421 East Canfield
Detroit, MI 48201-1976
• Cancer metabolism
• Mitochondrial metabolism
• Folates and one-carbon metabolism
• Drug discovery
• Translational studies of chemotherapy response and resistance
Metabolic reprogramming is a hallmark of cancer. Of the altered metabolic pathways in cancer, one-carbon (C1) metabolism is notable. C1 metabolism encompasses folate-mediated C1 transfer reactions and related processes, including nucleotide and amino acid biosynthesis, anti-oxidant regeneration, and epigenetic regulation. Uptake of folates into tissues is mediated by the major facilitative transporters, the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), and by folate receptors (FRs) α and β. C1 pathways are compartmentalized in the cytosol, mitochondria and nucleus. Current studies in the Matherly laboratory focus on understanding the biology of C1 metabolism and related processes in relation to therapy of cancer, as well as other diseases.
1. Based on patterns of tumor-selective expression and/or function of FRs and PCFT, our studies focus on discovery of novel cytotoxic drugs that target tumors via their selective membrane transport. For instance, solid tumors such as ovarian cancer express high levels of FRs, and tumors such as pancreatic ductal adenocarcinoma, lung adenocarcinoma, and malignant mesothelioma express high levels of PCFT. For PCFT, transport occurs under acidic pH conditions that characterize the tumor microenvironment. We are working to advance our most optimal agents with the best balance of FR and PCFT transport specificity and potent antitumor efficacy to the clinic.
2. Ongoing studies explore the transcriptional and posttranscriptional regulation of PCFT- and RFC-mediated transport in the context of targeted therapies with the goal of further harnessing these systems for tumor-selective delivery of PCFT-targeted therapies.
3. Recent insights into C1 metabolism in cancer cells, including the critical role of the mitochondrial C1 metabolism from serine as a major source of C1 units, glycine, reducing equivalents and ATP, suggests that key metabolic enzymes including serine hydroxymethyltransferase 2 (SHMT2) could be independent prognostic factors and important therapeutic targets for cancer. Based on our discovery of powerful inhibitors of SHMT2 with broad-based anti-tumor efficacy, we are now exploring the broader biological role of mitochondrial C1 metabolism in cancer cells with the goal of developing new therapies.
4. There is growing interest in the role of immune populations as critical determinants of anti-tumor responses to standard and targeted therapies for many cancers. Ongoing studies explore the potential of targeting FRβ-expressing tumor-associated macrophages (TAMs) for therapy of ovarian cancer. TAMs are the most abundant immune population in ovarian cancer and contribute to an immunosuppressive environment, permitting these tumors to evade immune detection.
Allison V Mitchell, Ling Wu, C James Block, Mu Zhang, Justin Hackett, Douglas B Craig, Wei Chen, Yongzhong Zhao, Bin Zhang, Yongjun Dang, Xiaohong Zhang, Shengping Zhang, Chuangui Wang, Heather Gibson, Lori A Pile, Benjamin Kidder, Larry Matherly, Zhe Yang, Yali Dou, Guojun Wu. FOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis. Nature Communications 2022;13:6548.
Hou Z, Gangjee A, Matherly LH. The evolving biology of the proton-coupled folate transporter: New insights into regulation, structure, and mechanism.
FASEB J. 2022;36:e22164.
Wallace-Povirk A, Hou Z, Nayeen MJ, Gangjee A, Matherly LH. Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer. Cancers (Basel). 2021;14:191.
O'Connor C, Wallace-Povirk A, Ning C, Frühauf J, Tong N, Gangjee A, Matherly LH, Hou Z. Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer. Sci Rep. 2021;11:6389.
Dekhne AS, Hou Z, Gangjee A, Matherly LH. Therapeutic targeting of mitochondrial one-carbon metabolism in cancer. Mol Cancer Ther 2020;19:2245–55.
Dekhne AS, Ning C, Nayeen MJ, Shah K, Kalpage H, Frühauf J, Wallace-Povirk A, O'Connor C, Hou Z, Kim S, Hüttemann M, Gangjee A, Matherly LH. Cellular pharmacodynamics of a novel pyrrolo[3,2-d]pyrimidine inhibitor targeting mitochondrial and cytosolic one-carbon metabolism. Mol Pharmacol. 2020;97:9-22.
Dekhne AS, Shah K, Ducker GS, Katinas JM, Wong-Roushar J, Nayeen MJ, Doshi A, Ning C, Bao X, Frühauf J, Liu J, Wallace-Povirk A, O'Connor C, Dzinic SH, White K, Kushner J, Kim S, Hüttemann M, Polin L, Rabinowitz JD, Li J, Hou Z, Dann CE 3rd, Gangjee A, Matherly LH. Novel pyrrolo[3,2-d]pyrimidine compounds target mitochondrial and cytosolic one-carbon metabolism with broad-spectrum antitumor efficacy. Mol Cancer Ther. 2019;18:1787-99.
Hou Z, O'Connor C, Frühauf J, Orr S, Kim S, Gangjee A, Matherly LH. Regulation of differential proton-coupled folate transporter gene expression in human tumors: transactivation by KLF15 with NRF-1 and the role of Sp1. Biochem J. 2019;476:1247-66.
PhD (1981): Pennsylvania State University, State College, Pennsylvania
CB7210 Fundamentals of Cancer Biology
CB7240 Principles of Cancer Therapy
CB7300 Special Topics F31 Grant Writing Course