TP53 is the most frequently mutated gene across many cancers and is associated with shorter survival in non-small cell lung cancer (NSCLC). To understand how TP53-mutant (TP53mut) malignant cells interact with the tumor microenvironment (TME) at a molecular, cellular, and tissue level, we built a multi-omic cellular and spatial tumor atlas of 23 treatment-naive NSCLC human tumors. We identified significant differences in malignant expression programs and spatial cell-cell interactions between TP53mut and TP53WT tumors and found that highly-entropic TP53mut malignant cells lose alveolar identity and coincide with an increased abundance of exhausted T cells and immune checkpoint interactions with implications for response to checkpoint blockade. We also identified a multicellular, pro-metastatic, hypoxic tumor niche, where highly-plastic, TP53mut malignant cells expressing epithelial to mesenchymal transition (EMT) programs associate with SPP1+ myeloid cells and collagen-expressing cancer-associated fibroblasts. Our approach can be further applied to investigate mutation-specific TME changes in other solid tumors.
The treatment of rectal carcinoma is based on multidisciplinary strategy and multimodal approaches including gastrointestinal tract specialists, medical oncologists, radiation oncologists and surgery. The different objectives should be declined according to the characteristics of the tumours. The aim of the therapist would be to select the best strategy offering to the patient to be cured with as less as possible late adverse toxicity. The challenge of the treatment of small tumours is to maintain a functional anal sphincter while minimizing the risk of local recurrence. The standard treatment of locally advanced disease is aiming firstly to cure the patient and secondly to prevent late complications. Each of these clinical presentations of the disease has to be considered as a whole taking into account the new surgical techniques and a personalized approach adapted to the tumour. Nowadays they should be studied with dedicated clinical trials.
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