Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells

Tominaga, Kunihiko; Minato, Hiroshi; Murayama, Takahiko; Sasahara, Asako; Nishimura, Tatsunori; Kiyokawa, Etsuko; Kanauchi, Hajime; Shimizu, Satoshi; Sato, Ayaka; Nishioka, Koki; Tsuji, Ei ichi; Yano, Masao; Ogawa, Toshihisa; Ishii, Hideshi; Mori, Masaki; Akashi, Koichi; Okamoto, Koji; Tanabe, Masahiko; Tada, Kei ichiro; Tojo, Arinobu; Gotoh, Noriko

doi:10.1073/pnas.1806851116

Cited by 47 publications

(40 citation statements)

References 38 publications

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“…Previous work from our group and others has shown that ACD is not the dominant mode of cell division used by CSCs during tumor growth (Lathia et al, 2011;Xin et al, 2012). These findings have also been confirmed using mathematical modelling to suggest an evolutionary disadvantage for ACD (Daynac et al, 2018;Guichet et al, 2016;Mukherjee et al, 2016;Obernier et al, 2018;Sugiarto et al, 2011;Tomasetti and Levy, 2010;Tominaga et al, 2019). However, these assessments have not been done in the context of the selective pressures induced by therapies.…”

Section: Discussion Of Key Findingssupporting

confidence: 60%

Asymmetric Division Promotes Therapeutic Resistance in Glioblastoma Stem Cells

Hitomi

Chumakova

Silver

et al. 2019

Preprint

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Asymmetric cell division (ACD) enables the maintenance of a stem cell population while simultaneously generating differentiated progeny. Cancer stem cells (CSCs) undergo multiple modes of cell division during tumor expansion and in response to therapy, yet the functional consequences of these division modes remain to be determined. Using a fluorescent reporter for cell surface receptor distribution during mitosis, we found that ACD in glioblastoma CSCs generated a daughter cell with enhanced therapeutic resistance and increased co-inheritance of epidermal growth factor receptor (EGFR) and neurotrophin receptor (p75NTR). Stimulation of both receptors maintained self-renewal under differentiation conditions. While p75NTR knockdown did not compromise CSC maintenance, therapeutic efficacy of EGFR inhibition was enhanced, indicating that co-inheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. These data demonstrate that ACD produces progeny with co-enriched growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population.

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Section: Discussion Of Key Findingssupporting

confidence: 60%

Asymmetric Division Promotes Therapeutic Resistance in Glioblastoma Stem Cells

Hitomi

Chumakova

Silver

et al. 2019

Preprint

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“…Recently, we have reported that semaphorin signaling via MICAL3/collapsin response mediator protein 2 (CRMP2)/Numb axis contributes to the maintenance of breast CSCs by inducing symmetric cell division [105] . .…”

Section: Treatment Approaches Targeting Other Activated Signaling Patmentioning

confidence: 99%

Drug resistance mechanisms of cancer stem-like cells and their therapeutic potential as drug targets

Murayama¹,

Gotoh²

2019

CDR

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Despite of recent advances in cancer research and development of new anti-cancer drugs, tumor patients' prognoses have not yet been improved well enough. Treatment failure of tumors is highly attributed to the drug resistance of a small population of cancer cell known as cancer stem-like cells (CSCs). CSCs also have the self-renewal activity and differentiation potency, conferring strong tumorigenicity on them. Therefore, development of CSC targeting therapy is urgently needed in order to overcome possible recurrence and metastasis by them after therapy. CSCs show some characteristic features that are not observed in other differentiated cancer cells, which give them higher resistance against conventional chemotherapy or radiotherapy. Targeting such specific features could be useful for CSC eradication. This review will summarize the recent advances in the study of CSC characteristics along with the promising therapeutic strategies targeting them.

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“…Researchers believe that as CSCs become more malignant, they become more likely to divide symmetrically. Since SCD produces both two daughter CSCs, SCD leads to effectively the expansion of the CSC population (33,(45)(46)(47)(48). The concept of ACD therapy, which suppresses CSCs symmetrical division and inhibits CSCs expansion, may establish a new strategy for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

BMP4 induces asymmetric cell division in human glioma stem-like cells

et al. 2019

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Glioblastoma (GBM) is a malignant tumor with a high recurrence rate and has very poor prognosis in humans. The median survival is still <2 years. Therefore, a new treatment strategy should be established. Recently, this cancer has been thought to be heterogeneous, consisting of cancer stem cells (CSCs) that are self-renewable, multipotent, and treatment resistant. So various strategies targeting glioma stem-like cells (GSCs) have been investigated. This study focused on strategies targeting GSCs through the induction of differentiation using bone morphogenetic protein 4 (BMP4). The expression of CD133, a cancer stem cell marker, under BMP4 treatment in GSCs was examined using flow cytometry, western blotting, and quantitative PCR. Immunofluorescent staining of GSCs was also performed to examine the type of cell division: asymmetric cell division (ACD) or symmetric cell division (SCD). We obtained the following results. The BMP4 treatment caused downregulation of CD133 expression. Moreover, it induced ACD in GSCs. While the ACD ratio was 23% without BMP4 treatment, it was 38% with BMP4 treatment (P=0.004). Furthermore, the tumor sphere assay demonstrated that BMP4 suppresses self-renewal ability. In conclusion, these findings may provide a new perspective on how BMP4 treatment reduces the tumorigenicity of GSCs.

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Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells

Cited by 47 publications

References 38 publications

Asymmetric Division Promotes Therapeutic Resistance in Glioblastoma Stem Cells

Asymmetric Division Promotes Therapeutic Resistance in Glioblastoma Stem Cells

Drug resistance mechanisms of cancer stem-like cells and their therapeutic potential as drug targets

BMP4 induces asymmetric cell division in human glioma stem-like cells

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