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Single-Cell Lineage Tracing in Clinically Relevant Lung Cancer Models Informs Actionable Programs to Delay EGFR-Targeted Therapy Resistance
Single-Cell Lineage Tracing in Clinically Relevant Lung Cancer Models Informs Actionable Programs to Delay EGFR-Targeted Therapy Resistance
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104723
- ISBN
- 9798293851621
- DDC
- 616.99
- 저자명
- Tamaki, Whitney.
- 서명/저자
- Single-Cell Lineage Tracing in Clinically Relevant Lung Cancer Models Informs Actionable Programs to Delay EGFR-Targeted Therapy Resistance
- 발행사항
- [Sl] : University of California, San Francisco, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 64 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-03, Section: B.
- 주기사항
- Advisor: Bivona, Trever;Goodarzi, Hani.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2025.
- 초록/해제
- 요약Lung cancer is the leading cause of cancer related deaths worldwide. Although mutation driven cancers, such as those harboring activating EGFR mutations, show a high rate of initial response to targeted tyrosine kinase inhibitors (TKIs), all patients eventually develop acquired resistance. This dissertation aims to investigate the residual disease state (RD) to better understand the responding, yet persistent, tumor and identify potentially targetable features of the tumor landscape.The first chapter leverages static genomic barcoding paired with single-cell RNA sequencing (scRNA-seq) to identify pre-existing features of two distinct TKI-resistant preclinical EGFRm models. The static genomic barcoding enabled the identification of cell lineages that were either susceptible or resistant to TKI therapy. scRNA-seq analysis of these lineages enabled identification of pre-treatment features, as well as the mapping of transcriptional changes over treatment time. First, in our patient-derived organoid model, we found that expression of the Hallmark Hedgehog Signaling gene set, pre-TKI treatment, is evidence of a plastic phenotype. This plastic phenotype is primed for transcriptional rewiring, allowing for adaptive mechanisms to improve survival in the presence of TKI therapy. In the cell-derived xenograft model, we provide evidence that expression of FOXD1 regulon genes is associated with TKI resistance. Although many FOXD1 regulon genes have independently been associated with disease progression, drug resistance, and metastasis in cancer, we hypothesize NR4A1 plays a significant role in the FOXD1-related osimertinib resistance identified.
- 일반주제명
- Oncology
- 일반주제명
- Medicine
- 일반주제명
- Pharmaceutical sciences
- 키워드
- Drug tolerance
- 키워드
- Lineage tracing
- 키워드
- Lung cancer
- 기타저자
- University of California, San Francisco Pharmaceutical Sciences and Pharmacogenomics
- 기본자료저록
- Dissertations Abstracts International. 87-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520260202104723
■006m o d
■007cr#unu||||||||
■020 ▼a9798293851621
■035 ▼a(MiAaPQ)AAI32121677
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.99
■1001 ▼aTamaki, Whitney.▼0(orcid)0000-0002-1124-628X
■24510▼aSingle-Cell Lineage Tracing in Clinically Relevant Lung Cancer Models Informs Actionable Programs to Delay EGFR-Targeted Therapy Resistance
■260 ▼a[Sl]▼bUniversity of California, San Francisco▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a64 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-03, Section: B.
■500 ▼aAdvisor: Bivona, Trever;Goodarzi, Hani.
■5021 ▼aThesis (Ph.D.)--University of California, San Francisco, 2025.
■520 ▼aLung cancer is the leading cause of cancer related deaths worldwide. Although mutation driven cancers, such as those harboring activating EGFR mutations, show a high rate of initial response to targeted tyrosine kinase inhibitors (TKIs), all patients eventually develop acquired resistance. This dissertation aims to investigate the residual disease state (RD) to better understand the responding, yet persistent, tumor and identify potentially targetable features of the tumor landscape.The first chapter leverages static genomic barcoding paired with single-cell RNA sequencing (scRNA-seq) to identify pre-existing features of two distinct TKI-resistant preclinical EGFRm models. The static genomic barcoding enabled the identification of cell lineages that were either susceptible or resistant to TKI therapy. scRNA-seq analysis of these lineages enabled identification of pre-treatment features, as well as the mapping of transcriptional changes over treatment time. First, in our patient-derived organoid model, we found that expression of the Hallmark Hedgehog Signaling gene set, pre-TKI treatment, is evidence of a plastic phenotype. This plastic phenotype is primed for transcriptional rewiring, allowing for adaptive mechanisms to improve survival in the presence of TKI therapy. In the cell-derived xenograft model, we provide evidence that expression of FOXD1 regulon genes is associated with TKI resistance. Although many FOXD1 regulon genes have independently been associated with disease progression, drug resistance, and metastasis in cancer, we hypothesize NR4A1 plays a significant role in the FOXD1-related osimertinib resistance identified.
■590 ▼aSchool code: 0034.
■650 4▼aOncology
■650 4▼aMedicine
■650 4▼aPharmaceutical sciences
■653 ▼aDrug tolerance
■653 ▼aEGFRm lung cancer
■653 ▼aLineage tracing
■653 ▼aLung cancer
■653 ▼aTyrosine kinase inhibitors
■690 ▼a0992
■690 ▼a0564
■690 ▼a0572
■71020▼aUniversity of California, San Francisco▼bPharmaceutical Sciences and Pharmacogenomics.
■7730 ▼tDissertations Abstracts International▼g87-03B.
■790 ▼a0034
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358585▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
