Skin basal cell carcinomas assemble a pro-tumorigenic spatially organized and self-propagating Trem2+ myeloid niche.
2023; 14 (1): 2685
Cancer immunotherapies have revolutionized treatment but have shown limited success as single-agent therapies highlighting the need to understand the origin, assembly, and dynamics of heterogeneous tumor immune niches. Here, we use single-cell and imaging-based spatial analysis to elucidate three microenvironmental neighborhoods surrounding the heterogeneous basal cell carcinoma tumor epithelia. Within the highly proliferative neighborhood, we find that TREM2+ skin cancer-associated macrophages (SCAMs) support the proliferation of a distinct tumor epithelial population through an immunosuppression-independent manner via oncostatin-M/JAK-STAT3 signaling. SCAMs represent a unique tumor-specific TREM2+ population defined by VCAM1 surface expression that is not found in normal homeostatic skin or during wound healing. Furthermore, SCAMs actively proliferate and self-propagate through multiple serial tumor passages, indicating long-term potential. The tumor rapidly drives SCAM differentiation, with intratumoral injections sufficient to instruct naive bone marrow-derived monocytes to polarize within days. This work provides mechanistic insights into direct tumor-immune niche dynamics independent of immunosuppression, providing the basis for potential combination tumor therapies.
View details for DOI 10.1038/s41467-023-37993-w
View details for PubMedID 37164949
A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs.
2022; 13 (1): 2690
The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using intratumoral heterogeneity in small-cell lung cancer as a tractable model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
View details for DOI 10.1038/s41467-022-30416-2
View details for PubMedID 35577801
c-FOS drives reversible basal to squamous cell carcinoma transition.
2021; 37 (1): 109774
While squamous transdifferentiation within subpopulations of adenocarcinomas represents an important drug resistance problem, its underlying mechanism remains poorly understood. Here, using surface markers of resistant basal cell carcinomas (BCCs) and patient single-cell and bulk transcriptomic data, we uncover the dynamic roadmap of basal to squamous cell carcinoma transition (BST). Experimentally induced BST identifies activator protein 1 (AP-1) family members in regulating tumor plasticity, and we show that c-FOS plays a central role in BST by regulating the accessibility of distinct AP-1 regulatory elements. Remarkably, despite prominent changes in cell morphology and BST marker expression, we show using inducible model systems that c-FOS-mediated BST demonstrates reversibility. Blocking EGFR pathway activation after c-FOS induction partially reverts BST in vitro and prevents BST features in both mouse models and human tumors. Thus, by identifying the molecular basis of BST, our work reveals a therapeutic opportunity targeting plasticity as a mechanism of tumor resistance.
View details for DOI 10.1016/j.celrep.2021.109774
View details for PubMedID 34610301
A Prediction Tool for the Presence of Ceftriaxone-Resistant Uropathogens upon Hospital Admission.
Antibiotics (Basel, Switzerland)
2020; 9 (6)
Antimicrobial resistance among uropathogens is a particularly pressing problem in the Asia-Pacific region. The objectives of this study were to determine the incidence and susceptibility of uropathogens upon hospital admission and to develop a risk-scoring model to predict the presence of ceftriaxone-resistance uropathogens (CrP). This was a retrospective observational cohort study of patients with a positive urine culture within 48 h of presentation at National University Hospital, Singapore between June 2015 and August 2015. Escherichia coli was the most common uropathogen isolated (51.7%), followed by Klebsiella pneumonia (15.1%) and Pseudomonas aeruginosa (8.2%). Overall, 372 out of 869 isolates (42.8%) were resistant to ceftriaxone. Hospitalization for ≥2 days within past 30 days, antibiotic use within the past 3 months and male gender were associated with the presence of CrP. A risk score based on these parameters successfully predicted CrP with an area under the curve of 0.68. The risk score will help clinicians to accurately predict antibiotic resistance at the individual patient level and allow physicians to safely prescribe empiric ceftriaxone in patients at low risk of CrP, thus reducing the antibiotic selection pressure that is driving carbapenem resistance in hospitals throughout Asia.
View details for DOI 10.3390/antibiotics9060316
View details for PubMedID 32531880