Related Experiment Video

Updated: Aug 16, 2025

A Novel Stromal Fibroblast-Modulated 3D Tumor Spheroid Model for Studying Tumor-Stroma Interaction and Drug Discovery
07:20

A Novel Stromal Fibroblast-Modulated 3D Tumor Spheroid Model for Studying Tumor-Stroma Interaction and Drug Discovery

Published on: February 28, 2020

10.0K

Sphingosine Kinase 2 in Stromal Fibroblasts Creates a Hospitable Tumor Microenvironment in Breast Cancer

Cynthia Weigel1, Melissa A Maczis1, Elisa N D Palladino1

  • 1Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Richmond, Virginia.

Cancer Research
|December 21, 2022
PubMed

Insights

Inhibiting sphingosine kinase 2 (SphK2) in mice suppressed breast cancer growth and metastasis. This occurred by increasing ceramides, which activated p53 in stromal cells, creating a hostile tumor microenvironment (TME).

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Interactions between breast cancer cells and the tumor microenvironment (TME) are critical for tumor progression and metastasis.
  • Sphingosine kinase 2 (SphK2) produces sphingosine-1-phosphate (S1P), a lipid mediator involved in various cellular processes.

Purpose of the Study:

  • To investigate the role of SphK2 in breast cancer progression and metastasis.
  • To explore the mechanism by which SphK2 influences the TME and cancer-associated fibroblast (CAF) activation.

Main Methods:

  • Utilized mouse models of syngeneic breast cancer with SphK2 deletion or inhibition.
  • Analyzed S1P and ceramide levels in stromal fibroblasts.
  • Assessed p53 activity and CAF markers in the TME.
  • Investigated the impact of p53 ablation in SphK2-deficient fibroblasts.

Main Results:

  • SphK2 deletion or inhibition significantly suppressed breast tumor growth and lung metastasis in mice.
  • SphK2 deficiency led to decreased S1P and increased ceramides in stromal fibroblasts.
  • Ceramide accumulation upregulated stromal p53, inhibiting CAF activation and tumor-promoting factor production.
  • Ablation of p53 in SphK2-deficient fibroblasts reversed these anti-tumor effects.

Conclusions:

  • SphK2 plays a crucial role in regulating the TME by modulating p53 activity in stromal fibroblasts.
  • Targeting SphK2 can reprogram the TME to restrict breast cancer establishment and metastasis.
  • SphK2 inhibition represents a potential therapeutic strategy to enhance anti-cancer efficacy by targeting the TME.

More Related Videos

A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth06:35

A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth

Published on: December 22, 2020

4.6K
Experimental Generation of Carcinoma-Associated Fibroblasts CAFs from Human Mammary Fibroblasts15:43

Experimental Generation of Carcinoma-Associated Fibroblasts CAFs from Human Mammary Fibroblasts

Published on: October 25, 2011

23.5K

Related Concept Videos

The Tumor Microenvironment02:17

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
6.7K
Regulation of Hematopoietic Stem Cells01:01

Regulation of Hematopoietic Stem Cells

All blood and immune cells are produced from the multipotent hematopoietic stem cells (HSCs) by the process of hematopoiesis. However, they all have a limited life span. In addition, many are depleted in immune surveillance or combatting an injury or infection. This makes blood one of the most regenerative tissues. Hematopoiesis helps replenish these blood and immune cells, restoring the body's normal functioning. However, overproduction of blood and immune cells can make them cancerous or...
3.3K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
Cancer Stem Cells and Tumor Maintenance02:40

Cancer Stem Cells and Tumor Maintenance

Early diagnosis and treatment can often cure cancer. However, even with treatment, residual cells called cancer stem cells (CSC) might remain, often causing tumor recurrence. These cancer stem cells possess the potential for self-renewal and multi-lineage differentiation and are often responsible for the therapeutic resistance displayed in most cancers.
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
5.0K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.6K