BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice

Yoku Hayakawa, Mayo Tsuboi, Samuel Asfaha, Hiroto Kinoshita, Ryota Niikura, Mitsuru Konishi, Masahiro Hata, Yukiko Oya, Woosook Kim, Moritz Middelhoff, Yohko Hikiba, Naoko Higashijima, Sozaburo Ihara, Tetsuo Ushiku, Masashi Fukayama, Yagnesh Tailor, Yoshihiro Hirata, Chandan Guha, Kelley S. Yan, Kazuhiko KoikeTimothy C. Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background & Aims: The intestinal epithelium is maintained by long-lived intestinal stem cells (ISCs) that reside near the crypt base. Above the ISC zone, there are short-lived progenitors that normally give rise to lineage-specific differentiated cell types but can dedifferentiate into ISCs in certain circumstances. However, the role of epithelial dedifferentiation in cancer development has not been fully elucidated. Methods: We performed studies with Bhlha15-CreERT, Lgr5-DTR-GFP, Apc flox/flox , LSL-Notch (IC), and R26-reporter strains of mice. Some mice were given diphtheria toxin to ablate Lgr5-positive cells, were irradiated, or were given 5-fluorouracil, hydroxyurea, doxorubicin, or dextran sodium sulfate to induce intestinal or colonic tissue injury. In intestinal tissues, we analyzed the fate of progeny that expressed Bhlha15. We used microarrays and reverse-transcription PCR to analyze gene expression patterns in healthy and injured intestinal tissues and in tumors. We analyzed gene expression patterns in human colorectal tumors using The Cancer Genome Atlas data set. Results: Bhlha15 identified Paneth cells and short-lived secretory precursors (including pre-Paneth label-retaining cells) located just above the ISC zone in the intestinal epithelium. Bhlha15 + cells had no plasticity after loss of Lgr5-positive cells or irradiation. However, Bhlha15 + secretory precursors started to supply the enterocyte lineage after doxorubicin-induced epithelial injury in a Notch-dependent manner. Sustained activation of Notch converts Bhlha15 + secretory precursors to long-lived enterocyte progenitors. Administration of doxorubicin and expression of an activated form of Notch resulted in a gene expression pattern associated with enterocyte progenitors, whereas only sustained activation of Notch altered gene expression patterns in Bhlha15 + precursors toward those of ISCs. Bhlha15 + enterocyte progenitors with sustained activation of Notch formed intestinal tumors with serrated features in mice with disruption of Apc. In the colon, Bhlha15 marked secretory precursors that became stem-like, cancer-initiating cells after dextran sodium sulfate–induced injury, via activation of Src and YAP signaling. In analyses of human colorectal tumors, we associated activation of Notch with chromosome instability-type tumors with serrated features in the left colon. Conclusions: In mice, we found that short-lived precursors can undergo permanent reprogramming by activation of Notch and YAP signaling. These cells could mediate tumor formation in addition to traditional ISCs.

Original languageEnglish (US)
Pages (from-to)1066-1081.e16
JournalGastroenterology
Volume156
Issue number4
DOIs
StatePublished - Mar 1 2019

Fingerprint

Intestines
Colon
Stem Cells
Enterocytes
Neoplasms
Doxorubicin
Intestinal Mucosa
Gene Expression
Colorectal Neoplasms
Wounds and Injuries
Paneth Cells
Diphtheria Toxin
Chromosomal Instability
Dextran Sulfate
Hydroxyurea
Atlases
Gene Expression Profiling
Dextrans
Fluorouracil
Reverse Transcription

Keywords

  • Colon Cancer
  • Interconversion
  • Tumorigenesis
  • Yes Associated Protein 1

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Hayakawa, Y., Tsuboi, M., Asfaha, S., Kinoshita, H., Niikura, R., Konishi, M., ... Wang, T. C. (2019). BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice. Gastroenterology, 156(4), 1066-1081.e16. https://doi.org/10.1053/j.gastro.2018.11.024

BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice. / Hayakawa, Yoku; Tsuboi, Mayo; Asfaha, Samuel; Kinoshita, Hiroto; Niikura, Ryota; Konishi, Mitsuru; Hata, Masahiro; Oya, Yukiko; Kim, Woosook; Middelhoff, Moritz; Hikiba, Yohko; Higashijima, Naoko; Ihara, Sozaburo; Ushiku, Tetsuo; Fukayama, Masashi; Tailor, Yagnesh; Hirata, Yoshihiro; Guha, Chandan; Yan, Kelley S.; Koike, Kazuhiko; Wang, Timothy C.

In: Gastroenterology, Vol. 156, No. 4, 01.03.2019, p. 1066-1081.e16.

Research output: Contribution to journalArticle

Hayakawa, Y, Tsuboi, M, Asfaha, S, Kinoshita, H, Niikura, R, Konishi, M, Hata, M, Oya, Y, Kim, W, Middelhoff, M, Hikiba, Y, Higashijima, N, Ihara, S, Ushiku, T, Fukayama, M, Tailor, Y, Hirata, Y, Guha, C, Yan, KS, Koike, K & Wang, TC 2019, 'BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice', Gastroenterology, vol. 156, no. 4, pp. 1066-1081.e16. https://doi.org/10.1053/j.gastro.2018.11.024
Hayakawa Y, Tsuboi M, Asfaha S, Kinoshita H, Niikura R, Konishi M et al. BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice. Gastroenterology. 2019 Mar 1;156(4):1066-1081.e16. https://doi.org/10.1053/j.gastro.2018.11.024
Hayakawa, Yoku ; Tsuboi, Mayo ; Asfaha, Samuel ; Kinoshita, Hiroto ; Niikura, Ryota ; Konishi, Mitsuru ; Hata, Masahiro ; Oya, Yukiko ; Kim, Woosook ; Middelhoff, Moritz ; Hikiba, Yohko ; Higashijima, Naoko ; Ihara, Sozaburo ; Ushiku, Tetsuo ; Fukayama, Masashi ; Tailor, Yagnesh ; Hirata, Yoshihiro ; Guha, Chandan ; Yan, Kelley S. ; Koike, Kazuhiko ; Wang, Timothy C. / BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice. In: Gastroenterology. 2019 ; Vol. 156, No. 4. pp. 1066-1081.e16.
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T1 - BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice

AU - Hayakawa, Yoku

AU - Tsuboi, Mayo

AU - Asfaha, Samuel

AU - Kinoshita, Hiroto

AU - Niikura, Ryota

AU - Konishi, Mitsuru

AU - Hata, Masahiro

AU - Oya, Yukiko

AU - Kim, Woosook

AU - Middelhoff, Moritz

AU - Hikiba, Yohko

AU - Higashijima, Naoko

AU - Ihara, Sozaburo

AU - Ushiku, Tetsuo

AU - Fukayama, Masashi

AU - Tailor, Yagnesh

AU - Hirata, Yoshihiro

AU - Guha, Chandan

AU - Yan, Kelley S.

AU - Koike, Kazuhiko

AU - Wang, Timothy C.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Background & Aims: The intestinal epithelium is maintained by long-lived intestinal stem cells (ISCs) that reside near the crypt base. Above the ISC zone, there are short-lived progenitors that normally give rise to lineage-specific differentiated cell types but can dedifferentiate into ISCs in certain circumstances. However, the role of epithelial dedifferentiation in cancer development has not been fully elucidated. Methods: We performed studies with Bhlha15-CreERT, Lgr5-DTR-GFP, Apc flox/flox , LSL-Notch (IC), and R26-reporter strains of mice. Some mice were given diphtheria toxin to ablate Lgr5-positive cells, were irradiated, or were given 5-fluorouracil, hydroxyurea, doxorubicin, or dextran sodium sulfate to induce intestinal or colonic tissue injury. In intestinal tissues, we analyzed the fate of progeny that expressed Bhlha15. We used microarrays and reverse-transcription PCR to analyze gene expression patterns in healthy and injured intestinal tissues and in tumors. We analyzed gene expression patterns in human colorectal tumors using The Cancer Genome Atlas data set. Results: Bhlha15 identified Paneth cells and short-lived secretory precursors (including pre-Paneth label-retaining cells) located just above the ISC zone in the intestinal epithelium. Bhlha15 + cells had no plasticity after loss of Lgr5-positive cells or irradiation. However, Bhlha15 + secretory precursors started to supply the enterocyte lineage after doxorubicin-induced epithelial injury in a Notch-dependent manner. Sustained activation of Notch converts Bhlha15 + secretory precursors to long-lived enterocyte progenitors. Administration of doxorubicin and expression of an activated form of Notch resulted in a gene expression pattern associated with enterocyte progenitors, whereas only sustained activation of Notch altered gene expression patterns in Bhlha15 + precursors toward those of ISCs. Bhlha15 + enterocyte progenitors with sustained activation of Notch formed intestinal tumors with serrated features in mice with disruption of Apc. In the colon, Bhlha15 marked secretory precursors that became stem-like, cancer-initiating cells after dextran sodium sulfate–induced injury, via activation of Src and YAP signaling. In analyses of human colorectal tumors, we associated activation of Notch with chromosome instability-type tumors with serrated features in the left colon. Conclusions: In mice, we found that short-lived precursors can undergo permanent reprogramming by activation of Notch and YAP signaling. These cells could mediate tumor formation in addition to traditional ISCs.

AB - Background & Aims: The intestinal epithelium is maintained by long-lived intestinal stem cells (ISCs) that reside near the crypt base. Above the ISC zone, there are short-lived progenitors that normally give rise to lineage-specific differentiated cell types but can dedifferentiate into ISCs in certain circumstances. However, the role of epithelial dedifferentiation in cancer development has not been fully elucidated. Methods: We performed studies with Bhlha15-CreERT, Lgr5-DTR-GFP, Apc flox/flox , LSL-Notch (IC), and R26-reporter strains of mice. Some mice were given diphtheria toxin to ablate Lgr5-positive cells, were irradiated, or were given 5-fluorouracil, hydroxyurea, doxorubicin, or dextran sodium sulfate to induce intestinal or colonic tissue injury. In intestinal tissues, we analyzed the fate of progeny that expressed Bhlha15. We used microarrays and reverse-transcription PCR to analyze gene expression patterns in healthy and injured intestinal tissues and in tumors. We analyzed gene expression patterns in human colorectal tumors using The Cancer Genome Atlas data set. Results: Bhlha15 identified Paneth cells and short-lived secretory precursors (including pre-Paneth label-retaining cells) located just above the ISC zone in the intestinal epithelium. Bhlha15 + cells had no plasticity after loss of Lgr5-positive cells or irradiation. However, Bhlha15 + secretory precursors started to supply the enterocyte lineage after doxorubicin-induced epithelial injury in a Notch-dependent manner. Sustained activation of Notch converts Bhlha15 + secretory precursors to long-lived enterocyte progenitors. Administration of doxorubicin and expression of an activated form of Notch resulted in a gene expression pattern associated with enterocyte progenitors, whereas only sustained activation of Notch altered gene expression patterns in Bhlha15 + precursors toward those of ISCs. Bhlha15 + enterocyte progenitors with sustained activation of Notch formed intestinal tumors with serrated features in mice with disruption of Apc. In the colon, Bhlha15 marked secretory precursors that became stem-like, cancer-initiating cells after dextran sodium sulfate–induced injury, via activation of Src and YAP signaling. In analyses of human colorectal tumors, we associated activation of Notch with chromosome instability-type tumors with serrated features in the left colon. Conclusions: In mice, we found that short-lived precursors can undergo permanent reprogramming by activation of Notch and YAP signaling. These cells could mediate tumor formation in addition to traditional ISCs.

KW - Colon Cancer

KW - Interconversion

KW - Tumorigenesis

KW - Yes Associated Protein 1

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