College of Medicine
UNMC_Acronym_Vert_sm_4c
University of Nebraska Medical Center

Research Projects

Project 1: Mechanism of pancreatic cancer stem cell maintenance

This project aims to understand and overcome the root causes of therapy resistance in pancreatic ductal adenocarcinoma. A small subset of tumor cells, known as cancer stem cells, drives recurrence, metastasis and poor patient outcomes. We focus on dissecting the mechanisms that sustain these CSCs by integrating multiple perspectives, like metabolic reprogramming, transporter biology, and microenvironmental influences. We discovered that the serotonin transporter SLC22A3 plays a central role in CSC maintenance by regulating serotonin uptake and signaling, while the metabolic enzyme PDK3 links energy metabolism to stemness. In parallel, we explore how the microbiome and its metabolites remodel the PDAC tumor microenvironment and immune response, ultimately promoting CSC enrichment. To study these complex interactions, we combine advanced 3D organoid and spheroid systems, in vivo mouse models, and patient-derived datasets. Together, these approaches help us identify new therapeutic vulnerabilities in CSC biology. Our long-term goal is to design innovative CSC-targeted therapies that prevent relapses, overcome drug resistance, and improve outcomes for pancreatic cancer patients.

  1. Nallasamy P, Nimmakayala RK, Karmakar S, Leon F, Seshacharyulu P, Lakshmanan I, Rachagani S, Mallya K, Zhang C, Ly QP, Myers MS, Josh L, Grabow CE, Gautam SK, Kumar S, Lele SM, Jain M, Batra SK, Ponnusamy MP*. Pancreatic Tumor Microenvironment Factor Promotes Cancer Stemness via SPP1-CD44 Axis. Gastroenterology, 2021 Aug 18:S0016-5085(21)03402-8. PMID: 34418441
  2. Nimmakayala RK, Leon F, Rachagani S, Rauth S, Nallasamy P, Marimuthu S, Shailendra GK, Chhonker YS, Chugh S, Chirravuri R, Gupta R, Mallya K, Prajapati DR, Lele SM, C Caffrey T, L Grem J, Grandgenett PM, Hollingsworth MA, Murry DJ, Batra SK*, Ponnusamy MP*. Metabolic programming of distinct cancer stem cells promotes metastasis of pancreatic ductal adenocarcinoma. Oncogene, 2021 Jan;40(1):215-231. PMID: 33110235.
  3. Karmakar S, Rauth S, Nallasamy P, Perumal NK, Nimmakalaya R, Leon F, Gupta G, Barkeer S, Chirravuri Venkata R, Raman V, Rachagani S, Ponnusamy MP*, and Batra SK*. PAF1 promotes stemness and pancreatic cancer oncogenesis independently of the canonical PAF1C via PHF5A and DDX3. Gastroenterology, 2020 Nov;159(5):1898-1915.e6. PMID: 32781084.
  4. Ganguly K, Krishn SR, Rachagani S, Jahan R, Shah A, Nallasamy P, Rauth S, Atri P, Cox JL, Pothuraju R, Smith LM, Ayala S, Evans C, Ponnusamy MP, Kumar S, Kaur S, Batra SK. Secretory mucin 5AC promotes neoplastic progression by augmenting KLF4-mediated pancreatic cancer cell stemness. Cancer Res., 2020 Oct 30:canres.1293.2020. PMID: 33127746.
  5. Nimmakayala RK, Rauth S, Chirravuri Venkata R, Marimuthu S, Nallasamy P, Vengoji R, Lele SM, Rachagani S, Mallya K, Malafa MP, Ponnusamy MP*, Batra SK. PGC1α-Mediated Metabolic Reprogramming Drives the Stemness of Pancreatic Precursor Lesions. Clin Cancer Res. 2021 Oct 1;27(19):5415-5429. PMID: 34172498

 

Project 2: Molecular mechanisms of progression and organ-specific metastasis in pancreatic and ovarian cancer

Our research investigates how cell-surface glycoconjugates, particularly mucins and glycosyltransferases, drive tumor progression and metastasis. We demonstrated that MUC4 alters HER2 signaling, induces EMT, and enriches cancer stem cell populations in ovarian cancer, highlighting its role in motility, drug resistance and metastatic spread. In pancreatic cancer, we are uncovering how glycosyltransferases GCNT3 and B3GNT3 remodel O-glycans and poly-LacNAc chains to bias metastasis toward liver versus lung. Using CRISPR-engineered models, glycoproteomic profiling, and functional assays, we define glycan-mediated mechanisms of dissemination. Our ultimate goal is to develop mucin- and glycan-targeted therapies that block progression and disrupt organ-specific metastatic outgrowth.

  1. Gupta R, Leon F, Thompson CM, Nimmakayala R, Karmakar S, Nallasamy P, Chugh S, Prajapati DR, Rachagani S, Kumar S, and Ponnusamy MP*. Global analysis of human glycosyltransferases reveals novel targets for pancreatic cancer pathogenesis. J. Cancer, 2020 May;122(11):1661-1672. PMID: 32203219
  2. Gupta R, Leon F, Rauth S, Batra SK, Ponnusamy MP*. A Systematic Review on the Implications of O-linked Glycan Branching and Truncating Enzymes on Cancer Progression and Metastasis. Cells, 2020 Feb 14;9(2). pii: E446. PMID: 32075174
  3. Chugh S, Barkeer S, Rachagani S, Nimmakayala RK, Perumal N, Pothuraju R, Atri P, Mahapatra S, Thapa I, Talmon GA, Smith LM, Yu X, Neelamegham S, Fu J, Xia L, Ponnusamy MP*, Batra SK*. Disruption of C1galt1 Gene Promotes Development and Metastasis of Pancreatic Adenocarcinomas in Mice. Gastroenterology, 2018 Nov;155(5):1608-1624. PMID: 30086262
  4. Ponnusamy MP, Lakshmanan I, Jain M, Das S, Chakraborty S, Dey P, Batra SK. MUC4 mucin-induced epithelial to mesenchymal transition: a novel mechanism for metastasis of human ovarian cancer cells. Oncogene, 2010 Oct 21;29(42):5741-54. PubMed PMID: 20697346
  5. Kaushik G, Seshacharyulu P, Rauth S, Nallasamy P, Rachagani S, Nimmakayala RK, Vengoji R, Mallya K, Chirravuri-Venkata R, Singh AB, Foster JM, Ly QP, Smith LM, Lele SM, Malafa MP, Jain M, Ponnusamy MP*, Batra SK*. Selective inhibition of stemness through EGFR/FOXA2/SOX9 axis reduces pancreatic cancer metastasis. Oncogene, 2021 Jan;40(4):848-862. PMID: 33288882


Project 3: Glycosylation–metabolism crosstalk in early PDAC metastasis

This project focuses on how aberrant glycosylation rewires metabolism to promote PDAC progression and early metastasis. Specifically, we investigate the role of C1GALT1, a core O-glycosyltransferase that generates mucin-type glycans. Using CRISPR-engineered C1GALT1 knockout models, we discovered that loss of this enzyme enhances cell migration and anoikis resistance, two hallmarks of metastatic initiation. Transcriptomic profiling revealed striking enrichment of cholesterol metabolism pathways, with upregulation of SQLE, SCARB1, and transcriptional regulators SREBF1/2. These findings point to a novel link between defective glycosylation and lipid metabolic reprogramming in PDAC. We are now dissecting how C1GALT1 loss drives cholesterol biosynthesis and uptake, and how this metabolic shift supports tumor aggressiveness. Functional assays in 3D culture systems and in vivo models allow us to test the contribution of cholesterol pathways to survival, invasion and early dissemination. By integrating glycoproteomic, transcriptomic and metabolic approaches, this project highlights how post-translational glycan remodeling creates metabolic flexibility in PDAC. Our ultimate goal is to identify actionable vulnerabilities that could be targeted to prevent or treat metastatic spread more effectively.

Project 4: GlycoRNA biology in pancreatic cancer

Our project investigates the emerging biology of glycoRNAs: RNA molecules that are post-transcriptionally modified with glycans, and their functional significance in PDAC. While glycans have long been studied on proteins and lipids, RNA glycosylation represents a newly discovered layer of regulation with unknown consequences in cancer. We aim to define how glycoRNAs contribute to PDAC progression, metastasis, and tumor cell plasticity. Specifically, we are profiling glycoRNA signatures in normal versus KRAS-driven tumor organoids, and examining how these signatures shift during epithelial-to-mesenchymal transition, a central process in invasion and dissemination. Using advanced biochemical enrichment and mass spectrometry, we collaborate with core facilities to map glycan structures attached to RNA. Complementary CRISPR-based approaches are used to identify glycosyltransferases and regulators that control RNA glycosylation. In vivo models, including KPC and KPCC mice, provide a platform to study how glycoRNAs function in tumor progression and organ-specific metastasis. By uncovering how RNA glycosylation shapes cellular behavior, our work provides a novel framework for understanding PDAC biology and reveals potential therapeutic opportunities targeting glycoRNA pathways.

  1. Varadharaj V, Petersen W, Batra SK, Ponnusamy MP*. Sugar symphony: glycosylation in cancer metabolism and stemness. Trends Cell Biol. 2025 May;35(5):412-425. doi: 10.1016/j.tcb.2024.09.006. Epub 2024 Oct 26. Review. PubMed PMID: 39462722; PubMed Central PMCID: PMC12032065.

Project 5: Risk factor-induced cancer stem cell enrichment and progression of pancreatic cancer

Despite evidence that long-term smoking is the leading risk factor for pancreatic malignancies, the underlying mechanism(s) for cigarette-smoke (CS)-induced pancreatic cancer (PC) pathogenesis has not been well established. We explore a potential link between MUC4 expression and smoking-mediated PC pathogenesis. Besides, we demonstrated that nicotine-mediated MUC4 up-regulation promotes PC cell migration by activating the downstream effectors, such as HER2, c-Src and FAK. Recently, we have demonstrated that chronic cigarette smoke exposure activates stem cell features of pancreatic cells via CHRNA7 signaling and FOSL1 activation of PAF1 expression. Levels of PAF1 are increased in pancreatic tumors of humans and mice with chronic cigarette smoke exposure.

  1. Nallasamy P, Nimmakayala RK, Karmakar S, Leon F, Seshacharyulu P, Lakshmanan I, Rachagani S, Mallya K, Zhang C, Ly QP, Myers MS, Josh L, Grabow CE, Gautam SK, Kumar S, Lele SM, Jain M, Batra SK, Ponnusamy MP*. Pancreatic Tumor Microenvironment Factor Promotes Cancer Stemness via SPP1-CD44 Axis. Gastroenterology, 2021 Dec;161(6):1998-2013.e7. PMID: 34418441
  2. Nimmakayala R, Seshacharyulu P, Lakshmanan I, Rachagani R, Chugh S, Karmakar S, Rauth S, Vengoji R, Atri P, Talmon GA, Lele SM, Smith LM, Thapa I, Bastola D, Ouellette MM, Batra SK*, and Ponnusamy MP*. Cigarette Smoke Induces Stem Cell Features of Pancreatic Cancer Cells via PAF1. Gastroenterology, 2018 Sep;155(3):892-908.e6. PMID: 29864419
  3. Ponnusamy MP, Batra SK. Insights into the role of nicotine in pancreatic stem cell activation and acinar dedifferentiation. Gastroenterology, 2014 Nov;147(5):962-5. PubMed PMID: 25265575.
  4. Momi N, Ponnusamy MP, Kaur S, Rachagani S, Kunigal SS, Chellappan S, Ouellette MM, Batra SK. Nicotine/cigarette smoke promotes metastasis of pancreatic cancer through α7nAChR-mediated MUC4 upregulation. Oncogene, 2013 Mar 14;32(11):1384-95. PubMed PMID: 22614008
  5. Momi N, Kaur S, Ponnusamy MP, Kumar S, Wittel UA, Batra SK. Interplay between smoking-induced genotoxicity and altered signaling in pancreatic carcinogenesis. Carcinogenesis, 2012 Sep;33(9):1617-28. PubMed PMID: 22623649
  6. Parte S, Kaur AB, Nimmakayala RK, Ogunleye AO, Chirravuri R, Vengoji R, Leon F, Nallasamy P, Rauth S, Alsafwani ZW, Lele S, Cox JL, Bhat I, Singh S, Batra SK, Ponnusamy MP*. Cancer-associated Fibroblast Induces Acinar-to-ductal Cell Transdifferentiation and Pancreatic Cancer Initiation via LAMA5/ITGA4 axis. Gastroenterology. 2023 Dec 26:S0016-5085(23)05683-4