Pancreatic cancer cells consuming lipoproteins

Pancreatic Cancer's Sweet Tooth: How Lipids Could Be the Key to New Treatments

Elliot Brynn in Health & Wellness July 2025 • 4 min read.

"New research uncovers the critical role of fat metabolism in pancreatic cancer, offering hope for innovative therapies."

Pancreatic ductal adenocarcinoma (PDAC) is a particularly aggressive form of cancer, notorious for its late diagnosis and resistance to conventional antitumor therapies. This grim combination leads to a poor prognosis, with a survival rate of just 5% beyond five years post-diagnosis. The disease is often accompanied by a severe wasting syndrome known as cachexia, further complicating treatment and diminishing the patient's quality of life.

Cachexia, arising from a complex interplay between the host's metabolic tissues and the pancreatic tumor, disrupts metabolic processes. Key features include significant muscle loss, alongside irregularities in lipid (fat) and glucose (sugar) metabolism. This highlights the intricate metabolic dependencies that fuel the tumor's growth and survival.

The pancreatic tumor environment is distinct, characterized by a poorly vascularized stroma that surrounds cancer cells, limiting their access to oxygen and essential nutrients. This forces the tumor cells to undergo metabolic reprogramming, adapting their consumption of energy and nutrients to sustain their rapid expansion.

Why Pancreatic Cancer Is Unlike Any Other

Pancreatic cancer cells consuming lipoproteins

To better understand this unique cancer, researchers often turn to the Pdx1-Cre; K-RasG12D; Ink4a/Arffl/fl (PKI) mouse model. This model faithfully replicates the characteristics of human pancreatic cancer, making it invaluable for studying the disease's progression and therapeutic responses. These mice spontaneously develop pancreatic ductal adenocarcinomas, mirroring the genetic mutations observed in a large proportion of human patients (80-95%).

One striking feature of these tumors is the presence of hypoxic regions, where oxygen levels are severely reduced. These areas account for approximately 20% of the tumor's total surface area. Within these oxygen-starved zones, a subset of epithelial tumor cells undergoes a process called epithelial-mesenchymal transition (EMT), gaining invasive properties that contribute to metastasis.

The hypoxic environment drives several metabolic adaptations:

Increased Glycolysis: Hypoxic cells primarily rely on glycolysis, producing excessive lactate. This lactate can then be utilized as an alternative metabolic fuel by neighboring, oxygenated tumor cells.
Glutamine Degradation: The breakdown of glutamine is accelerated, further contributing to metabolic flexibility.
Activation of Hexosamine Pathway: This pathway stabilizes pro-tumorigenic proteins through a process called O-N-acetyl-glucosaminylation.

This intra-tumoral metabolic heterogeneity underscores the complexity of pancreatic cancer's metabolic reprogramming. It's far more than just increased glycolysis; it's a sophisticated adaptation to nutrient scarcity and oxygen deprivation, orchestrated to fuel relentless tumor growth. The limited access to nutrients and oxygen, combined with the constitutive activation of the K-Ras oncogene, triggers crucial metabolic shifts that enable tumor cell expansion. Unraveling these mechanisms is a major challenge, but it's essential for developing new therapeutic strategies.

The Promising Role of Lipoproteins and Cholesterol

By studying the PKI mouse model, researchers have mapped out the altered metabolic pathways within pancreatic cancer, and surprisingly, the pathways involved in lipid metabolism are the most activated, particularly those associated with lipoprotein catabolism. This suggests that pancreatic cancer cells have a strong affinity for lipoproteins, especially LDL (low-density lipoprotein), the body's main carrier of cholesterol.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1051/medsci/20153108009, Alternate LINK

Title: L’Adénocarcinome Pancréatique : Une Tumeur Dépendante Des Lipoprotéines

Subject: General Biochemistry, Genetics and Molecular Biology

Journal: médecine/sciences

Publisher: EDP Sciences

Authors: Sophie Vasseur, Fabienne Guillaumond

Published: 2015-08-01

Everything You Need To Know

Why is pancreatic ductal adenocarcinoma (PDAC) such an aggressive cancer, and what makes it so difficult to treat effectively?

Pancreatic ductal adenocarcinoma, or PDAC, is an aggressive cancer due to its late diagnosis and resistance to conventional antitumor therapies. These factors contribute to a poor prognosis, with a low survival rate. The presence of cachexia, a wasting syndrome involving muscle loss and metabolic irregularities, further complicates treatment, underscoring the metabolic dependencies that fuel tumor growth. The tumor's environment, characterized by a poorly vascularized stroma, limits access to oxygen and nutrients, forcing tumor cells to undergo metabolic reprogramming.

How does the Pdx1-Cre; K-RasG12D; Ink4a/Arffl/fl (PKI) mouse model help researchers better understand pancreatic cancer?

The Pdx1-Cre; K-RasG12D; Ink4a/Arffl/fl, or PKI, mouse model is invaluable because it replicates characteristics of human pancreatic cancer, enabling researchers to study the disease's progression and therapeutic responses effectively. These mice spontaneously develop pancreatic ductal adenocarcinomas, mirroring the genetic mutations observed in a large proportion of human patients. This includes hypoxic regions and metabolic adaptations seen in human tumors.

What metabolic adaptations occur within pancreatic cancer cells in hypoxic regions, and how do these changes contribute to tumor growth?

In hypoxic regions of pancreatic cancer, several metabolic adaptations occur, including increased glycolysis, which produces excessive lactate used by neighboring oxygenated tumor cells. Glutamine degradation is accelerated, contributing to metabolic flexibility. Additionally, the hexosamine pathway is activated, stabilizing pro-tumorigenic proteins through O-N-acetyl-glucosaminylation. These changes fuel tumor growth by enabling cells to adapt to nutrient scarcity and oxygen deprivation.

The text mentions that 'lipid metabolism' is activated, especially those associated with lipoprotein catabolism, what implications does it have?

The activation of lipid metabolism pathways, particularly those associated with lipoprotein catabolism, suggests that pancreatic cancer cells have a strong affinity for lipoproteins like LDL (low-density lipoprotein), the body's main carrier of cholesterol. This affinity for lipoproteins indicates that pancreatic cancer cells may rely on lipids and cholesterol for energy and growth, which could be exploited therapeutically. Further research could focus on targeting these lipid metabolic pathways to disrupt the tumor's energy supply.

How does the epithelial-mesenchymal transition (EMT) contribute to the aggressiveness of pancreatic cancer, and what role does hypoxia play in this process?

The epithelial-mesenchymal transition, or EMT, is a process where epithelial tumor cells gain invasive properties that contribute to metastasis, increasing the aggressiveness of pancreatic cancer. Hypoxia, or low oxygen levels, within the tumor environment drives EMT, leading to increased invasiveness and the ability of cancer cells to spread to other parts of the body. Hypoxia-induced EMT is therefore a critical factor in the progression and metastasis of pancreatic cancer.