# Tumor Macroenvironment and the Circadian Metabolic Clock

> **NIH NIH K22** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $202,284

## Abstract

Project Summary/Abstract
Cancer cells exhibit a heightened metabolic demand that is satisfied by an increased
rate of aerobic glycolysis, termed the Warburg effect. Yet, this metabolic demand of
cancer cells also results in metabolic ‘waste’ by-products that are secreted systemically.
As an example, the glycolytic by-product lactate is reported to be involved in metabolic
reprogramming of adjacent tissues and can induce a pro-inflammatory response.
Similarly, tumor-derived pro-inflammatory cytokines have been reported to alter
functions of metabolic tissues such as liver, fat and the pancreas. We hypothesize that
these tumor-dependent metabolic waste by-products and inflammatory cytokines, the
so-called tumor ‘macroenvironment,’ can distally reprogram the functions of the circadian
metabolic clocks in the liver and pancreas. Using a lung adenocarcinoma mouse model,
we hypothesize that the tumor macroenvironment inhibits clock-controlled insulin
secretion in lung tumor-bearing (TB) mice, resulting in an enhanced rate of hepatic
gluconeogenesis. We aim to provide the molecular mechanism for the changes in clock-
controlled hepatic glucose production. Moreover, we propose that this enhanced hepatic
glucose production could feedback and satisfy the metabolic demand of the tumor, and
experiments will be performed to address this. We also hypothesize that the
inflammatory response is targeting pancreatic islet function, subsequently resulting in
inhibition of insulin production or secretion. We propose a metabolic profiling of the
serum over the circadian cycle to determine in an unbiased manner what tumor-
dependent metabolites could be mediating this crosstalk with peripheral metabolic
clocks, such as liver and pancreas. Overall, we hypothesize that the tumor
macroenvironment could play an important role in reprogramming circadian metabolic
functions of the liver and pancreas. This work has important clinical implications for
potential novel systemic therapeutic strategies to treat cancer.

## Key facts

- **NIH application ID:** 9844410
- **Project number:** 5K22CA212045-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Selma Masri
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,284
- **Award type:** 5
- **Project period:** 2017-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844410

## Citation

> US National Institutes of Health, RePORTER application 9844410, Tumor Macroenvironment and the Circadian Metabolic Clock (5K22CA212045-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9844410. Licensed CC0.

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