Monday, April 29, 2024
4/29/2024
PROJECT SUMMARY Breast cancer is a heterogeneous disease, which partly explains differences in prognosis, treatment response, and metastasis between patients. Breast cancer is classified into histological subtypes (ESR1+;PGR+/-, HER2+, and “triple-negative” (TNBC)), which are prognostic and predict responsiveness to hormonal and HER2-targeted therapies. Of these subtypes, TNBC is associated with a worse prognosis and lacks a targeted therapy. The lethality of TNBC is largely attributed to its aggressiveness and to resistance to traditional therapeutics, especially as metastases. TNBC show substantial inter- and intratumoral heterogeneity, with phenotypically and molecularly distinct tumor cell subpopulations existing within a single tumor. A rare subpopulation of cells known to have intrinsic resistance to chemo- and targeted therapies are called tumor-initiating cells (TICs) (a.k.a. cancer stem cells). TICs have the ability to self-renew and recapitulate clonally-derived cellular hierarchies upon generation of a new tumor. Metastasis-initiating cells (MICs), thought to be derived from TICs, possess similar phenotypic properties to TICs, but are also capable of seeding tumors at distant sites. Current chemotherapies target the bulk of a lesion, but in many cases, do not effectively eliminate TICs resulting in metastatic recurrence years after initial treatment. Cell surface markers and signaling reporters have been used to study TICs. However, such markers are neither unique to TICs nor phenotypically stable, and there is no established method to lineage trace TICs as they undergo cell state changes. As a result, studying TICs has been a significant challenge. To address this issue, we have developed a novel Tamoxifen-inducible, Cre recombinase-dependent, STAT3 signaling-specific lentiviral lineage-tracing (LT) system that will allow us to identify TICs in primary tumors, to probe their behaviors and phenotypes, and to identify candidate genetic vulnerabilities. The central hypothesis of this proposal is that a subset of STAT3 signaling TICs in some TNBC tumors represent MICs, which possess a distinct transcriptional program that can be targeted to eliminate TICs and improve response to chemotherapy. In Aim 1, we will clarify whether STAT3 signaling TICs represent the MIC population. In Aim 2 we will determine whether STAT3 signaling TICs in the primary tumor express distinct genes that can be targeted to prevent tumor progression. The results of this proposal will have a positive impact on the field as it will uncover the role of STAT3 signaling TICs in metastasis and identify genetic vulnerabilities that may be targeted to eliminate TICs and improve chemotherapy response. The identification of new therapeutic targets that eliminate the TIC population can improve clinical outcomes for TNBC patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
