Research

Recent and Past Areas of Focus

1) Immune checkpoint inhibition, obesity, and the microbiome in anti-tumor immunity. Since my recruitment from UNC to UTHSC, I have established a robust collaboration with Dr. Joe Pierre in Pediatrics where my expertise in obesity and cancer have complemented well his expertise in obesity and the microbiome. The basis of our recently awarded R01 is focused on using bariatric surgical weight loss approaches, immune checkpoint inhibitors, and pharmaceuticals to reprogram the immune microenvironment to improve anti-tumor immunity (Imm Rev ’20, Imm Rev ’20, Front Cell Dev Bio ‘20). I have also contributed to projects in the Pierre lab on the role of fungi in obesity and insulin resistance (manuscripts in prep). Last, in collaboration with Dr. Athena Starlard-Davenport, I contributed to her work wherein she, Dr. Pierre, and I demonstrated that the microbiome of both breast and tumor are associated with race for the first time, as well as tumor stage or tumor subtype (Sci Reports ’19). She was awarded a Tennessee-Clinical and Translational Science Institute (TN-CTSI) Research Pilot Projects on which I serve as co-I. These studies establish a role of the microbiome impacting the tumor microenvironment, potentially through microbially-derived metabolites that are under investigations for impacts on immunotherapy.

  • Smith, A, Pierre JF, Makowski L, Tolley E, Lyn-Cook B, Lu L, Vidal G, Starlard-Davenport A. Distinct microbial communities that differ by race, stage, or breast tumor subtype in breast tissues from African American and European American women, Scientific Reports. 2019;9(1):11940 PMC6697683
  • #Sipe LM*, #Chaib M*, Pingili AK, Pierre JF, Makowski L. Microbiome, Bile Acids, and Obesity: How Microbially Modified Metabolites Shape Anti-Tumor Immunity. Immunological Reviews. 2020 May;295(1):220-239. PMID32320071. *co-first
  • Makowski L, #Chaib M, Rathmell JC. Immunometabolism: From basic mechanisms to translation. Immunological Reviews. 2020 May;295(1):5-14. PMID: 32320073.
  • #Chaib M, Chauhan SC, Makowski L. Friend or Foe? Recent strategies to target myeloid cells in cancer. Cell Dev. Biol. 19 May 2020. PMC7249856.

 

2) Demonstrated that immunometabolic reprogramming directs macrophage biology in efferocytosis, obesity, and atherosclerosis. A large body of work from my lab focuses on macrophage immunometabolism. i) We demonstrated that substrate metabolism alters macrophage plasticity through metabolic reprogramming. We reported that fatty acid transport protein (FATP1) regulates macrophage lipid metabolism and glucose tolerance in obesity (Molecular Metabolism ‘16). ii) We showed that glucose transporter 1 (GLUT1) expression drove glucose uptake, reactive oxygen species generation, and inflammation in macrophages (J Biol Chem ‘14). iii) Using a novel model created in our lab, we discovered defects in macrophage infiltration and pro-inflammatory activation in the absence of macrophage GLUT1 when mice were made obese (Journal of Immunology, ’19). iv) With American Heart Association funding, we showed that 1) GLUT1 is central for macrophage efferocytosis and may contribute to necrosis in an atherosclerotic lesion (JI ‘18: Nature ‘18); and 2) FATP1 regulates the size and severity of atherosclerotic lesions (Atherosclerosis ‘17). These studies defined metabolic mechanisms in macrophages leading to inflammation, efferocytosis, phagocytosis, atherosclerosis, and systemic glucose intolerance.

  • Freemerman AJ*, Zhao L*^, Pingili AK, Teng B, Cozzo AJ^, Fuller AM^, Johnson AR^, Milner JJ^, Lim MF^, Galanko JA, Beck MA, Bear JE, Rotty JD, Lee DP, Bezavada L, Smallwood HS, Puchowicz MA, Liu J, Locasale JW, Bennett BJ, Abel ED, Rathmell JC, Makowski L. Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1. Journal of Immunology. 2019. PMC6360258.
  • Morioka S, Perry JSA, Raymond MH, Medina CB, Zhu Y, #Zhao L, Serbulea V, Onengut-Gumuscu S, Leitinger N, Kucenas S, Rathmell JC, Makowski L, and Ravichandran KS. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature, PMC6331005.
  • #Johnson AR*, #Qin YY*, #Cozzo A, Freemerman AJ, #Huang MJ, #Zhao L, #Sampey BP, #Milner JJ, Beck MA, Edin ML, Zeldin D, Galanko JA, Lee DP, Fueger PT, Damania B, Bivins B, Stahl A, Wu Y, Mohlke K, Makowski L. Macrophage Fatty Acid Transporter 1 (FATP1) Drives Alternative Macrophage Polarization and Limits Obesity-Induced Inflammation. *denotes co-first authorship. Molecular Metabolism, PMC4921943.
  • Freemerman AJ, #Johnson AR, #Sacks GN, #Milner JJ, Kirk EL, Troester MA, Macintyre AN, Goraksha-Hicks P, Rathmell JC, Makowski L. Metabolic reprogramming of macrophages: Glucose Transporter (GLUT1)-mediated glucose metabolism drives a pro- inflammatory phenotype. J Biol Chem. 2014. PMC3953299.

 

3) Established genetically engineered mouse model (GEMM) of obesity associated basal-like breast cancer and demonstrated role for HGF-cMet using translational multi-disciplinary approaches. i) Using a unique murine model that resembles human basal-like breast cancer (an aggressive triple negative breast cancer, TNBC), we demonstrated that high fat diet-induced obesity drove aggressive tumors– e.g., early tumor onset (latency) and tumor progression (growth) with changes in growth factors and inflammatory cytokines regulated by adiposity (BCRT ’13). ii) We published the first evidence for obesity-induced HGF and activation of its receptor cMet in the etiology of basal-like breast cancer, which had not been previously identified in any cancer type as obesity sensitive. Based on these findings, I was awarded two grants including a highly competitive NCI Provocative Question R21 and Mary Kay Foundation grant to test the role of weight loss and pharmacologic inhibition of cMet in reducing BBC through reversal of obesity-associated factors. iii) Inhibition of cMet with a small molecule reduced tumor burden and angiogenesis (Springerplus ‘16). iv) We showed obesity-driven basal like TNBC could be reversed by weight loss -before tumor onset- in mice (Frontiers in Oncology ’14, CCI ’16). Obesity-driven activation of several kinases in pre-neoplastic lesions of the mammary gland were detected using proteomics/kinomics and specificity was determined by reversal of activation by weight loss (Qin CCI ’16). In patients, v) We reported that a significant majority of patients with basal-like breast cancer had activation of the aforementioned HGF-cMet pathway. We provided in vitro evidence of the importance of stromal-epithelial interactions in cancer promotion (Breast Cancer Res ‘13). vi) In patients, upon investigation of macrophages and cancer cell interactions, we demonstrated elevated macrophages in the obese normal breast microenvironment in subjects who have undergone reduction mammoplasty compared to non-obese (Sun BRCT ‘11). vii) We showed that basal-like tumor cells activate macrophages to a greater extent than less aggressive luminal subtype breast cancer cells (Molecular Cancer Research ‘12). viii) We reported that more clinically aggressive breast cancer subtypes including basal-like displayed different metabolomic profiles than that of less aggressive tumors from patient samples using metabolomics. We further demonstrated that glucose metabolism, HGF, and GLUT1 were linked and integral in maintaining high glycolytic rates of human cancer cells in vitro (CCR ‘12). ix) Finally, we demonstrated that the breast tumor intrinsic subtype is reflected in cancer-adjacent “normal” tissue in patients (Cancer Epidemiol Biomarkers Prev ‘15).

  • #Qin Y, #Sundaram S, #Essaid L, Miller SM, Darr DB, Galanko JA, Montgomery SA, Major B, Johnson GL, Troester MA, Makowski L. Weight loss reduces basal-like breast cancer through kinome reprogramming. 16:26 Cancer Cell International. PMC4818517.
  • #Cozzo AJ*, #Sundaram S*, #Zattra O, #Qin Y, Freemerman AJ, #Essaid L, Darr DB, Montgomery SA, McNaughton KK, Ezzell JA, Galanko JA, Troester MA, Makowski L. cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer. Springer Plus Breast Cancer Collection Springerplus. 2016 PMC4799044 *co-first.
  • #Sundaram S, #Le TL, #Essaid L, Freemerman AJ, #Huang MJ, Galanko JA, McNaughton KK, Bendt KM, Darr DB, Troester MA, Makowski L. Weight loss prevents obesity-associated basal-like breast cancer progression: Role of hepatocyte growth factor. Frontiers in Oncology PMC4085881.

 

4) Determined underlying mechanisms and metabolite biomarkers in GEMMs of obesity-associated ovarian cancer and endometrial cancer with clinical correlates. i) In patients, we demonstrated that BMI is associated with endometrial cancer in TCGA samples (Roque Gyn Oncol ’16). ii) In mice, we showed obesity drives ovarian cancer progression in a novel murine model (Makowski Gyn Oncol ’14). iii) Reversal of obesity-driven aggressiveness of endometrial cancer (Guo AJCR ’19) and ovarian cancer (Han Oncotarget ’17) in mouse models by metformin was possible. iv) Current studies involving clinical trials using metformin and other targeted therapies are ongoing led by long term collaborator Dr. Vickie Bae-Jump at UNC Chapel Hill (Shuler Can Med ‘14).

  • Guo H, Kong W, Zhang L, Han J, Clark LH, Yin Y, Fang Z, Sun W, Wang J, Gilliam TP, Lee D, Makowski L, Zhou C, Bae-Jump VL. Reversal of obesity-driven aggressiveness of endometrial cancer by metformin. Am J Cancer Res. 2019. PMID: 31720081.
  • Roque DR, Makowski L, Chen T-H, Rashid N, Hayes DN, Bae-Jump V. Association between differential gene expression and body mass index among endometrial cancers from The Cancer Genome Atlas (TCGA) Project. Gynecol Oncol. PMID:27288544.
  • Schuler KM, Rambally BS, DiFurio MJ, Sampey BP^, Gehrig PA, Makowski L, Bae-Jump VL. Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer. Cancer Med. PMC4329001.
  • Makowski L, Zhou C, Zhong Y, Kuan P-F, Fan C, Sampey BP^, Difurio M, Bae-Jump VL. Obesity Increases Tumor Aggressiveness in a Genetically Engineered Mouse Model of Serous Ovarian Cancer. Gynecologic Oncology– The Obesity Crisis: Impact of Gynecologic Cancer issue. PMID3904507.

# Denotes students and postdoctoral fellows mentored by Makowski.