Systematic Identification of MACC1-Driven Metabolic Networks in Colorectal Cancer

Abstract

MACC1 is a prognostic and predictive metastasis biomarker for more than 20 solid cancer entities. However, its role in cancer metabolism is not sufficiently explored. Here, we report on how MACC1 impacts the use of glucose, glutamine, lactate, pyruvate and fatty acids and show the comprehensive analysis of MACC1-driven metabolic networks. We analyzed concentration-dependent changes in nutrient use, nutrient depletion, metabolic tracing employing 13C-labeled substrates, and in vivo studies. We found that MACC1 permits numerous effects on cancer metabolism. Most of those effects increased nutrient uptake. Furthermore, MACC1 alters metabolic pathways by affecting metabolite production or turnover from metabolic substrates. MACC1 supports use of glucose, glutamine and pyruvate via their increased depletion or altered distribution within metabolic pathways. In summary, we demonstrate that MACC1 is an important regulator of metabolism in cancer cells.

Obesity, colorectal cancer and MACC1 expression: A possible novel molecular association

“…Since the discovery of MACC1, the authors of the present study, as well as several other research groups have demonstrated the clinical significance of MACC1 as a causal, prognostic and predictive biomarker for >20 solid cancer types ( 14 ), including meta-analyses for solid cancers, cancers of the digestive system, colorectal, hepatocellular, gastric, gynecological and breast cancer ( 17 - 22 ). The causal contribution of MACC1 for rewiring cell metabolism has been demonstrated by the authors of the present study, as well as others ( 23 - 25 ). A recent study reported MACC1-driven metabolic networks in CRC, such as rewiring glucose and glutamine metabolism, an increase in glucose use by the enhanced surface of glucose transporter 1 (GLUT1) or an increase in glutamine and pyruvate use by enhanced uptake ( 25 ).…”

“…The causal contribution of MACC1 for rewiring cell metabolism has been demonstrated by the authors of the present study, as well as others ( 23 - 25 ). A recent study reported MACC1-driven metabolic networks in CRC, such as rewiring glucose and glutamine metabolism, an increase in glucose use by the enhanced surface of glucose transporter 1 (GLUT1) or an increase in glutamine and pyruvate use by enhanced uptake ( 25 ). It was thus concluded that MACC1 is an important regulator of cancer metabolism.…”

“…MACC1 was discovered to be expressed in human CRC tissue ( 13 , 14 ). Moreover, in vitro and in vivo studies have revealed the effects of MACC1 in tumor metabolism, proliferation, migration and invasion, and have demonstrated that MACC1 is a potent prognostic and predictive biomarker for several tumor entities, including CRC ( 13 , 15 , 16 , 25 ). The present study, to the best of our knowledge, is the first to investigate the potential association between MACC1 expression, obesity and obesity-induced CRC.…”

A Flexible Tool to Correct Superimposed Mass Isotopologue Distributions in GC-APCI-MS Flux Experiments

“…To test CorMID on complex biological samples, we used previously published data from a flux experiment in colon cancer cell cultures applying glucose and glutamine as tracer molecules to incorporate labelled carbon. Here, SW620 and SW480 cells (ATCC, Manassas, VA, USA) were grown, propagated, treated, harvested, and prepared as previously described [ 15 ].…”

Immune Response and Metastasis—Links between the Metastasis Driver MACC1 and Cancer Immune Escape Strategies

“…One study, however, reported that MACC1 defects during embryonal development can lead to malformations [9]. Additionally, MACC1 has been linked to metabolic pathways that mainly regulate glucose and glutamine metabolism [10]. Functionally, MACC1 acts as a transcription factor within the hepatocyte growth factor (HGF)/c-MET signaling pathway, therein relaying extracellular signals [4].…”