“The 83rd of Stem Cell Biology and Regenerative Medicine Forum”
Date：Jul 31st (Fri) 2015
Time : 18:00 〜 19:30
Place：8th fl of New Hospital Building------------------------------------------------------------------------------------------------------------------------------------（Internal Speaker）
18:00-18:30
Kana Tominaga (Division of Molecular Therapy, IMSUT. Division of Internal
medicine, Graduate School of Medicine, University of Tokyo, JSPS Research
Fellow DC2)
Dependence on the HER2/3-IGF2-ID1 circuit as a fundamental
mechanism for stabilization of the stemness of breast cancer cells（External Speaker）
18:30-19:30
Atsushi Hirao (Division of Molecular Genetics, Cancer Research Institute,Kanazawa University)
Molecular mechanisms of the maintenance of stem cells in normal andmalignant hematopoiesis-------------------------------------------------------------------------------------------------------------------------------------

Hosted by Center for Stem Cell Biology and Regenerative Medicine---Information--＊ Please register attendance at the reception desk.

＊ Next forum（the84th）will be held on

Sep. 15th（Tue）13:00〜 at Auditorium＊ Please contact tatsu-m@ims.u-tokyo.ac.jp, for Forum speaker recommendations

Dependence on the HER2/3-NF -IGF2-ID1 circuit as a fundamental
mechanism for stabilization of the stemness of breast cancer cells
Kana Tominaga (Division of Molecular Therapy, IMSUT. Division of Internal
medicine, Graduate School of Medicine, University of Tokyo, JSPS Research
Fellow DC2)
Many breast cancer patients suffer from relapse, which is potentially due to cancer stem cells thatwere not eliminated by treatment. Not only is it difficult to eradicate cancer stem cells, but thecancer cells themselves even appear to have plasticity by which they can acquire cancer stem cellproperties. There may be unknown mechanisms to stabilize cancer stemness. Since theHER2/3—PI3K—NF
downstream molecules in this pathway by comprehensive analysis of gene expression profiles
over time. Insulin-like growth factor 2 (IGF2) was identified as a key downstream molecule,since anti-IGF2 antibody treatment blocked tumor sphere formation, characteristic of stemness,even in the presence of other growth factors/cytokines. IGF2—PI3K signaling induced tumor
sphere formation and enhanced the expression of genes favoring stemness, including thetranscription regulator ID1 and IGF2 itself. ID1 and the IGF2 receptor IGF-1R were specifically
expressed at high levels in cancer stem cell-enriched populations in freshly obtained primarybreast cancer cells derived from patients and patient-derived xenografts (PDXs). Moreover, ID1
knockdown suppressed IGF2-induced expression of IGF2. Thus, HER2/3—PI3K—
signaling may trigger IGF2—PI3K—ID1—IGF2 positive feedback circuits and PI3K-mediatedfeed-forward circuits that stabilize the stemness of cancer cells, and on which they are dependent.
It would be critical to target these stemness circuits for eradication of cancer stem cells,
irrespective of breast cancer subtypes.

Molecular mechanisms of the maintenance of stem cells in normal andmalignant hematopoiesis
Atsushi Hirao (Division of Molecular Genetics, Cancer Research Institute,
Kanazawa University)
Hematopoietic stem cells (HSCs) are able to reproduce themselves, a property known as
self-renewal, and to give rise to mature hematopoietic cells. Under steady-state conditions, HSCs
are maintained as a quiescent population and their numbers in the BM and circulation are tightly
regulated by microenvironment components. In order to maintain HSC homeostasis over the lifeof an animal, HSCs must either be long-lived or self-renew. In either case, the quality of HSCs
must be sustained during aging. Although aging is a complicated phenomenon, its effects on
HSCs have been dissected by examining DNA damage response processes, cellular senescence,and metabolism. Recent studies have suggested that shared mechanisms regulate stem cellproperties ”stemness” in both HSCs and leukemia stem cells (LSCs). Despite the differing
origins of LSCs among different leukemias, there appears to be a common regulatory mechanism
governing “stemness” and thus the behavior of LSCs.
We have been focusing on mTOR complex (mTORC) and forkhead transcription factor FOXO
family members, which function in nutrient sensing signaling pathways. We revealed that FOXO
activity is essential for maintaining self-renewal of HSCs and contributes to blockade ofdifferentiation programs in leukemia, suggesting that the nutrient pathways may be commonly
critical for normal and malignant stem cell systems. We have also found that modulation ofcell-cell interaction controls HSC function and that actin polymerization may be involved inHSC aging. Thus, identification of stemness regulators would lead to deep understanding ofmechanisms of aging and tumorigenesis.