Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification

Saatçi, Özge; Akbulut, Özge; Çetįn, Metin; Sikirzhytski, Vitali; Şahin, Özgür

doi:10.1101/2022.05.18.492567

Cited by 3 publications

(1 citation statement)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As reported previously (33,34), centrioles are remarkably overduplicated in breast cancer cells such as MDA-MB-436, MDA-MB-231, SKBR3 and HCC1806 cells, but not in the spontaneously immortalized, non-malignant breast cell line MCF10A (Figure 2A). In particular, centriole 8 / 45 overduplication was found to be particularly severe in the MDA-MB-436 line (approximately 80%) (Figure 1B and Figure 2B), suggesting that it CEP44 may play critical role in regulating centriole duplication in breast cancer cells.…”

Section: Cep44 Is a Negative Regulator Of Centriole Duplicationsupporting

confidence: 82%

CEP44 is required for maintaining centriole duplication and spindle integrity

Zhang,

Wei,

Zou

et al. 2023

Preprint

View full text Add to dashboard Cite

In animal cells, the centrosome, consisting of two centrioles, duplicates only once per cell cycle for bipolar spindle formation. Defective centriole duplication results in abnormal spindle formation and chromosome missegregation, which is closely linked to tumor growth. However, the molecular mechanisms licensing only one centriole duplication cycle within a cell cycle are less well known. Here we found that CEP44 is negatively correlated with breast carcinoma. CEP44, jointly with CEP57 and CEP57L1, maintains centriole engagement in the interphase to ensure centriole duplication once per cell cycle. Depletion of CEP44 leads to centriole overduplication because of premature centriole disengagement and multipolar spindle formation. Additionally, CEP44 is phosphorylated by Aurora A at the G2/M phase to facilitate spindle localization and maintain spindle integrity. Collectively, our results reveal the function of CEP44 in spindle formation by preventing centriole overduplication and maintaining spindle integrity, and CEP44 may serve as a potential marker for breast carcinoma prognosis.

show abstract

Section: Cep44 Is a Negative Regulator Of Centriole Duplicationsupporting

confidence: 82%

CEP44 is required for maintaining centriole duplication and spindle integrity

Zhang,

Wei,

Zou

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer

Gedik,

Saatci,

Oberholtzer

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Immunogenic cell death (ICD), an immune-priming form of cell death, has been shown to be induced by several different anti-cancer therapies. Despite being the first and one of the most successful antibody-drug conjugates (ADCs) approved for refractory HER2-positive breast cancer, little is known if response and resistance to trastuzumab emtansine (T-DM1) involves ICD modulation that can be leveraged to enhance T-DM1 response. Here, we report that T-DM1 induces spindle assembly checkpoint (SAC)-dependent ICD in sensitive cells by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which are lost in resistance. Accordingly, an ICD-related gene signature correlates with clinical response to T-DM1-containing therapy. We found that transforming acidic coiled-coil containing 3 (TACC3) is overexpressed in T-DM1 resistant cells, and that T-DM1 responsive patients have reduced TACC3 protein while the non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 revives T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition elicits ICD in vivo shown by vaccination assay, and it potentiates T-DM1 by inducing dendritic cell (DC) maturation and enhancing infiltration of cytotoxic T cells in the human HER2-overexpressing MMTV.f.huHER2#5 (Fo5) transgenic model. Together, our results show that ICD is a key mechanism of action of T-DM1 which is lost in resistance, and that targeting TACC3 restores T-DM1-mediated ICD and overcomes resistance.

show abstract

PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis

Liu,

Hou,

Jin

et al. 2024

Preprint

View full text Add to dashboard Cite

Erythropoiesis and megakaryopoiesis are stringently regulated by signaling pathways. However, the precise molecular mechanisms through which signaling pathways regulate key transcription factors controlling erythropoiesis and megakaryopoiesis remain partially understood. Herein, we identified heat shock cognate B (HSCB), which is well known for its iron-sulfur cluster delivery function, as an indispensable protein for friend of GATA 1 (FOG1) nuclear translocation during erythropoiesis of K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+ hematopoietic stem cells (HSCs), as well as during megakaryopoiesis of the CD34+CD90+ HSCs. Mechanistically, HSCB could be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detained FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation. Given that PI3K is activated during both erythropoiesis and megakaryopoiesis, and that FOG1 a key transcription factor for these processes, our findings elucidate an important, previously unrecognized iron-sulfur cluster delivery independent function of HSCB in erythropoiesis and megakaryopoiesis.

show abstract

Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification

Cited by 3 publications

References 65 publications

CEP44 is required for maintaining centriole duplication and spindle integrity

CEP44 is required for maintaining centriole duplication and spindle integrity

Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer

PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis

Contact Info

Product

Resources

About