Nagireddy Putluri Lab

Our laboratory investigates how metabolic, epigenetic, and signaling alterations drive bladder cancer initiation, progression, metastasis, and therapeutic resistance. Using mass spectrometry-based metabolomics, lipidomics, stable-isotope tracing, metabolic flux analysis, and integrated multi-omics approaches, we define how tumor metabolism changes across patient populations, environmental exposures such as tobacco use, oncogenic alterations, and disease stages. By connecting metabolic phenotypes to molecular mechanisms and functional tumor biology, our goal is to identify clinically relevant biomarkers and metabolic vulnerabilities that can be translated into mechanism-based therapies, including rational combinations with targeted and immune-based therapies for patients with aggressive bladder cancer.

We investigate how loss of SMARCB1, a key component of the SWI/SNF chromatin-remodeling complex, reshapes the epigenetic and transcriptional landscape of bladder cancer. Our studies indicate that SMARCB1 deficiency promotes activation of the IL6/JAK/STAT3 signaling axis, contributing to tumor growth, invasion, and metastasis. We are defining how SMARCB1 loss connects chromatin dysregulation with altered signaling and cellular metabolism to identify molecular biomarkers and therapeutic vulnerabilities associated with this aggressive subtype of bladder cancer. These studies may provide a mechanistic foundation for developing targeted strategies for SMARCB1-deficient tumors.

We investigate how oncogenic PIK3CA mutations reprogram cellular metabolism to support bladder cancer growth and survival. Our work demonstrates that PIK3CA activation promotes increased glutamine utilization, mitochondrial oxidative phosphorylation, reductive carboxylation, and fatty-acid biosynthesis, creating metabolic dependencies that can be exploited therapeutically. By combining metabolomics, stable-isotope tracing, metabolic flux analysis, and molecular approaches, we aim to define how PI3K signaling coordinates nutrient utilization and mitochondrial metabolism. These studies seek to identify metabolic vulnerabilities that can be targeted together with PI3K pathway inhibitors or other precision therapies.

We have identified a distinct glutamine-dependent oxidative phosphorylation (OXPHOS) metabolic subtype of bladder cancer characterized by increased reliance on mitochondrial respiration and complex I activity. Tumors within this subtype exhibit enhanced glutamine utilization and a feed-forward metabolic relationship between NDUFB8 and GLS1 that sustains mitochondrial respiration and tumor growth. Pharmacologic targeting of either complex I or GLS1 reduces mitochondrial respiration and tumor growth in preclinical models, supporting a functional dependence on glutamine-fueled OXPHOS. This work defines a metabolically distinct bladder cancer subtype and provides a framework for identifying patients whose tumors may be particularly vulnerable to therapeutic targeting of glutamine metabolism and mitochondrial oxidative phosphorylation.

We investigate how fatty-acid metabolism is rewired during bladder cancer progression, with a particular focus on the balance between fatty-acid oxidation and de novo fatty-acid synthesis. Our studies identified loss of CPT1B, a key regulator of mitochondrial fatty-acid oxidation, as a metabolic feature of high-grade bladder cancer. Restoration of CPT1B reprograms fatty-acid metabolism and suppresses epithelial–mesenchymal transition, tumor growth, and metastasis, establishing fatty-acid oxidation as an important determinant of aggressive disease. We also investigate how environmental exposures, particularly cigarette smoking, reshape tumor lipid metabolism. Our recent work demonstrates that smoking promotes glutamine-fueled, FASN-dependent fatty-acid synthesis, creating a metabolic program that supports bladder cancer progression. Pharmacologic inhibition of FASN suppresses smoke-induced tumor growth in preclinical models. Together, these studies reveal distinct alterations in fatty-acid synthesis and oxidation associated with tumor progression and environmental exposure and identify fatty-acid metabolism as a therapeutically actionable vulnerability in bladder cancer.

Our laboratory investigates how alterations in xenobiotic and lipid-mediator metabolism contribute to bladder cancer progression. As tumors progress, they can lose enzymes that normally metabolize xenobiotics and bioactive lipid mediators, resulting in profound metabolic and signaling changes. We found that loss of AOX1, mediated in part by EZH2-dependent epigenetic silencing, rewires tryptophan and NADP metabolism, promoting nucleotide biosynthesis and invasive tumor behavior. We also study EPHX2, an enzyme involved in the metabolism of epoxyeicosatrienoic acids (EETs). EPHX2 loss increases EET accumulation and activates an AKT–PKN3 signaling axis, with potential consequences for the tumor microenvironment. We are investigating whether targeting PKN3 can enhance NECTIN4-directed therapies and immune checkpoint blockade in EPHX2-deficient bladder cancer.