Oilseed crops are used to produce vegetable oil. Sesame (Sesamum indicum), an oilseed crop grown worldwide, has high oil content and a small diploid genome, but the genetic basis of oil production and quality is unclear. Here we sequence 705 diverse sesame varieties to construct a haplotype map of the sesame genome and de novo assemble two representative varieties to identify sequence variations. We investigate 56 agronomic traits in four environments and identify 549 associated loci. Examination of the major loci identifies 46 candidate causative genes, including genes related to oil content, fatty acid biosynthesis and yield. Several of the candidate genes for oil content encode enzymes involved in oil metabolism. Two major genes associated with lignification and black pigmentation in the seed coat are also associated with large variation in oil content. These findings may inform breeding and improvement strategies for a broad range of oilseed crops.

Autotaxin is a secreted enzyme that produces most extracellular lysophosphatidate, which stimulates 6 G-protein-coupled receptors. Lysophosphatidate promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The present work investigated whether inhibiting autotaxin could decrease breast tumor growth and metastasis. We used a new autotaxin inhibitor (ONO-8430506; IC90=100 nM), which decreased plasma autotaxin activity by >60% and concentrations of unsaturated lysophosphatidates by >75% for 24 h compared with vehicle-treated mice. The effects of ONO-8430506 on tumor growth were determined in a syngeneic orthotopic mouse model of breast cancer following injection of 20,000 BALB/c mouse 4T1 or 4T1-12B cancer cells. We show for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastatic nodules both by 60% compared with vehicle-treated mice. Significantly, 4T1 cells express negligible autotaxin compared with the mammary fat pad. Autotaxin activity in the fat pad of nontreated mice was increased 2-fold by tumor growth. Our results emphasize the importance of tumor interaction with its environment and the role of autotaxin in promoting breast cancer growth and metastasis. We also established that autotaxin inhibition could provide a novel therapeutic approach to blocking the adverse effects of lysophosphatidate in cancer.

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Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC 90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-a and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX.-Benesch, M. G. K., Tang, X., Dewald, J., Dong, W.-F., Mackey, J. R., Hemmings, D. G., McMullen, T. P. W., Brindley, D. N. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression. FASEB J. 29, 3990-4000 (2015). www.fasebj.org

The present work elucidates novel mechanisms for lysophosphatidate (LPA)-induced chemoresistance using human breast, lung, liver, and thyroid cancer cells. LPA (0.5-10 mM) increased Nrf2 transcription factor stability and nuclear localization by £5-fold. This involved lysophosphatidate type 1 (LPA 1 ) receptors as identified with 1 mM wls-31 (LPA 1/2 receptor agonist) and blocking this effect with 20 mM Ki16425 (LPA 1-3 antagonist, K i = 0.34 mM). Knockdown of LPA 1 by 50% to 60% with siRNA decreased Nrf2 stability and expressing LPA 1 , but not LPA 2/3 , in human HepG2 cells increased Nrf2 stabilization. LPA-induced Nrf2 expression increased transcription of multidrug-resistant transporters and antioxidant genes by 2-to 4-fold through the antioxidant response element. This protected cells from doxorubicin-induced death. This pathway was verified in vivo by orthotopic injection of 20,000 mouse 4T1 breast cancer cells into syngeneic mice. Blocking LPA production with 10 mg/kg per d ONO-8430506 (competitive autotaxin inhibitor, IC 90 = 100 nM) decreased expression of Nrf2, multidrug-resistant transporters, and antioxidant genes in breast tumors by £90%. Combining 4 mg/kg doxorubicin every third day with ONO-8430506 synergistically decreased tumor growth and metastasis to lungs and liver by >70%, whereas doxorubicin alone had no significant effect. This study provides the first evidence that LPA increases antioxidant gene and multidrug-resistant transporter expression. Blocking this aspect of LPA signaling provides a novel strategy for improving chemotherapy.-Venkatraman, G., Benesch, M. G. K., Tang, X., Dewald, J., McMullen, T. P. W., Brindley, D. N. Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: implications for cancer treatment. FASEB J. 29, 772-785 (2015). www.fasebj.org