immunotherapy and microbiome. S.S.N. received personal fees from Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Bluebird Bio, and Unum Therapeutics; research support from Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences, and Acerta; royalties from Takeda Pharmaceuticals; and has intellectual property rights related to cell therapy. M.G. reports research funding from Sanofi, Kite/Gilead, Abbvie, and Allogene, honoraria from Tessa Therapeutics and Daiichi Sankyo, and stock ownership of KDAc Therapeutics. P.S. received research support from Astrazeneca-Acerta and from ALX Oncology and is a consultant for Roche-Genentech and Hutchinson MediPharma. S.S.N. has received personal fees from Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics, and Bluebird Bio; research support from Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences, and Acerta; and patents, royalties, or other intellectual property from Takeda Pharmaceuticals., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance., Competing Interests: Declaration of interests H.Y. has patent applications related to cell-penetrating peptide. Y.-J.L. and H.Y. serve as consultants at Inova BioTherapeutics, Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Universal cancer screening based on circulating DNA, proteins, metabolites, or other combinations has the potential to revolutionize early cancer detection, especially for cancers with no available screening modalities. Two recent publications in Science and Annals of Oncology highlight the potential benefits and limitations of single-test, multiple cancer screens., Competing Interests: Declaration of Interests S.H. has IP filings related to pancreatic cancer and lung cancer biomarkers with applications to cancer detection. One IP filing was licensed to Thrive Technologies (one author of Lennon et al., 2020 is affiliated with Thrive Technologies)., (Published by Elsevier Inc.)

Cancer stem cells (CSCs) are critical for cancer progression and chemoresistance. How lipid metabolism regulates CSCs and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and cancer chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self-renewal and expression of diverse lipid metabolic genes, including carnitine palmitoyltransferase 1B (CPT1B), which encodes the critical enzyme for fatty acid β-oxidation (FAO). Moreover, mammary-adipocyte-derived leptin upregulates STAT3-induced CPT1B expression and FAO activity in BCSCs. Human breast-cancer-derived data suggest that the STAT3-CPT1B-FAO pathway promotes cancer cell stemness and chemoresistance. Blocking FAO and/or leptin re-sensitizes them to chemotherapy and inhibits BCSCs in mouse breast tumors in vivo. We identify a critical pathway for BCSC maintenance and breast cancer chemoresistance., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

One histologic subtype of ovarian carcinoma, ovarian endometrioid adenocarcinoma (OEA), frequently harbors mutations that constitutively activate Wnt/beta-catenin-dependent signaling. We now show that defects in the PI3K/Pten and Wnt/beta-catenin signaling pathways often occur together in a subset of human OEAs, suggesting their cooperation during OEA pathogenesis. Deregulation of these two pathways in the murine ovarian surface epithelium by conditional inactivation of the Pten and Apc tumor suppressor genes results in the formation of adenocarcinomas morphologically similar to human OEAs with 100% penetrance, short latency, and rapid progression to metastatic disease in upwards of 75% of mice. The biological behavior and gene expression patterns of the murine cancers resemble those of human OEAs with defects in the Wnt/beta-catenin and PI3K/Pten pathways.

Two-dimensional gel electrophoresis followed by silver-staining was utilized to visualize platelet polypeptides for genetic analysis. A subset of 33 polypeptides that were most suited for scoring was selected. Families consisting of father-mother-child trios were studied. Thirty-six polypeptides of a total of 1,413 scored in children's gels exhibited the combination of a normal and a variant polypeptide. The observed index of heterozygosity of 2.55% is comparable to our previously reported findings for red cell proteins.

Two-dimensional gel electrophoresis followed by silver-staining has been employed to study 27 red cell lysates for genetic variation. Forty-six polypeptides selected without respect to variability were considered suitable for scoring. Only 23 of the total of 1,242 polypeptides could not be scored unambiguously. Of the remaining 1,219 polypeptides, 38 exhibited the combination of a normal and a variant polypeptide. All variants were present in either the father or the mother of the subjects. The observed index of heterozygosity was 3.1% +/- 0.5%.

Peripheral blood lymphocytes from 40 children have been examined for genetic variation in their protein constituents by two-dimensional polyacrylamide gel electrophoresis. One hundred six polypeptides chosen without respect to genetic variability were scored in gels from the 40 children. For each child, gels from both parents were also examined to substantiate the genetic basis of variants observed. Of the total of 4,240 polypeptides, 23 could not be scored unambiguously. Fourteen of the polypeptides showed genetic variants in one or more of the children. One hundred twenty-nine of 4,217 polypeptides scored exhibited the combination of a normal and a variant polypeptide. All variants were present in at least one of the parents of the subject. The index of heterozygosity observed (3.05% +/- .23%) indicates substantial genetic variation in cellular protein constituents.