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PreprintCC BYbioRxiv

Cross-species analysis links cell-cell communication rewiring to NOTCH2 during serous endometrial carcinogenesis

  • M. G. Pirtz
  • A. Flesken-Nikitin
  • C. Q. Ralston
  • D. J. Phuong
  • N. Wang
  • T. Chu
  • S. Chen
  • Y. Zheng
  • E. Schmoeckel
  • A. Yemelyanova
  • I.-M. Shih
  • C. G. Danko
2 more authors
  • B. D. Cosgrove
  • A. Y. Nikitin1
  1. 1Cornell University
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Abstract

Cell-cell interactions shape the fate of mutant cells during cancer initiation but how these interactions evolve during progression to pathologically recognizable lesions remain poorly understood. Here, we investigated cell-cell communication during serous endometrial carcinoma (SEC; also known as uterine serous carcinoma) development using a lineage-traceable mouse model and cross-species analyses of the mouse and human neoplastic endometrium. In mice, the early, pre-dysplastic stage was marked by a global decrease in inferred cell-cell interactions, followed by extensive communication network rewiring during neoplastic progression. Pathway-specific analysis revealed a similar pattern for NOTCH signaling, with NOTCH2 emerging as the dominant NOTCH receptor in Trp53/Rb1-mutant immature epithelial cells. Functionally, NOTCH2 promoted the outgrowth of more proliferative mutant organoids. Cross-species transcriptomic analysis identified conserved immature epithelial states in mouse and human neoplastic endometrial epithelium. In human tissues, NOTCH2 was overexpressed in serous endometrial intraepithelial carcinoma, a precursor of SEC, and in overt SEC. Furthermore, elevated NOTCH2 expression was associated with poor patient survival. These findings link cell-cell communication rewiring during experimental SEC development to conserved neoplastic epithelial states and identify NOTCH2 as an early marker and a potential target of disease interception.

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Cite

BibTeXRIS
BibTeX
@misc{pirtz2026crossspecies,
  title = {{Cross-species analysis links cell-cell communication rewiring to NOTCH2 during serous endometrial carcinogenesis}},
  author = {M. G. Pirtz and A. Flesken-Nikitin and C. Q. Ralston and D. J. Phuong and N. Wang and T. Chu and S. Chen and Y. Zheng and E. Schmoeckel and A. Yemelyanova and I.-M. Shih and C. G. Danko and B. D. Cosgrove and A. Y. Nikitin},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.01.748540},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748540v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Cross-species analysis links cell-cell communication rewiring to NOTCH2 during serous endometrial carcinogenesis
AU  - M. G. Pirtz
AU  - A. Flesken-Nikitin
AU  - C. Q. Ralston
AU  - D. J. Phuong
AU  - N. Wang
AU  - T. Chu
AU  - S. Chen
AU  - Y. Zheng
AU  - E. Schmoeckel
AU  - A. Yemelyanova
AU  - I.-M. Shih
AU  - C. G. Danko
AU  - B. D. Cosgrove
AU  - A. Y. Nikitin
PY  - 2026
DA  - 2026/09/01
PB  - bioRxiv
DO  - 10.64898/2026.09.01.748540
UR  - https://www.biorxiv.org/content/10.64898/2026.09.01.748540v1
AB  - Cell-cell interactions shape the fate of mutant cells during cancer initiation but how these interactions evolve during progression to pathologically recognizable lesions remain poorly understood. Here, we investigated cell-cell communication during serous endometrial carcinoma (SEC; also known as uterine serous carcinoma) development using a lineage-traceable mouse model and cross-species analyses of the mouse and human neoplastic endometrium. In mice, the early, pre-dysplastic stage was marked by a global decrease in inferred cell-cell interactions, followed by extensive communication network rewiring during neoplastic progression. Pathway-specific analysis revealed a similar pattern for NOTCH signaling, with NOTCH2 emerging as the dominant NOTCH receptor in Trp53/Rb1-mutant immature epithelial cells. Functionally, NOTCH2 promoted the outgrowth of more proliferative mutant organoids. Cross-species transcriptomic analysis identified conserved immature epithelial states in mouse and human neoplastic endometrial epithelium. In human tissues, NOTCH2 was overexpressed in serous endometrial intraepithelial carcinoma, a precursor of SEC, and in overt SEC. Furthermore, elevated NOTCH2 expression was associated with poor patient survival. These findings link cell-cell communication rewiring during experimental SEC development to conserved neoplastic epithelial states and identify NOTCH2 as an early marker and a potential target of disease interception.
ER  -