TY - JOUR
T1 - Developmental pluripotency-associated 4 increases aggressiveness of pituitary neuroendocrine tumors by enhancing cell stemness
AU - Chaudhary, Shaista
AU - Das, Ujjal
AU - Jabbar, Shaima
AU - Gangisetty, Omkaram
AU - Rousseau, Bénédicte
AU - Hanft, Simon
AU - Sarkar, Dipak
N1 - Publisher Copyright: © The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
PY - 2025/1/1
Y1 - 2025/1/1
N2 - Background. Pituitary neuroendocrine tumors, PitNETs, are often aggressive and precipitate in distant metastases that are refractory to current therapies. However, the molecular mechanism in PitNETs’ aggressiveness is not well understood. Developmental pluripotency-associated 4 (DPPA4) is known as a stem cell regulatory gene and overexpressed in certain cancers, but its function in the context of PitNETs’ aggressiveness is not known. Methods. We employed both rat and human models of PitNETs. In the rat pituitary tumor model, we used prenatal-alcohol-exposed (PAE) female Fischer rats which developed aggressive PitNETs following estrogen treatment, while in the human pituitary tumor model, we used aggressively proliferative cells from pituitary tumors of patients undergone surgery. Various molecular, cellular, and epigenetic techniques were used to determine the role of DPPA4 in PitNETs’ aggressiveness. Results. We show that DPPA4 is overexpressed in association with increased cell stemness factors in aggressive PitNETs of PAE rats and of human patients. Gene-editing experiments demonstrate that DPPA4 increases the expression of cell stemness and tumor aggressiveness genes and promotes proliferation, colonization, migration, and tumorigenic potential of PitNET cells. ChIP assays and receptor antagonism studies reveal that DPPA4 binds to canonical WINTs promoters and increases directly or indirectly the WNT/β-CATENIN control of cell stemness, tumor growth, and aggressiveness of PitNETs. Epigenetic studies show the involvement of histone methyltransferase in alcohol activation of DPPA4. Conclusions. These findings support a role of DPPA4 in tumor stemness and aggressiveness and provide a preclinical rationale for modulating this stemness regulator for the treatment of PitNETs.
AB - Background. Pituitary neuroendocrine tumors, PitNETs, are often aggressive and precipitate in distant metastases that are refractory to current therapies. However, the molecular mechanism in PitNETs’ aggressiveness is not well understood. Developmental pluripotency-associated 4 (DPPA4) is known as a stem cell regulatory gene and overexpressed in certain cancers, but its function in the context of PitNETs’ aggressiveness is not known. Methods. We employed both rat and human models of PitNETs. In the rat pituitary tumor model, we used prenatal-alcohol-exposed (PAE) female Fischer rats which developed aggressive PitNETs following estrogen treatment, while in the human pituitary tumor model, we used aggressively proliferative cells from pituitary tumors of patients undergone surgery. Various molecular, cellular, and epigenetic techniques were used to determine the role of DPPA4 in PitNETs’ aggressiveness. Results. We show that DPPA4 is overexpressed in association with increased cell stemness factors in aggressive PitNETs of PAE rats and of human patients. Gene-editing experiments demonstrate that DPPA4 increases the expression of cell stemness and tumor aggressiveness genes and promotes proliferation, colonization, migration, and tumorigenic potential of PitNET cells. ChIP assays and receptor antagonism studies reveal that DPPA4 binds to canonical WINTs promoters and increases directly or indirectly the WNT/β-CATENIN control of cell stemness, tumor growth, and aggressiveness of PitNETs. Epigenetic studies show the involvement of histone methyltransferase in alcohol activation of DPPA4. Conclusions. These findings support a role of DPPA4 in tumor stemness and aggressiveness and provide a preclinical rationale for modulating this stemness regulator for the treatment of PitNETs.
KW - DPPA4
KW - WNT/β-CATENIN
KW - histone methyltransferase
KW - pituitary neuroendocrine tumors
KW - prenatal alcohol
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U2 - 10.1093/neuonc/noae148
DO - 10.1093/neuonc/noae148
M3 - Article
C2 - 39093695
SN - 1522-8517
VL - 27
SP - 123
EP - 139
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - 1
ER -