Biology subjects

Reich, N. C.

Publications and source records attributed to Reich, N. C..

3 recordsLinked to original sources

bioRxiv2025

STAT3 Sustains Tumorigenicity Following Mutant KRAS Ablation

Oncogenic KRAS mutations underlie some of the deadliest human cancers. Genetic or pharmacological inactivation of mutant KRAS is not sufficient for long-term control of advanced tumors. Using a conceptual framework of pancreatic ductal adenocarcinoma, we find that CRISPR-mediated ablation of mutant KRAS can terminate tumor progression contingent on the concomitant inactivation of STAT3. STAT3 inactivation is needed to ensure that KRAS-ablated tumor cells lose their malignant identity. Mechanistically, the combined loss of mutant KRAS and STAT3 disrupts a core transcriptional program of cancer cells critical to oncogenic competence. This in turn impairs tumor growth in mice and enhances immune rejection, leading to tumor clearance. We propose that the STAT3 transcriptional program operating in cancer cells enforces their malignant identity, rather than providing classical features of transformation, and shapes cancer persistence following KRAS inactivation. Our findings establish STAT3 as a critical enforcer of oncogenic identity in KRAS-ablated tumors, revealing a key vulnerability that could be exploited for combination therapies. SignificanceThe limited clinical success of KRAS inhibitors points to the need to identify means by which tumor cells maintain stemness and immune evasion. We make an unprecedented finding that the STAT3 transcription factor can sustain tumorigenicity of pancreatic cancer cells following depletion of the KRAS oncogenic driver. The results have important implications for successful therapeutic intervention.

cancer biology↗

bioRxiv2023

STAT3 is a genetic modifier of TGF-beta induced EMT in KRAS mutant pancreatic cancer

Oncogenic mutations in KRAS are among the most common in cancer. Classical models suggest that loss of epithelial characteristics and the acquisition of mesenchymal traits are associated with cancer aggressiveness and therapy resistance. However, the mechanistic link between these phenotypes and mutant KRAS biology remains to be established. Here we identify STAT3 as a genetic modifier of TGF-beta-induced epithelial to mesenchymal transition. Gene expression profiling of pancreatic cancer cells identifies more than 200 genes commonly regulated by STAT3 and oncogenic KRAS. Functional classification of STAT3 responsive program reveals its major role in tumor maintenance and epithelial homeostasis. The signatures of STAT3-activated cell states can be projected onto human KRAS mutant tumors, suggesting that they faithfully reflect characteristics of human disease. These observations have implications for therapeutic intervention and tumor aggressiveness. SignificanceThe identification of the molecular and genetic characteristics of tumors is essential for understanding disease progression and aggressiveness. KRAS mutations are the most frequent oncogenic drivers in human cancer. In this study we demonstrate that the ubiquitously expressed transcription factor STAT3 is a genetic modifier of TGF-beta-induced EMT, and thereby oncogenic KRAS dependency. Both in vitro and in vivo studies demonstrate that STAT3 responsive program is an inherent part of oncogenic KRAS outcome.

cancer biology↗

bioRxiv2023

B cell-intrinsic STAT3-mediated support of latency and interferon suppression during murine gammaherpesvirus 68 infection revealed through an in vivo competition model

Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor STAT3. To better understand the role of STAT3 during gammaherpesvirus latency and immune control, we utilized murine gammaherpesvirus 68 (MHV68) infection. Genetic deletion of STAT3 in B cells of CD19cre/+Stat3f/fmice reduced peak latency approximately 7-fold. However, infected CD19cre/+Stat3f/f mice exhibited disordered germinal centers and heightened virus-specific CD8 T cell responses compared to WT littermates. To circumvent the systemic immune alterations observed in the B cell-STAT3 knockout mice and more directly evaluate intrinsic roles for STAT3, we generated mixed bone marrow chimeras consisting of WT and STAT3-knockout B cells. Using a competitive model of infection, we discovered a dramatic reduction in latency in STAT3-knockout B cells compared to their WT B cell counterparts in the same lymphoid organ. RNA sequencing of sorted germinal center B cells revealed that STAT3 promotes proliferation and B cell processes of the germinal center but does not directly regulate viral gene expression. Last, this analysis uncovered a STAT3-dependent role for dampening type I IFN responses in newly infected B cells. Together, our data provide mechanistic insight into the role of STAT3 as a latency determinant in B cells for oncogenic gammaherpesviruses. IMPORTANCEThere are no directed therapies to the latency program of the gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus. Activated host factor STAT3 is a hallmark of cancers caused by these viruses. We applied the murine gammaherpesvirus pathogen system to explore STAT3 function upon primary B cell infection in the host. Since STAT3 deletion in all CD19+ B cells of infected mice led to altered B and T cell responses, we generated chimeric mice with both normal and STAT3-deleted B cells. B cells lacking STAT3 failed to support virus latency compared to normal B cells from the same infected animal. Loss of STAT3 impaired B cell proliferation and differentiation and led to a striking upregulation of interferon-stimulated genes. These findings expand our understanding of STAT3-dependent processes key to its function as a pro-viral latency determinant for oncogenic gammaherpesviruses in B cells and may provide novel therapeutic targets.

microbiology↗