Activation of invasion by oncogenic reprogramming of cholesterol metabolism via increased NPC1 expression and macropinocytosis
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Activation of invasion by oncogenic reprogramming of cholesterol metabolism via increased NPC1 expression and macropinocytosis. / Skorda, Aikaterini; Lauridsen, Anna Røssberg; Wu, Chengnan; Huang, Jinrong; Mrackova, Monika; Winther, Nuggi Ingholt; Jank, Vanessa; Sztupinszki, Zsofia; Strauss, Robert; Bilgin, Mesut; Maeda, Kenji; Liu, Bin; Luo, Yonglun; Jäättelä, Marja; Kallunki, Tuula.
In: Oncogene, Vol. 42, 2023, p. 2495–2506.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Activation of invasion by oncogenic reprogramming of cholesterol metabolism via increased NPC1 expression and macropinocytosis
AU - Skorda, Aikaterini
AU - Lauridsen, Anna Røssberg
AU - Wu, Chengnan
AU - Huang, Jinrong
AU - Mrackova, Monika
AU - Winther, Nuggi Ingholt
AU - Jank, Vanessa
AU - Sztupinszki, Zsofia
AU - Strauss, Robert
AU - Bilgin, Mesut
AU - Maeda, Kenji
AU - Liu, Bin
AU - Luo, Yonglun
AU - Jäättelä, Marja
AU - Kallunki, Tuula
N1 - Funding Information: This project has received funding from the Grosserer Alfred Nielsen og Hustrus Fond and from the European Union’s Horizon 2020 Research and Innovation programme under grant agreement No 965193 for DECIDER (TK), from the Danish Cancer Society Scientific Committee (KBVU) R273-A16.084 (AS) and R228-A13637 (ZW), from the Danish National Research Foundation DNRF125 (MJ) and Novo Nordisk Foundation, NNF19OC0054296 (MJ).
PY - 2023
Y1 - 2023
N2 - Cancer cells are dependent on cholesterol, and they possess strictly controlled cholesterol homeostasis mechanisms. These allow them to smoothly switch between cholesterol synthesis and uptake to fulfill their needs and to adapt environmental changes. Here we describe a mechanism of how cancer cells employ oncogenic growth factor signaling to promote uptake and utilization of extracellular cholesterol via Myeloid Zinc Finger 1 (MZF1)-mediated Niemann Pick C1 (NPC1) expression and upregulated macropinocytosis. Expression of p95ErbB2, highly oncogenic, standard-treatment resistant form of ErbB2 mobilizes lysosomes and activates EGFR, invasion and macropinocytosis. This is connected to a metabolic shift from cholesterol synthesis to uptake due to macropinocytosis-enabled flow of extracellular cholesterol. NPC1 increase facilitates extracellular cholesterol uptake and is necessary for the invasion of ErbB2 expressing breast cancer spheroids and ovarian cancer organoids, indicating a regulatory role for NPC1 in the process. The ability to obtain cholesterol as a byproduct of increased macropinocytosis allows cancer cells to direct the resources needed for the energy-consuming cholesterol synthesis towards other activities such as invasion. These results demonstrate that macropinocytosis is not only an alternative energy source for cancer cells but also an efficient way to provide building material, such as cholesterol, for its macromolecules and membranes. [Figure not available: see fulltext.]
AB - Cancer cells are dependent on cholesterol, and they possess strictly controlled cholesterol homeostasis mechanisms. These allow them to smoothly switch between cholesterol synthesis and uptake to fulfill their needs and to adapt environmental changes. Here we describe a mechanism of how cancer cells employ oncogenic growth factor signaling to promote uptake and utilization of extracellular cholesterol via Myeloid Zinc Finger 1 (MZF1)-mediated Niemann Pick C1 (NPC1) expression and upregulated macropinocytosis. Expression of p95ErbB2, highly oncogenic, standard-treatment resistant form of ErbB2 mobilizes lysosomes and activates EGFR, invasion and macropinocytosis. This is connected to a metabolic shift from cholesterol synthesis to uptake due to macropinocytosis-enabled flow of extracellular cholesterol. NPC1 increase facilitates extracellular cholesterol uptake and is necessary for the invasion of ErbB2 expressing breast cancer spheroids and ovarian cancer organoids, indicating a regulatory role for NPC1 in the process. The ability to obtain cholesterol as a byproduct of increased macropinocytosis allows cancer cells to direct the resources needed for the energy-consuming cholesterol synthesis towards other activities such as invasion. These results demonstrate that macropinocytosis is not only an alternative energy source for cancer cells but also an efficient way to provide building material, such as cholesterol, for its macromolecules and membranes. [Figure not available: see fulltext.]
U2 - 10.1038/s41388-023-02771-x
DO - 10.1038/s41388-023-02771-x
M3 - Journal article
C2 - 37420029
AN - SCOPUS:85164196472
VL - 42
SP - 2495
EP - 2506
JO - Oncogene
JF - Oncogene
SN - 0950-9232
ER -
ID: 360026542