Detalles del proyecto
Description
PROJECT SUMMARY
During tumor evolution, cancer cells can acquire phenotypic heterogeneity, enabling them to grow more
aggressively, invade neighboring tissues, evade the immune system and therapeutic challenges, and
metastasize to distant sites. The ability of cancer cells to change their phenotypes can be broadly defined as
cancer cell plasticity, which can be influenced by both tumor intrinsic and extrinsic factors. However, the
underlying molecular mechanisms that regulate cancer cell state transitions throughout tumor evolution remain
poorly understood. A comprehensive understanding of these mechanisms will uncover key gene networks and
potentially inform novel therapeutic approaches.
Studying cancer cell state transitions in vivo has been challenging due to the lack of tools for tracking cell
lineage relationships at high resolution. To overcome this, I have recently contributed to the development of an
evolving lineage tracer that leverages CRISPR/Cas9 technology to simultaneously report each cancer cell’s
lineage history and transcriptional state in vivo. By applying this tool to the well-characterized Kras;Trp53 (KP)
autochthonous mouse model of lung adenocarcinoma, I was able to reconstruct the entire tumor evolution history
and measure cancer plasticity by quantifying cell state changes in phylogenetically-related cancer cells. Built on
this innovative system, this proposal aims to investigate the mechanisms underlying lung cancer cell plasticity,
both cell-autonomous and non-cell-autonomous. Leveraging my expertise in cancer biology and the evolving
lineage tracing model, I will quantitatively track cancer cell state transitions within the native microenvironment.
Specifically, I will delineate cell-autonomous regulators of cancer cell plasticity by CRISPR knockout of putative
regulators of plasticity, identify plasticity-associated tumor microenvironmental factors and dissect non-cell-
autonomous regulation of plasticity using spatial transcriptomics, and explore the role of plasticity in resistance
development to anti-cancer therapies. Addressing these fundamental questions will provide new insights into the
biology of cancer cell state regulation. Moreover, the experimental and computational framework from this
proposal can be applicable for studying cancer plasticity in other genetic perturbations and therapeutic contexts,
serving as a general template for understanding the molecular basis of cancer cell plasticity and tumor evolution.
My diverse expertise in cancer biology, mouse modeling, technology and single cell genomics positions me
to execute the proposed projects and help me acquire important preliminary data to apply for future research
grants. As part of this grant, I will assemble an advisory team at my institution to support my transition and career
development training activities outlined in this proposal. I will also take advantage of the varied resources at my
postdoctoral institutions and the institution where I secure an independent position to develop skills related to
mentorship, communication, and research ethics. Overall, I believe my focused research plan, detailed training
goals, and a strong advisory team will facilitate a successful transition to independence.
Estado | Activo |
---|---|
Fecha de inicio/Fecha fin | 9/1/24 → 8/31/25 |
Keywords
- Investigación sobre el cáncer
- Oncología
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