NIH grant: Engineered tissues to identify cellular crosstalk required for early tumor development (1R21EB038495-01)

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NIH grant 1R21EB038495-01: Engineered tissues to identify cellular crosstalk required for early tumor development
Institute: {'code': 'EB', 'abbreviation': 'NIBIB', 'name': 'National Institute of Biomedical Imaging and Bioengineering', 'admin_org_id': '12500035', 'admin_funding_url': ''}. PI: Ellen Marie Langer. Award: $195000.
Start: 2026-08-01T00:00:00.
PROJECT SUMMARY
Recent autopsy studies in epithelial organs have revealed high prevalence of premalignant lesions, even in
adults with no cancer history. Despite expression of oncogenic driver mutations, most of these lesions will remain
indolent. Stromal cells associated with premalignant lesions can restrict progression of disease, but we lack a
full understanding of the changes to molecular and cellular crosstalk events that underlie the malignant switch.
There is a critical need for robust and manipulable model systems of human tissues that can be leveraged to
understand the evolution from premalignancy to early cancer and to validate therapies for interception.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive epithelial tumor with a dismal prognosis when
diagnosed at late stage. Multifocal low-grade precursors for PDAC that express mutant KRAS are abundant in
the general population, but most lesions have very low risk of progressing to PDAC. Germline BRCA2 mutations
(gBRCA2) significantly increase the risk of developing PDAC, even in the absence of loss of heterozygosity
(LOH). Whether, and how, haploinsufficiency of gBRCA2 contributes to the PanIN to PDAC transition is not
known. In advanced PDAC, BRCA mutations in cancer cells signal to fibroblasts to elicit an HSF1-induced
Clusterin positive stromal phenotype that contributes to aggressive disease. In a recent breast cancer study,
gBRCA1 mutations in fibroblasts themselves drove a change in their secretome that accelerated disease
progression. Based on these findings, this proposal will address the hypothesis that fibroblast states in gBRCA2
pancreata are altered directly due to haploinsufficiency in fibroblasts and indirectly due to crosstalk from epithelial
cells, and that these changes to fibroblast state induce secreted factors that promote PanIN to PDAC
progression. This work will develop a modular engineered tissue platform to interrogate the dynamic, reciprocal
interactions between (pre)malignant cells and their environment over a time course of malignant transition. It will
test how specific factors in (pre)cancer cells and their co-evolving microenvironment can accelerate malignant
progression. In Aim 1, a series of human organoid models will be generated carrying distinct mutations
associated with gBRCA2 PDAC. Organoids modeling low grade or progressive disease will be incorporated into
heterotypic tissue models with multiple microenvironmental cell types. Through the use of cell-niche labeling
reporter system, single cell analyses, and cell-specific proteomics of secreted proteins, the mechanisms and
impact of bidirectional cell-cell crosstalk will be assessed. In Aim 2, strategies to intercept tumor progression in
the gBRCA2 setting will be validated in bioprinted tissues and complementary mouse models. While this work
focuses on early pancreatic cancer, the engineered tissue platform developed is expected to be readily
applicable to studies of additional tissues and diseases long term.

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