Ras Drives Malignancy Through Stem Cell Crosstalk with the Microenvironment

Author

Shaopeng Yuan

Date of Award

2022

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Fuchs Laboratory

Abstract

Squamous cell carcinomas (SCCs) are triggered by marked elevation of RAS/MAPK signaling and progression from benign papilloma to invasive malignancy. A subset of tumor-initiating basal progenitors, the cancer stem cells, obtain increased resistance to chemo and immunotherapy along this path. However, the distribution and changes in cancer stem cells during progression from a benign state to an invasive SCC remain elusive. Here we show that following HRASG12V activation, cancer stem cells rewire their gene expression program and trigger self-propelling, aberrant signaling crosstalk with their tissue microenvironment that drives their malignant progression. Surprisingly, the non-genetic, dynamic cascade of crosstalk involves pathways often mutated in advanced metastatic SCCs with a high mutational burden. Coupling our clonal skin HRASG12V model with single-cell transcriptomics, chromatin-landscaping, lentiviral reporters and lineage-tracing, we show that the aberrant cancer stem cell-microenvironment crosstalk creates conditions ripe for hijacking leptin receptor (LEPR)-signaling, which in turn launches downstream PI3K-AKT-mTOR signaling at the benign-malignant transition. By functionally interrogating each step in this pathway, we unravel how dynamic temporal crosstalk with the microenvironment and orchestrated by the stem cells, profoundly fuels this path to malignancy. This discovery provides new insights into the path to malignancy and suggests broad implications for cancer therapeutics.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Yuan, Shaopeng, "Ras Drives Malignancy Through Stem Cell Crosstalk with the Microenvironment" (2022). Student Theses and Dissertations. 689.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/689