# Project 1:  Evolution of transcriptional programs in lung cancer progression

> **NIH NIH P01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $420,760

## Abstract

Project Summary – Project 1
Tumor progression is the product genetic mutations that affect gene function and epigenetic alterations that
affect patterns of gene expression and cellular states. Together with the effects of the tumor microenvironment,
these changes produce the phenotypes that underlie the biology of cancer. From extensive genomic studies
performed over the past decade the genetic landscape of cancer progression is beginning to emerge, but
much less is know about how tumors evolve epigenetically. Project 1 is focused on the investigation of tumor
evolution through the lens of changes in epigenetic states and gene expression programs. It is anticipated that
an improved understanding of these aspects of tumor development will yield new strategies to intervene in this
process as well as to treat established tumors. Three Specific Aims will be pursued addressing these questions
in the context of well-established genetically-engineered mouse models of human lung adenocarcinoma
(LUAD) based on mutations of K-ras (“K”) or the combination of K-ras and p53 (“KP”). Of note, K-ras mutations
occur in approximately 30% of human LUAD and targeted therapies do not exist for this subtype of the
disease. Preliminary data in support of the Project 1 demonstrates that as tumors progress in the KP model
they develop subpopulations of cells that have cancer stem-cell like properties and show markers of response
to the Wnt signaling pathway and other cells that markers of Wnt-producing cells that express the enzyme
Porcupine (Porcn). It is hypothesized that these Porcn+ cells act as niche cells for the cancer stem-like cells. In
Aim 1, a combination of genetic marking, molecular profiling and cell ablation studies will be used to
characterized and functionally test these putative niche cells for their importance in tumor development. These
studies may identify new targets for the treatment of human lung cancer. Using single cell mRNA sequencing
(SCmRNAseq), performed in collaboration with the laboratory of Aviv Regev, the Jacks laboratory has profiled
individual cancer cells from K and KP tumors. These data reveal extensive intratumoral and intertumoral
transcriptional heterogeneity. Aim 2 of Project 1 will complete the characterization of transcriptional
heterogeneity as a function of tumor genotype and tumor progression as well as explore the epigenetic
mediators of these effects. Finally, the transcriptional programs of cancer cells are expected to be affected by
immune infiltration and anti-tumor immune responses, potentially in a heterogeneous fashion across tumors.
These questions will be explored in Aim 3 of Project 1 using SCmRNAseq-based profiling and functional
studies of “immunogenic and “nonimmunogenic” tumors. The identification and functional validation of
pathways that contribute to immune suppression in this model could reveal new targets of therapy for human
lung cancer and other cancer types. In all of the Aims of Project 1, a series of...

## Key facts

- **NIH application ID:** 10215397
- **Project number:** 5P01CA042063-35
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** TYLER E. JACKS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $420,760
- **Award type:** 5
- **Project period:** 1997-05-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215397

## Citation

> US National Institutes of Health, RePORTER application 10215397, Project 1:  Evolution of transcriptional programs in lung cancer progression (5P01CA042063-35). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10215397. Licensed CC0.

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