Investigating disseminated cancer cell clonal cooperation and immune control in dormancy and metastasis

NIH RePORTER · CA · U01 · $693,712 · view on reporter.nih.gov ↗

Abstract

SUMMARY. We revealed that cancer cells can disseminate from early stages of cancer progression and after variable periods of dormancy they go on to form metastasis. Knowledge about how early DCCs (eDCCs) shape metastatic progression, how they remain dormant and immune evasive for years and how they get reactivated, is limited, but critically needed to develop more effective treatments. We discovered that as the primary tumor evolves genetically and grows, target organs are seeded by more genetically evolved late DCCs (L-DCCs) that can be dormant but also may carry more growth prone programs. How the first arriving eDCC and following L- DCCs crosstalk to affect immune niches in the lung for metastasis development has never been explored. Using genetic lineage tracing, protein barcoding, and single cell RNAseq (scRNAseq) we found that 79% of metastasis were derived from eDCCs and that eDCCs and L-DCCs cooperate in lungs to initiate metastasis. We also discovered that dormancy of eDCCs is driven by ZFP281 and NR2F1 and that interaction of eDCC and L-DCC downregulates NR2F1 expression to cooperatively found metastasis. Mouse models and human data suggest that immune-surveillance does not fully eliminate eDCCs, but how eDCCs evade immune targeting is unclear. To this end, we discovered that eDCCs have a low mutational burden, downregulate MHC-I compared to L- DCCs and upregulate the immune suppressors Gal-1 and TGFβ2. In Lungs with eDCCs CD4 and CD8 T cells seem to be dysfunctional, as depletion of CD8 T cells does not lead to eDCC outgrowth and treatment with anti- PD-L1 therapy does cause eDCC eradication. We also find that tissue resident alveolar macrophages (AMs) maintain dormancy of eDCCs but may contribute to immune evasion while also suppressing metastatic outgrowth. We hypothesize that eDCCs and L-DCCs cooperate to found metastasis by (a) the ability of L-DCCs to awaken dormant eDCCs via the production of inhibitors of pro-dormancy pathways and (b) eDCCs creatin

Key facts

NIH application ID
11319813
Project number
5U01CA284085-03
Recipient
ALBERT EINSTEIN COLLEGE OF MEDICINE
Principal Investigator
Julio A. Aguirre-Ghiso; Brian D Brown; Maria Sosa
Activity code
U01
Funding institute
CA
Fiscal year
2026
Award amount
$693,712
Award type
5
Project period
2024-05-21T00:00:00 → 2029-04-30T00:00:00