First Use of AXL Targeting in Metastatic, Refractory, Adenoid Cystic Carcinoma: A Case Report.

First use of AXL-targeting in adenoid cystic carcinoma (ACC); with positive results, ACC now included in AXL studies.

Mutant p53 protects triple-negative breast adenocarcinomas from ferroptosis in vivo.

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells from ferroptosis inducers, and ferroptosis inhibitors reverse the effects of mutant p53 loss in vivo. Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6, which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death.

Is Primary Poorly Differentiated Sarcomatoid Malignancy of the Parotid Gland Sarcomatoid Undifferentiated/Dedifferentiated Melanoma? Report of Three Unusual Cases Diagnosed by Fine-Needle Aspiration Combined with Histological, Immunohistochemical, and Molecular Analyses.

INTRODUCTION: Poorly differentiated primary sarcomatoid parotid malignancies are extremely rare. These tumors have not been consistently studied by morphology, immunohistochemistry, or molecular techniques. CASE PRESENTATION: We report three unusual cases of parotid gland poorly-differentiated sarcomatoid malignancy investigated by fine-needle aspiration and studied histologically, by immunohistochemistry and molecular investigations. Aspirates showed poorly specific polymorphous sarcomatoid malignancy in all cases. Histologically, all cases were polymorphous high-grade malignancies, and additionally, one case showed epithelial structures and was finally classified as salivary carcinosarcoma. Immunohistochemistry showed classical melanocytic markers negativity but positivity for PRAME, CD10, and WT1 in all three tumors and for CD56 in two tumors, which can potentially be supportive of melanocytic origin. Although not entirely specific, molecular characterization also suggested the melanocytic lineage of these tumors. CONCLUSION: Although rare, primary malignant melanoma of salivary gland was already described, but undifferentiated/dedifferentiated amelanotic forms are unknown in this localization up today. Further case reports of similar presentations are required to confirm the unequivocal primary origin of these obscure neoplasms in the parotid gland.

p53R172H and p53R245W Hotspot Mutations Drive Distinct Transcriptomes in Mouse Mammary Tumors Through a Convergent Transcriptional Mediator.

Aggressive breast cancers harbor TP53 missense mutations. Tumor cells with TP53 missense mutations exhibit enhanced growth and survival through transcriptional rewiring. To delineate how TP53 mutations in breast cancer contribute to tumorigenesis and progression in vivo, we created a somatic mouse model driven by mammary epithelial cell-specific expression of Trp53 mutations. Mice developed primary mammary tumors reflecting the human molecular subtypes of luminal A, luminal B, HER2-enriched, and triple-negative breast cancer with metastases. Transcriptomic analyses comparing MaPR172H/- or MaPR245W/- mammary tumors to MaP-/- tumors revealed (1) differences in cancer-associated pathways activated in both p53 mutants and (2) Nr5a2 as a novel transcriptional mediator of distinct pathways in p53 mutants. Meta-analyses of human breast tumors corroborated these results. In vitro assays demonstrate mutant p53 upregulates specific target genes that are enriched for Nr5a2 response elements in their promoters. Co-immunoprecipitation studies revealed p53R172H and p53R245W interact with Nr5a2. These findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer. SIGNIFICANCE: Our findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer. NR5A2 may be an important therapeutic target in hard-to-treat breast cancers such as endocrine-resistant tumors and metastatic triple-negative breast cancers harboring TP53 missense mutations.

Intratumoral microbiome of adenoid cystic carcinomas and comparison with other head and neck cancers.

Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the ACC exhibited diverse levels of species richness. We identified two main microbial subtypes within the ACC: oral-like and gut-like. Oral-like microbiomes, characterized by increased diversity and abundance of Neisseria, Leptotrichia, Actinomyces, Streptococcus, Rothia, and Veillonella (commonly found in healthy oral cavities), were associated with a less aggressive ACC-II molecular subtype and improved patient outcomes. Notably, we identified the same oral genera in oral cancer and head and neck squamous cell carcinomas. In both cancers, they were part of shared oral communities associated with a more diverse microbiome, less aggressive tumor phenotype, and better survival that reveal the genera as potential pancancer biomarkers for favorable microbiomes in ACC and other head and neck cancers. Conversely, gut-like intratumoral microbiomes, which feature low diversity and colonization by gut mucus layer-degrading species, such as Bacteroides, Akkermansia, Blautia, Bifidobacterium, and Enterococcus, were associated with poorer outcomes. Elevated levels of Bacteroides thetaiotaomicron were independently associated with significantly worse survival and positively correlated with tumor cell biosynthesis of glycan-based cell membrane components.