Madhura Patankar’s research while affiliated with University of California, Davis and other places

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Publications (5)


Abstract 4296: Investigating metabolic sensitivity and organization of renal cell carcinoma: To enhance effective therapies and patient survival
  • Article

March 2024

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1 Read

Cancer Research

Madhura Patankar

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John Albeck

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Shuchi Gulati

Background: Renal cell carcinoma (RCC) is the 6th most common cancer in men and the 9th most common in women in the United States. RCC tissues are metabolically dysfunctional, often resulting from loss of von-Hippel Lindau (VHL) and consequent upregulation of hypoxia-inducible factor (HIF1/2). HIF1a is a transcription factor that upregulates glycolytic gene expression. Current therapies, including immune checkpoint inhibitors and tyrosine kinase inhibitors, have shown improvements in the outcomes of RCC patients, however, there are no biomarkers clinically available to predict the efficacy of these drugs. While genomic data and transcriptomic signatures have been investigated, they are not used in clinical practice due to lack of prospective validation. Understanding additional pathways pertaining to metabolic features of RCC, is critical. Our bulk gene expression analysis of primary RCC samples from TCGA-KIRC show a predominance of genes expressing mitochondrial ribosomal proteins and electron transport chain in tumors that relapsed early after nephrectomy, warranting further validation. Aim: We aim to investigate changes in metabolic adaptation in RCC cells from kidney cancer cell lines (VHL mutant) and primary cells from human-matched primary and metastatic kidney cancer sites. Using a novel biosensor-based technique developed in the Albeck lab, we aim to identify the dependence of live RCC cells on specific metabolic pathways and test the effect of standard-of-care (SOC) pathway inhibitors such as tyrosine kinase, HIF pathway, metabolic pathway inhibitors impacting tumorigenicity. Methods: To examine functional metabolic behavior in single cells, we generated immortalized cell lines (MCF10A, 184A1, FL83B and HBE-1) stably transfected with biosensors for the activity of AKT, glycolysis, mTOR and AMPK pathway. Data from Live-cells treated with metabolic inhibitors were collected and analyzed using our MATLAB-based pipeline. We have extended the analysis to RCC cell lines (786-O cell lines) and primary cells collected from nephrectomy specimens and matched metastatic biopsy samples, using current SOC pathway inhibitors (including sorafenib, sunitinib, belzutifan) and investigational metabolic drugs (metformin, IACS-010759, niclosamide). Results & Conclusion: Our preliminary results show an association of high OX-PHOS with primary tumors from early relapse after nephrectomy than the relapsed late tumors. Our biosensor single cell data show that even genetically homogeneous cell populations can vary in their usage of OXPHOS and glycolysis to supply ATP for cell growth. Tumor gene expression profile coupled with biosensor data, will address mechanism behind this metabolic shift in RCC tumors in primary cells isolated from primary and metastatic sites. Our research will improve tumor prognosis and allow designing therapeutic trials. Citation Format: Madhura Patankar, John Albeck, Shuchi Gulati. Investigating metabolic sensitivity and organization of renal cell carcinoma: To enhance effective therapies and patient survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4296.


Figure 1. Differential gene expression responses to ERK signaling.
A guide to ERK dynamics, part 2: downstream decoding
  • Article
  • Full-text available

December 2023

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110 Reads

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11 Citations

Biochemical Journal

Abhineet Ram

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Devan Murphy

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[...]

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Signaling by the extracellular signal-regulated kinase (ERK) pathway controls many cellular processes, including cell division, death, and differentiation. In this second installment of a two-part review, we address the question of how the ERK pathway exerts distinct and context-specific effects on multiple processes. We discuss how the dynamics of ERK activity induce selective changes in gene expression programs, with insights from both experiments and computational models. With a focus on single-cell biosensor-based studies, we summarize four major functional modes for ERK signaling in tissues: adjusting the size of cell populations, gradient-based patterning, wave propagation of morphological changes, and diversification of cellular gene expression states. These modes of operation are disrupted in cancer and other related diseases and represent potential targets for therapeutic intervention. By understanding the dynamic mechanisms involved in ERK signaling, there is potential for pharmacological strategies that not only simply inhibit ERK, but also restore functional activity patterns and improve disease outcomes.

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A guide to ERK dynamics, part 1: mechanisms and models

December 2023

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63 Reads

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13 Citations

Biochemical Journal

Extracellular signal-regulated kinase (ERK) has long been studied as a key driver of both essential cellular processes and disease. A persistent question has been how this single pathway is able to direct multiple cell behaviors, including growth, proliferation, and death. Modern biosensor studies have revealed that the temporal pattern of ERK activity is highly variable and heterogeneous, and critically, that these dynamic differences modulate cell fate. This two-part review discusses the current understanding of dynamic activity in the ERK pathway, how it regulates cellular decisions, and how these cell fates lead to tissue regulation and pathology. In part 1, we cover the optogenetic and live-cell imaging technologies that first revealed the dynamic nature of ERK, as well as current challenges in biosensor data analysis. We also discuss advances in mathematical models for the mechanisms of ERK dynamics, including receptor-level regulation, negative feedback, cooperativity, and paracrine signaling. While hurdles still remain, it is clear that higher temporal and spatial resolution provide mechanistic insights into pathway circuitry. Exciting new algorithms and advanced computational tools enable quantitative measurements of single-cell ERK activation, which in turn inform better models of pathway behavior. However, the fact that current models still cannot fully recapitulate the diversity of ERK responses calls for a deeper understanding of network structure and signal transduction in general.



Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis

September 2023

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43 Reads

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3 Citations

eLife

mTORC1 senses nutrients and growth factors and phosphorylates downstream targets, including the transcription factor TFEB, to coordinate metabolic supply and demand. These functions position mTORC1 as a central controller of cellular homeostasis, but the behavior of this system in individual cells has not been well characterized. Here, we provide measurements necessary to refine quantitative models for mTORC1 as a metabolic controller. We developed a series of fluorescent protein-TFEB fusions and a multiplexed immunofluorescence approach to investigate how combinations of stimuli jointly regulate mTORC1 signaling at the single-cell level. Live imaging of individual MCF10A cells confirmed that mTORC1-TFEB signaling responds continuously to individual, sequential, or simultaneous treatment with amino acids and the growth factor insulin. Under physiologically relevant concentrations of amino acids, we observe correlated fluctuations in TFEB, AMPK, and AKT signaling that indicate continuous activity adjustments to nutrient availability. Using partial least squares regression modeling, we show that these continuous gradations are connected to protein synthesis rate via a distributed network of mTORC1 effectors, providing quantitative support for the qualitative model of mTORC1 as a homeostatic controller and clarifying its functional behavior within individual cells.

Citations (3)


... The extracellular signal-regulated kinase 1/2 (ERK), a member of the MAPK family, plays a central role in signaling cascades from extracellular stimuli such as epidermal growth factor to intracellular targets 11 . ...

Reference:

ERK1/2 gene expression and hypomethylation of Alu and LINE1 elements in patients with type 2 diabetes with and without cataract: Impact of hyperglycemia‐induced oxidative stress
A guide to ERK dynamics, part 1: mechanisms and models

Biochemical Journal

... We next set out to test whether the observed signal corruption in PIK3CA H1047R mutant cells translates into altered transcriptional and phenotypic responses. First, enhanced EGF signaling through AKT and ERK should lead to an amplification of EGF-specific transcriptional responses, which are sensitive to the relative amplitude and duration of upstream signals such as ERK activation (Avraham and Yarden, 2011;Ram et al, 2023). Consistent with this prediction, we observed increased and more sustained mRNA expression of known EGF-dependent immediately early and delayed early genes in PIK3CA H1047R spheroids stimulated with EGF ( Fig. 5A). ...

A guide to ERK dynamics, part 2: downstream decoding

Biochemical Journal

... Cell-to-cell variation in cellular metabolism was also observed in vivo using intravital imaging of an AMPK biosensor [2]. Multiplexed analysis of AMPK, mTOR, and AKT biosensors within the same cells demonstrated concerted fluctuations in all of these pathways, revealing the dynamics by which these regulators help to maintain cellular homeostasis [50]. Further extending these analyses, a new AMPK biosensor design has enabled high dynamic range measurements of AMPK activity in subcellular locations [7]. ...

Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis

eLife