Emergence of Stress-Adaptive Tumor Subclones and Associated Vulnerabilities in Therapy-Resistant Cancer Yue Claire Shao

Format:

Book

Thesis/Dissertation

Author/Creator:

Shao, Yue Claire, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

0212.

0379.

0982.

0992.

Local Subjects:

0212.

0379.

0982.

0992.

Physical Description:

1 electronic resource (137 pages)

Contained In:

Dissertations Abstracts International 87-07A

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Immune checkpoint blockade (ICB) has transformed cancer treatment, yet many patients ultimately relapse due to acquired resistance. As tumors progress, they accumulate intratumoral heterogeneity, generating diverse subpopulations that fuel adaptive escape from therapy. Accurate characterization of these resistant states and their evolutionary dynamics is therefore critical for developing durable treatment strategies.Using lineage tracing and single cell transcriptome profiling in ICB-relapsed melanoma and lung cancer models, we identified distinct subpopulations that expand under therapeutic pressure. One population, Res1, is defined by AP-1-driven stress and epithelial-to-mesenchymal transition (EMT) programs. Remarkably, Res1 cells not only display resistance to ICB therapy, but also exhibit cross-resistance to mitogen-activated protein kinase (MAPK)-targeted inhibitors, underscoring their central role in therapeutic failure.To identify strategies to target Res1, we designed a compact genome-wide CRISPR-Cas12a library and performed genome-wide in vivo screening. Functional genomics revealed that the secondary MAPK kinase, Map2k4, represents a selective dependency in ICB-relapsed melanoma and lung cancer tumors. Single-cell Perturb-seq demonstrated that Map2k4 disruption selectively eliminates stress- and EMT-high Res1 cells. The depletion of Res1 cells from the tumor microenvironment was sufficient to restore sensitivity to both ICB and MAPK inhibitors.These findings highlight the need for subpopulation-aware therapeutic strategies, including sequential and adaptive treatment regimens, to more effectively constrain tumor evolution. Together, our work establishes a framework for managing intratumoral heterogeneity by mapping resistant cell states, defining their molecular dependencies, and leveraging these insights to design rational strategies for durable cancer therapy

Notes:

Advisors: Minn, Andy J. Committee members: Greenberg, Roger A.; Fuchs, Serge Y.; Shalem, Ophir; Guo, Wei

Source: Dissertations Abstracts International, Volume: 87-07, Section: A.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276005355

Access Restriction:

Restricted for use by site license