MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Ghukasyan, Razmik; Liang, Keke; Chau, Kevin; Li, Luyi; Chan, Charlotte; Abt, Evan R.; Le, Thuc; Park, Joon Y.; Wu, Nanping; Premji, Alykhan; Damoiseaux, Robert; Luu, Tony; Labora, Amanda; Rashid, Khalid; Link, Jason M.; Radu, Caius G.; Donahue, Timothy R.

doi:10.1158/1078-0432.ccr-22-3322

Cited by 3 publications

(1 citation statement)

References 54 publications

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“…It is, therefore, possible that even “normal” cells in BRCA1 and BRCA2 mutation carriers have elevated basal STING activity and chronic inflammatory phenotype. As STING agonists are currently being tested in preclinical models to improve immunotherapy ( 59 ), STING antagonists may need to be developed as chemoprevention agents for BRCA1/2 mutation carriers.…”

Section: Discussionmentioning

confidence: 99%

Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene

Bhat-Nakshatri,

Khatpe,

Chen

et al. 2024

Cancer Research Communications

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Single cell transcriptomics studies have begun to identify breast epithelial cell and stromal cell specific transcriptome differences between BRCA1/2 mutation carriers and non-carriers. We generated a single cell transcriptome atlas of breast tissues from BRCA1, BRCA2 mutation carriers and compared this single cell atlas of mutation carriers with our previously described single cell breast atlas of healthy non-carriers. We observed that BRCA1 but not BRCA2 mutations altered the ratio between basal (basal-myoepithelial, BM), luminal progenitor (luminal adaptive secretory precursor, LASP) and mature luminal (luminal hormone sensing, LHS) cells in breast tissues. A unique subcluster of cells within LASP cells is underrepresented in case of BRCA1 and BRCA2 mutation carriers compared to non-carriers. Both BRCA1 and BRCA2 mutations specifically altered transcriptomes in epithelial cells which are an integral part of NF-B, LARP1, and MYC signaling. Signaling pathway alterations in epithelial cells unique to BRCA1 mutations included STAT3, BRD4, SMARCA4, HIF2A/EPAS1, and Inhibin-A signaling. BRCA2 mutations were associated with upregulation of IL-6, PDK1, FOXO3, and TNFSF11 signaling. These signaling pathway alterations are sufficient to alter sensitivity of BRCA1/BRCA2-mutant breast epithelial cells to transformation as epithelial cells from BRCA1 mutation carriers overexpressing hTERT + PIK3CAH1047R generated adenocarcinomas, whereas similarly modified mutant BRCA2 cells generated basal carcinomas in NSG mice. Thus, our studies provide a high-resolution transcriptome atlas of breast epithelial cells of BRCA1 and BRCA2 mutation carriers and reveal their susceptibility to PIK3CA mutation-driven transformation.

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Section: Discussionmentioning

confidence: 99%

Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene

Bhat-Nakshatri,

Khatpe,

Chen

et al. 2024

Cancer Research Communications

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Suppressing Pancreatic Cancer Survival and Immune Escape via Nanoparticle-Modulated STING/STAT3 Axis Regulation

Li,

Liu,

et al. 2024

Bioconjugate Chem.

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Pancreatic ductal adenocarcinoma (PDAC) poses a challenge in oncology due to its high lethality and resistance to immunotherapy. Recently, emerging research on the stimulator of interferon gene (STING) pathway offers novel opportunities for immunotherapy. Although STING expression is retained in PDAC cells, the response of PDAC cells to STING agonists remains ineffective. Signal transducer and activator of transcription 3 (STAT3), a downstream pathway of STING, is notably overexpressed in pancreatic cancer and related to tumor survival and immune escape. We observed that inhibiting STAT3 signaling post-STING activation effectively suppressed tumor growth through signal transducer and activator of transcription 1 (STAT1)-mediated apoptosis but led to a potential risk of immune-related adverse events (irAEs). To address this issue, we designed a tumor-penetrating liposome for the codelivery of STING agonist and STAT3 inhibitor. These nanoparticles regulated the STING/STAT3 signaling axis and effectively inhibited the proliferation and survival of tumor. Simultaneously, we found a significant increase in the activation of NK cells and CD8 + T cells after treatment, leading to robust innate immunity and adaptive immune response. We highlight the potential of regulating the STING/STAT3 axis as a promising treatment for improving clinical outcomes in PDAC patients.

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Circulating Neoplastic-Immune Hybrid Cells Are Biomarkers of Occult Metastasis and Treatment Response in Pancreatic Cancer

Patel,

Parappilly,

Farley

et al. 2024

Cancers

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Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) presents significant diagnostic and prognostic challenges, as current biomarkers frequently fail to accurately stage disease, predict rapid metastatic recurrence (rPDAC), or assess response to neoadjuvant therapy (NAT). We investigated the potential for circulating neoplastic-immune hybrid cells (CHCs) as a non-invasive, multifunctional biomarker for PDAC. Methods: Peripheral blood specimens were obtained from patients diagnosed with PDAC. CHCs were detected by co-expression of pan-cytokeratin and CD45, normalized to 50,000 peripheral blood mononuclear cells. rPDAC was defined as metastatic recurrence within six months of margin-negative pancreatectomy. Cyclic immunofluorescence (CyCIF) analyses compared hybrid phenotypes in blood and tumors. Results: Blood samples were collected from 42 patients with PDAC prior to resection. Those with radiographically occult metastatic disease and rPDAC had higher preoperative CHC numbers compared to patients who did not (65.0 and 74.4, vs. 11.52 CHCs; p < 0.001). Patients with complete or near-complete pathologic responses to NAT had lower preoperative CHC numbers than partial and/or non-responders (1.7 vs. 13.1 CHCs; p = 0.008). When assessed longitudinally, those with partial pathologic response saw CHC levels become undetectable while on treatment but increase in the interval between NAT completion and resection. In contrast, patients with poor responses or development of metastatic disease experienced persistent CHC detection during therapy or rising levels prior to radiographic evidence of metastases. Further, in metastatic PDAC patients, treatment-induced phenotypic changes in hybrid cells mirrored those in paired metastatic tumor samples. Conclusions: CHC enumeration and phenotyping display promise as a real-time indicator of disease burden, recurrence risk, and treatment response in PDAC. CHCs have great potential as tumor-derived biomarkers to optimize therapeutic strategies and improve survival in patients with PDAC.

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MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Cited by 3 publications

References 54 publications

Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene

Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene

Suppressing Pancreatic Cancer Survival and Immune Escape via Nanoparticle-Modulated STING/STAT3 Axis Regulation

Circulating Neoplastic-Immune Hybrid Cells Are Biomarkers of Occult Metastasis and Treatment Response in Pancreatic Cancer

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